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Immune System

IMMUNE SYSTEM

The immune system provides the body with resistance to disease. Innate immunity is furnished by relatively nonspecific mechanisms, such as the rapid inflammation experienced shortly after injury or infection. In contrast to innate mechanisms that hinder the entrance and initial spread of disease, adaptive immunity is more selective in its activity, and upon repeated exposures to pathogens can often prevent disease. There are two kinds of adaptive immune responses. Humoral immune responses are effective against agents that act outside of cells, such as bacteria and toxins. During humoral immune responses, proteins called antibodies, which can bind to and destroy pathogens, are secreted into the blood and other body fluids. In contrast, cell-mediated immune responses are important in resisting diseases caused by pathogens that live within cells, such as viruses. During cell-mediated responses, immune cells that can destroy infected host cells become active. Furthermore, cell-mediated immunity may also destroy cells making aberrant forms or amounts of normal molecules, as in some cancers.

Numerous aspects of adaptive immunity differ substantially in aged individuals from what is seen in young adults. For example, aged individuals often have attenuated or otherwise impaired immune responses to various bacterial and viral pathogens. Indeed, this general trend forms the basis for recommended immunizations against infectious agents that younger individuals resist easily. Aged individuals often respond differently to vaccination, however, sometimes resulting in a lack of protective immunity. In addition, unto-ward immune phenomena, such as certain forms of autoimmunity, as well as cancers involving cells of the immune system, show increased incidence in aged individuals. A complete understanding of these age-associated changes in immune status and function remains elusive, requiring knowledge of the mechanisms underlying maintenance, activation, and control of the immune system.

Lymphocytes, clonal selection, and antigen recognition

Lymphocytes are central to all adaptive immune responses. They originate from stem cells in the bone marrow. Cells destined to become lymphocytes either mature in the bone marrow or exit the marrow and mature in the thymus (because they are sites of lymphocyte production, the bone marrow and thymus are termed the primary lymphoid organs ). Lymphocytes that mature in the bone marrow make antibodies and are called B lymphocytes (B cells); whereas lymphocytes that mature in the thymus are called T lymphocytes (T cells). The T lymphocytes are further subdivided into functional subsets: cytotoxic T lymphocytes (Tc cells) generate cell-mediated immune responses and can destroy other cells that have pieces of antigen on their surface; helper T lymphocytes (Th cells) regulate the immune system, governing the quality and strength of all immune responses. Tc and Th cells are often termed CD8+ and CD4+ T cells, based on so-called "cluster designation" (CD) molecules found on their surface.

The notion that specificity in adaptive immune responses derives from a clonal distribution of antigen receptors, coupled with requisite receptor ligation for activation, is the central argument of the generally accepted clonal selection hypothesis. Simply put, while billions of different antigen receptors can be made (in terms of antigen-binding specificity), each lymphocyte makes only one kind. Engagement of this receptor is requisite for lymphocyte activation, so a given antigen activates only those lymphocytes whose receptors bind well, yielding appropriate specificity in the overall response.

Antigen recognition by lymphocytes. The B lymphocyte's antigen receptor is a membrane-bound version of the antibody it will secrete if activated. When activated, a B lymphocyte's secreted antibodies enter the blood and other body fluids, where the bind the antigen and help destroy it. In contrast, a T lymphocyte's antigen receptor (TcR) is not secreted, but instead binds antigen displayed on the surface of other cells. Further, while B lymphocytes can bind native antigens directly, T lymphocytes can only bind an antigen when it is degraded and presented. Antigen presentation occurs when degradation products of protein antigens become attached to molecules encoded by a group of genes called the Major Histocompatibility Complex (MHC) and displayed on cell surfaces. All vertebrates have a homologue of this gene complex; for example, the human MHC is named HLA. When proteins either are made within a cell or are ingested by phagocytosis, they may be degraded by a variety of systems. The resulting small peptides become associated with binding clefts in MHC molecules. This peptide-MHC molecule combination is then displayed on the cell's surface for recognition by T lymphocytes. Different categories of MHC molecules exist, encoded by different genes within the MHC. Class I MHC molecules tend to become associated with the degradation products of proteins that were synthesized inside the cell. Further, class I molecules generally present antigen to cytotoxic T cells, so if a cell makes class I MHC molecules, it can present antigen to cytotoxic T cells. Most kinds of cells in the body express MHC class I molecules, so nearly any cell that is synthesizing nonself proteins (such as those from a viral infection) can be destroyed by cytotoxic T cells. In contrast, class II MHC molecules present antigen to helper T cells, so a cell that makes class II MHC molecules can present antigen to helper T cells. Only a few kinds of cells, including dendritic cells, macrophages, and B lymphocytes, normally express class II MHC molecules and present antigen to Th cells.

Lymphocyte development, production, and receptor diversity. Since antigen receptor specificities are clonally distributed, the selectivity of immune responses relies on the constant availability of a large and diverse pre-immune lymphocyte pool. Towards this end, millions of lymphocytes are produced daily in the marrow and thymus. As lymphocytes develop and mature, they begin to express their surface-bound antigen receptor. The receptor's expression and specificity are established through a series of DNA rearrangement and splicing events that yield functional antigen receptor genes. Because the portion of the receptor molecule that will interact with antigen derives from such pseudorandom gene-splicing mechanisms, the number of permutations available to afford diversity among clonally distributed antigen-combining sites is enormousin the range of 1012.

Age-associated changes in lymphocyte development and selection. Lymphocyte production and selection changes with age. For example, the rate at which lymphocytes are generated in the thymus and bone marrow, which will dictate the turnover of mature lymphocytes in the periphery, has been shown to decrease with age. These shifts appear to reflect a combination of factors, which may include a lower frequency of successful antigen-receptor-gene expression, reflecting intrinsic changes in B cell progenitors. Further, failure or diminution of stromal trophic elements necessary for the survival of developing lymphocytes may occur with increasing age. Finally, shifts in the representation of various differentiation subsets, likely reflecting changes in the homeostatic processes that govern steady state numbers, shift with age.The mechanistic bases for these changes remain unclear, and are the subject of intense investigation.

In addition to changes in lymphocyte production, the degree of receptor diversity within both mature and developing lymphoid compartments may become truncated with age. This may alter the frequency or breadth of available primary clones that can engage in immune responses, affecting the outcome of immunization or vaccination. Similar to the factors contributing to reduced production rates, the basis for truncated antigen receptor diversity appears manifold. For example, it likely involves downstream effects precipitated by altered lymphocyte production and selection; but probably also originates from the life-long accumulation of expanded memory clones, which are the result of antigen-driven expansion, and perforce less diverse.

Secondary lymphoid organs and immune responses

Lymphoid organs, vessels, and recirculation. Mature lymphocytes constantly travel through the blood to the lymphoid organs and then back to the blood. This constant recirculation insures that the body is continuously monitored for invading substances. The major areas of antigen contact and lymphocyte activation are the secondary lymphoid organs. These include the lymph nodes, spleen, and tonsils, as well as specialized areas of the intestine and lungs. Appropriate recirculation and compartmentalization is essential to vigorous immune function, since this provides appropriate surveillance of the host for antigens, as well as the appropriate juxtaposition of all cellular elements to insure fruitful interaction.

Cell interactions in immune responses. Although antigen binding is necessary to activate a B or T cell, that alone is insufficient to induce an immune response. Instead, both humoral and cell-mediated responses require interactions between three cell types: antigen-presenting cells (APCs), Th cells, and either a B cell or Tc cell. Generally, the interaction between the APC and Th cells involves not only the binding of the TcR by the antigenic peptides in association with the MHC, but a series of second signals. These requisite second signals are afforded by the interactions of both membrane-bound ligand receptor pairs, known collectively as costimulators, as well as a variety of soluble growth and differentiation factors secreted by the antigen-presenting cells.

Humoral immune responses involve several events following the entry of antigen. First, antigen-presenting cells take up some of the antigen, attach pieces of it to Class II MHC molecules, and present it to T-helper cells. Binding the presented antigen activates T-helper cells, which then divide and secrete stimulatory molecules called interleukins. These stimulatory molecules in turn activate any B lymphocytes that have bound the antigen, and these activated B cells then divide, differentiate, and secrete antibody. Finally, the secreted antibodies bind the antigen and help destroy it through a variety of so-called effector mechanisms, including neutralization, complement fixation, and opsonization.

Cell-mediated immune responses involve several events following the entry of antigen. Helper T cells are required, so some of the antigen must be taken up by APCs and presented to T-helper cells. Binding the presented antigen activates the T-helper cells to divide and secrete interleukins. These in turn activate any cytotoxic T cells that have bound pieces of the antigen presented by class I MHC molecules on infected cells. The activated cytotoxic cells can then serially kill cells displaying antigen presented by class I MHC molecules, effectively eliminating any cells infected with the antigen.

Age-associated changes in recirculation, interaction, and immune responses. The patterns of compartmentalization and recirculation may vary with age, and again likely reflect a combination of factors. These probably include relative increases in memory-cell populations, whose recirculation and compartmentalization properties differ from primary lymphocytes, as well as alterations in the efficacy and structure of the lymphatics caused by either intrinsic or extrinsic factors. Of course, these shifts may alter the handling and recognition of antigens by APCs and lymphocytes, consequently impacting heavily on all negative and positive selective processes. It is also clear that the strength and duration of immune responses can change with age. Most reports of such changes are largely descriptive and subject to great variability.

Immune tolerance and autoimmunity

The immune system generates significant numbers of lymphocytes whose antigen receptors bind "self" molecules strongly enough to engender immune activity against self components. Indeed, the random processes responsible for antigen receptor diversity, coupled with genetic polymorphism in most structural genes, makes generation of such "autoreactive" receptors unavoidable. The random processes responsible for antigen-receptor diversity, coupled with genetic polymorphism in most structural genes, makes generation of such autoreactive receptors unavoidable. The avoidance of pathogenic autoreactivity, despite this likelihood of developing receptors capable of binding to self molecules, is collectively termed immunologic tolerance.

How cells bearing potentially autoreactive receptors are controlled remains an area of intense investigation, but several mechanisms clearly play important roles. Many autoreactive clones are eliminated before they mature in the marrow and thymus, because when immature B or T cells have their antigen receptor occupied they undergo deletion via apoptotic cell death. In contrast, mature lymphocytes resist death induced via receptor ligation. Regardless of the exact mechanisms involved, these so-called central deletion mechanism provide a means to screen and eliminate incipient autoreactive cells before they completely mature. However, these central tolerance mechanisms, while clearly an important element of immunologic tolerance, are insufficient to fully explain the lack of auto-reactivity. For example, some self molecules are expressed only in tissues found outside of the thymus or bone marrow, precluding exposure of developing lymphocytes. Thus, a variety of peripheral tolerance mechanisms are believed to be important in successful avoidance of self reactivity. These include the functional inactivation of lymphocytes through anergy, the blockage or prevention of appropriate second signals, discussed above, and the sequestration of certain self components in areas where lymphocytes do not recirculate, such as the chamber of the eye.

If the immune system fails to appropriately eliminate or control self-reactive cells, they may cause life-threatening autoimmune disease. These diseases may involve cell-mediated responses, humoral responses, or both. Examples of autoimmunity include: type I diabetes, where individuals make an immune response against their insulin-producing cells, destroying them and resulting in abnormal sugar metabolism; myasthenia gravis, where one makes antibodies against normal molecules that control neuromuscular activity, resulting in weakness and paralysis; and systemic lupus erythematosus, where antibodies to many normal body constituents are made, resulting in widespread symptoms. Some autoimmune diseases lead to the deposition of antibody-antigen aggregates called immune complexes in the kidney, lungs, or joints. Because these complexes will trigger complement and other inflammatory processes, they can result in severe damage to the affected areas.

Age-associated changes involving immune tolerance. Age-associated changes in the susceptibility to autoimmune phenomena are well-established. Indeed, epidemiological evidence shows that the incidence of various autoimmune diseases peaks at certain ages. Thus, while many other risk factors are also involved, elucidating the links between various autoimmune syndromes and age forms an important immunologic problem. Because the mechanisms that mediate immune tolerance per se are poorly understood, it is even more difficult to establish how age-associated factors can influence susceptibility. Clearly, shifts in the production, selection, and homeostatic processes that govern lymphocyte activity may play a role, but causal relationships await further research.

Michael P. Cancro

See also Immunology, Human; Immunology: Animal Models.

BIBLIOGRAPHY

Hodes, R. J. "Aging and the Immune System." Immunology Review 160 (1997): 58.

Janeway, C. A., Jr.; Travers, P.; Walport, M.; and Shlomchik. Immunobiology, 5th ed. New York: Garland Publishing, 2001.

Kline, G. H.; Hayden, T. A.; and Klinman, N. R. "B Cell Maintenance in Aged Mice Reflects Both Increased B Cell Longevity and Decreased B Cell Generation." Journal of Immunology 162, no. 6 (1999): 33423349.

Klinman, N. R. and Kline, G. H. "The B-Cell Biology of Aging." Immunology Review 160 (1997): 103114.

Lerner, A.; Yamada, T.; and Miller, R. A. "Pgplhi T Lymphocytes Accumulate with Age in Mice and Respond Poorly to Concanavalin A." European Journal of Immunology 19, no. 6 (1989): 977982.

Linton, P., and Thoman, M. L. "T Cell Senescence." Front Biosci. 6 (2001): D248D261.

Miller, R. A. "Effect of Aging on T Lymphocyte Activation." Vaccine 18, no. 16 (2000): 16541660.

Mountz, J. D.; Van Zant, G. E.; Zhang, H. G.; Grizzle, W. E.; Ahmed, R.; Williams, R. W.; and Hsu H. C. "Genetic Dissection of Age-Related Changes of Immune Function in Mice." Scand J Immunol. 54, no. 12 (2001): 1020.

Paul, W. Fundamentals of Immunology, 4th ed. New York: Lippincott-Raven, 1999.

Stephan, R. P.; Sanders, V. M.; and Witte, P. L. "Stage-Specific Alterations in Murine B Lymphopoiesis with Age." Int Immunol. 4 (1996): 509518.

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Immune System Regulation and Nutrients

IMMUNE SYSTEM REGULATION AND NUTRIENTS

IMMUNE SYSTEM REGULATION AND NUTRIENTS. Chicken soup, herbal tea, and vitamin C pills take on special meaning in cold and flu season. But beyond their possible role in treatment and comfort, nutrients are essential and fundamental parts of immune system function. To understand nutrient-immune interactions, it is helpful to understand how the body's immune system functions in general.

The human immune system has evolved to the state where it cannot only maintain continual vigilance against new challenges, but can "learn" from past challenges and "remember" more efficient means of resolving those challenges if they are ever encountered again. The numerous cooperative mechanisms by which the immune system addresses (but does not "remember") novel challenges are collectively termed "innate immunity." These mechanisms include proteins that can bind to or neutralize a wide variety of foreign particles, and cells that can phagocitize foreign particles to remove them from the body. In the process of neutralizing and removing foreign particles, other cells within the immune system (mainly dendritic cells) transport samples of the foreign particles (antigens) to specialized tissues and organs (spleen, lymph nodes, Peyer's patches) where naive cells (T cells and B cells) not previously exposed to foreign particles can adapt their surface molecules (through gene recombination) in order to increase the efficiency with which later encounters with the foreign particle can be resolved. These adapted cells and associated specialized proteins (immunoglobulinsproteins that function as antibodies) provide immunological memory of past encounters and form what is termed "acquired immunity."

The body's ability to resolve infections can be likened to the running of a race. The infectious agent must elude detection by the immune system until it can proliferate and establish itself within the body. The earlier the body can detect this infection (by maintaining a critical concentration of innate immune system cells and proteins throughout the body) and the faster the body can produce new protective cells and proteins, the better the chance of winning the race. The key steps in this processefficient communication and rapid biosynthesisare constrained by the availability of raw material, and in the body, raw material means nutrients. In this light, well-established nutritional principles can also be regarded as immunological paradigms.

Biosynthesis: Building New Cells and Proteins

The immune system is continually producing a remarkable number of new cells and proteins to provide a broad repertoire of potential immune responses and maintain functional concentrations in the periphery. An average adult has nearly six pounds of bone marrow, which produces about one trillion white blood cells per day, accounting for 8 percent or more of the total protein synthesis in the body. About 60 percent of bone-marrow biosynthesis is devoted to producing neutrophils (innate immune system phagocytes), amounting to about 100 billion cells a day, which then survive only one to two days in circulation. Studies in laboratory rats indicate that in the acquired immune system, cell turnover is ten times higher in the thymus than in the liver. Of the millions of naive T cells and B cells produced in the thymus and bone marrow every day, only about 3 to 5 percent of T cells and 10 to 20 percent of B cells pass positive and negative selection steps to reach the periphery and enter the "race" that was described.

As for proteins, more than two-thirds of the IgA (an acquired immune system protein useful in protecting mucosal surfaceseyes, mouth, etc.) produced by the body every day (more than three grams per day for a 155-pound person) is secreted onto the body's mucosal surfaces for short-term disposal. Immunoglobulins also account for a significant fraction of total blood protein (second only to albumin) and must be replenished continually at a rate of about six grams of immunoglobulins per day for a 155-pound person. Clearly, maintaining the immune system is a demanding process for the human body.

On the cellular level, upon activation, a lymphocyte doubles the amount of intracellular energy (ATPthat is, adenosine triphosphate) committed to protein synthesis (up to 20 percent of total cell energy use), while nucleotide synthesis begins consuming about 10 percent of the cell's energy. This ATP is ultimately derived from dietary macronutrients (protein, carbohydrate, or fat) through metabolic steps that require thiamin, riboflavin, biotin, pantothenic acid, and niacin. When ATP supply is limited, protein and nucleotide syntheses are the first cellular processes to suffer. The building of proteins and nucleotides from amino acids also requires folate, vitamin B6, and vitamin B12 as the essential cofactors. Enzymes that build immunologically active proteins and cells also rely on diet-derived transitional metal atoms (iron, zinc, copper, etc.) for stability and to serve as functional centers. For example, ribonucleotide reductase is a rate-limiting enzyme in nucleotide synthesis, but the only way to maintain the loosely bound iron atom in its functional center is with adequate dietary iron intake. When deprived of multiple nutrients during malnutrition, these immunological processes are clearly compromised as exemplified by reduced thymus mass, lower IgA secretion, and poor proliferation of immune cells in vitro.

Signaling and Gene Regulation

The ability to expand or direct an immune response depends on communication between and within cells. In the innate immune system, various cells can produce signaling molecules (eicosanoids, chemokines, etc.) that attract phagocytes to the site of a challenge (inflammation) while alerting the rest of the immune system. In the acquired immune system, the adaptation of immune cells can be directed toward more efficacious products by signals between cells (cytokines, receptor interaction, etc.) and inside of cells (intracellular signaling molecules, nuclear binding factors, etc.).

Perhaps the clearest relationship between essential nutrients and immune system signaling is the transformation of dietary essential fatty acids into eicosanoids. Certain kinds of fat, which synthesize polyunsaturated fatty acids, are essential to life. These fatty acids are classified as omega-3 or omega-6 fatty acids based on their chemical structure. These fatty acids are used by the body to manufacture eicosanoids (prostaglandins, thromboxanes, and leukotrienes) that regulate inflammation and other body functions. At a molecular level, the distinction between dietary intake of omega-3 versus omega-6 fats is functionally important since eicosanoids derived from omega-3 fats do not produce as much inflammation as omega-6 fats.

An area of immunological research that has rapidly expanded in recent years is the discovery and characterization of proteins that carry signals between the cell surface and nucleus as well as where these proteins bind within various genes. Both vitamin A and vitamin D regulate gene expression by binding to specific gene sequences including, for example, the genes that regulate production of the antiviral protein interferon-gamma. A deficiency of either of these vitamins can impair immune function. Pharmacological doses of vitamin D have been investigated for their therapeutic potential in autoimmune disorders.

Immune system cells also initiate intracellular signals in response to oxidation. Oxidative stress induces expression of intracellular proteins (AP-1 and NF-kB), which leads to increased production of pro-inflammatory signaling molecules (such as cytokines and chemokines) and their receptors. Vitamin E, vitamin C, and other antioxidants can reduce NF-kB expression, which may contribute to their wide variety of effects on the immune system. Intracellular oxidation state also may alter acquired immune responses, but further research is needed to determine if dietary antioxidants can modify oxidation-sensitive genes and proteins.

Life-Cycle Stages

Different stages of the life cycle have unique nutritional demands and are characterized by unique immunological functionality. Both young children and the elderly have clear age-related immune function deficiencies. In addition, many children in the United States do not meet their daily requirements for several immunologically relevant nutrients, including vitamin E, iron, zinc, and vitamin B6. The elderly may also have difficulty meeting their requirements for vitamin B12, zinc, vitamin E, iron, vitamin D, and vitamin B6 as a result of physiological changes due to aging or to inadequate dietary intakes. Pregnant and lactating women are remarkable because they produce acquired immune system products for the sole apparent purpose of export to the infant. Likewise, pregnant and lactating women frequently do not meet their nutritional demands for folate, vitamin B6, iron, and zinc. Few studies have examined the interaction between nutrients and life-cycledependent immune outcomes in otherwise healthy people, but the available data indicate that these interactions have immunological impactfor example, vitamin E among the elderly and iron among postpartum women. Given the susceptibility of these populations to infectious disease, a better understanding of nutrient-immune life-cycle interactions is needed to promote optimal immune status through adequate nutrition.

Nonnutritive Food Components and the Immune Response

For immunologists, developing more efficacious vaccines and certain anticancer agents is a process of improving immune system performance. As nutritional paradigms have shifted from preventing deficiency to promoting optimal health, nutrition scientists have also sought to improve immune system performance. Many in vivo studies have examined more or less purified food components like phytochemicals (polyphenols), herbs, and carotenoids. Such studies frequently use classic immunological testscell proliferation, blood lymphocyte counts, skin hypersensitivity responses, etc.but the results of these tests should be interpreted with caution. For example, a food component that increases cell proliferation may be beneficial if it is the protective cells that proliferate more readily. Conversely, increased cell proliferation would be harmful if autoreactive T-cell or B-cell clones were expanded or inflammatory responses were boosted inappropriately. Although these measures are useful for preliminary identification of nutrient-immune interactions, additional studies using efficacy-related immune measures (infectious disease risk, vaccine titers, etc.) are needed before such phenomena can be termed beneficial.

Summary

To maintain immunological competence, the immune system must quickly alert the body to foreign challenges and rapidly manufacture the cells and proteins needed to stop exponentially dividing infectious organisms. It is apparent that some essential nutrients are signaling molecules. Others can be rate-limiting factors in cell division and protein synthesis. The brevity of this review has prohibited the exploration of many other important nutritional immunology topics: nutrient interactions with infectious agents, treatment of autoimmune disorders, cancer biology, and metabolic functions of nutrients unrelated to biosynthesis or signal transduction. Clearly, the most venerable nutritional paradigms of growth and development are important for shaping the magnitude and character of immune responses.

See also Fats ; Gene Expression, Nutrient Regulation of ; Iron ; Nutrients ; Vitamins: Overview ; Vitamins: Water-Soluble and Fat-Soluble Vitamins .

BIBLIOGRAPHY

Buttgereit, F., G.-R. Burmester, and M. D. Brand. "Bioenergetics of Immune Functions: Fundamental and Therapeutic Aspects." Immunology Today 21 (2000): 192199.

Delves P. J., and I. M. Roitt. "The Immune System: First of Two Parts. " New England Journal of Medicine 343 (2000): 3749.

Delves P. J., and I. M. Roitt. "The Immune System: Second of Two Parts." New England Journal of Medicine 343 (2000): 108117.

Inserra, P. F, S. K. Ardestani, and R. R. Watson. "Antioxidants and Immune Function." In Antioxidants and Disease Prevention, edited by H. S. Garewal, pp. 1929. New York: CRC Press, 1997.

James, M. J., R. A. Gibson, and L. G. Cleland. "Dietary Polyunsaturated Fatty Acids and Inflammatory Mediator Production." American Journal of Clinical Nutrition 71 (2000): 343S348S.

Prentice, A. M. "The Thymus: A Barometer of Malnutrition." British Journal of Nutrition 81 (1999): 345347.

Ross, A. C, and U. G. Hammerling. "Retinoids and the Immune System." In The Retinoids: Biology, Chemistry and Medicine, edited by M. B. Sporn, A. B. Roberts, and D. S. Goodman, 2nd ed., pp. 521543. New York: Raven Press, 1994.

J. Paul Zimmer

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Immune System Development

Immune system development

Definition

The child's immune system is an intricate network of interdependent cell types, substances, and organs that collectively protect the body from bacterial, parasitic, fungal, viral infections, and tumor cells.

Description

The immune system was not recognized as a functional unit of the body until the late twentieth century, probably because its parts are not directly connected to each other and are spread in different parts of the body.

Organs of the immune system

The immune system contains the following organs and cells: tonsils and adenoids; the thymus gland; lymph nodes; bone marrow; and white blood cells that leave blood vessels and migrate through tissues and lymphatic circulation. The spleen, appendix, and patches of lymphoid tissue in the intestinal tract are also parts of the immune system.

The essential job of this system is to distinguish self-cells from foreign substances and to recognize and take protective action against any materials that ought not to be in the body, including abnormal and damaged cells. The immune system can seek out and destroy disease germs, infected cells, and tumor cells. The immune system includes the following cells:

  • T lymphocytes (T cells)
  • B lymphocytes (B cells)
  • natural killer cells (NK cells)
  • dendritic cells
  • phagocytic cells
  • complement proteins

These cells develop from "pluripotential hematopoietic stem cells" starting from a gestational age of about five weeks. They circulate through various organs in the lymphatic system as the fetus develops. T and B lymphocytes are the only units of the immune system that have antigen-specific recognition powers; they are responsible for adaptive immunity. In other words, the T and B cells are important in the immunity that vaccination promotes.

How immunity works

The lymphatic system is a key participant in the body's immune actions. It is a network of vessels and nodes unified by the circulatory system. Lymph nodes occur along the course of the lymphatic vessels and filter lymph fluid before it returns to the bloodstream. The system removes tissue fluids from intercellular spaces and protects the body from bacterial invasions.

Types of immunity

Immunity is the ability of the body to resist the infecting agent. When an infectious agent enters the body, the immune system develops antibodies which can weaken or destroy the disease-producing agent or neutralize its toxins. If the body is re-introduced to the same agent at a later time, it is capable of developing antibodies at a much faster pace. As a result, the individual would likely not become sick, and immunity has developed.

Natural immunity is present when a person is immune to a disease despite not having either the disease itself nor any vaccination against it. Acquired immunity may be either active or passive. Active immunity comes from having the disease or by inoculation with antigens, such as dead organisms, weakened organisms, or toxins of organisms. The antigens introduced during vaccination produce antibodies that protect the body against the infecting agent, despite the fact that the person does not become sick. Passive immunity is relatively short lived and is acquired by transferring antibodies from mother to child in the uterus or by inoculation with serum that contains antibodies from immune persons or animals. Passive immunization is used to help a person who has been exposed or is already infected to fight off disease. Although various types of serums may be used to produce passive immunization, gamma globulin is the most frequently used source of human antibodies.

Development of the immune response

Normal infants have the capability to develop responses to antigens at birth. Infants also start life with some immunoglobulin antibodies acquired from the mother. These antibodies cross the placental barrier, but not all types are transmitted equally. In particular, infants start with antibodies to viruses and gram-positive organisms, but not to gram-negative organisms. Gram is the name of a stain that distinguishes broad classes of bacteria. Gram-negative organisms are responsible for many diseases, including gonorrhea, pertussis (whooping cough), salmonella poisoning, and cholera. Escherichia coli (E. coli) is another common gram-negative organism.

Immunoglobulin antibodies are divided into five classes. The capacity of the body to produce each immunoglobulin varies with age. Newborn babies (premature and full-term) begin to synthesize antibodies at an increased rate soon after birth in response to antigenic stimulation of their new environment. At about six days after birth the serum concentration of specific antibodies rises sharply, and this rise continues until adult levels are achieved by approximately the end of the first year. Maternal immunity gradually disappears during the first six to eight months of life. A concentrated level of antibodies is reached and maintained by seven to eight years of age.

Common problems

Persistent infections

One of the greatest strains on the immune system is an infection it cannot remove. Parents should pay attention to unexplained fevers; night sweats; or tender, swollen lymph nodes. These symptoms can signify a hidden infection or cancer . Infections of the mouth and gums as well as sexually transferred infections often go unnoticed while they drain the vitality of the immune system.

Indiscriminate use of antibiotics

When the immune system successfully controls an infection on its own, it becomes stronger and better able to handle future threats. Antibiotics are powerful medicines that should be given only when the immune system cannot contain a bacterial infection. Overuse of antibiotics may cause the body to breed new strains of antibiotic-resistant or more dangerous bacteria. In the long run, overuse of antibiotics weakens the immune system.

Misuse of immunosuppressive drugs

Immunosuppressive drugs used in cancer chemotherapy or to suppress rejection of organ transplants are necessary. Of greater concern is the widespread use of corticosteroids or steroid derivatives used to treat allergies , autoimmune diseases, and inflammatory conditions. Though sometimes necessary, these drugs cripple the immune response and are often misunderstood, abused, and over-prescribed.

Radiation and hazardous chemicals

Exposure to radiation and hazardous chemicals may also damage the immune system. Excessive radiation of diagnostic x rays of the neck and chest may damage the thymus gland behind the breastbone. The thymus gland is an integral part of the immune system.

Blood transfusions and injections of blood products

Blood transfusions and injections of blood products may broadcast viral diseases like hepatitis that stress the immune system by flooding it with foreign proteins. In an emergency it may not be possible to do without blood transfusions. Sources of blood and blood products are regulated and screened for infectious substances and were as of 2004 much safer.

Other factors

Certain factors have damaging effects on the immune system of infants. Excessive consumption of alcohol during pregnancy leads to depressive levels of vitamin B and zinc, which are essential to immune competence. Alcoholism can also reduce the uptake of several other important nutrients needed for neonatal immune systems. Prolonged stress during pregnant and in breastfeeding mothers reduces the effectiveness of the immune system as well as the quality of immunologic factors in breast milk.

Cigarette smoking raises the white blood cells count, activating the immune system; however, smoking causes low-grade chronic bronchitis , low birth weight infants, and weakened natural immunity in newborns. Infants and children constantly exposed to cigarette smoke have weakened immune systems.

Toxic pointsareas of localized infections such as dental abscesses or infected tonsilsmay disturb the normal neutralization and weaken the cellular defenses in pregnant mothers and in children.

Deficiencies of many nutrients, especially certain vitamins and minerals , may weaken the immune system. Excessive exercise may depress the immune system temporarily.

Autoimmunity

Autoimmunity occurs when the immune system mistakenly attacks the body's own tissues, resulting in disease that can be mild or severe. Common autoimmune disorders are rheumatoid arthritis, glomerulonephritis, rheumatic fever , and systemic lupus erythematosus (SLE). Autoimmune reactions may be set off by infection, tissue injury, or emotional trauma in people with a genetic tendency to them.

Parental concerns

Parents may be concerned that children with acute illnesses have compromised immune systems and are less likely to have a positive response to vaccines or may be more likely to develop adverse reaction to the vaccine than healthy children. Parents may also believe that children who are ill should not further burden an immune system already committed to fighting an infection.

Most pediatricians would agree that there should be a delay in vaccinations for children with severe illnesses until the symptoms of illness are gone. The reason for deferring immunization is to avoid superimposing a reaction to the vaccine on the underlying illness or attributing symptoms of the underlying illness to the vaccine by mistake. However, a low-grade fever or cold is not a contraindication for routine vaccinations.

Parents may also be concerned that the many different vaccines that infants are given may overwhelm a child's immune system. However, infants have the capacity to respond to large numbers of antigens. Parents who worry about the increasing number of recommended vaccines may take comfort in knowing that children are exposed to fewer antigens in vaccines as of the early 2000s than in previous decades. Two reasons account for this decline: the worldwide elimination of smallpox and advances in protein chemistry in vaccines with fewer antigens.

Vaccines may cause temporary suppression of delayed-type hypersensitivity skin reactions or alter certain lymphocyte function tests. However, the short-lived immunosuppression caused by certain vaccines does not result in an increased risk of infections from other pathogens soon after vaccination.

KEY TERMS

Antibody A special protein made by the body's immune system as a defense against foreign material (bacteria, viruses, etc.) that enters the body. It is uniquely designed to attack and neutralize the specific antigen that triggered the immune response.

Antigen A substance (usually a protein) identified as foreign by the body's immune system, triggering the release of antibodies as part of the body's immune response.

Corticosteroids A group of hormones produced naturally by the adrenal gland or manufactured synthetically. They are often used to treat inflammation. Examples include cortisone and prednisone.

Immune system The system of specialized organs, lymph nodes, and blood cells throughout the body that work together to defend the body against foreign invaders (bacteria, viruses, fungi, etc.).

Immunization A process or procedure that protects the body against an infectious disease by stimulating the production of antibodies. A vaccination is a type of immunization.

Lymphocyte A type of white blood cell that participates in the immune response. The two main groups are the B cells that have antibody molecules on their surface and T cells that destroy antigens.

Phagocytosis A process by which certain cells envelope and digest debris and microorganisms to remove them from the blood.

Resources

BOOKS

Burney, Lucy. Boost Your Child's Immune System: A Program and Recipes for Raising Strong, Healthy Kids. New York: Newmarket Press, 2005.

Janeway, Charles. Immunobiology: The Immune System in Health and Disease. New York: Garland Publishing, 2004.

Parham, P. The Immune System. New York: Garland Publishing, 2004.

PERIODICALS

Offit, Paul A. "Addressing Parents' Concerns: Do Multiple Vaccines Overwhelm or Weaken the Infant's Immune System?" Pediatrics 109 (January 2002): 124.

Aliene Linwood, RN, DPA

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Immune System

Immune system

The immune system in a vertebrate (an organism with a backbone) consists of all the cells and tissues that recognize and defend the body against foreign chemicals and organisms. For example, suppose that you receive a cut in your skin. Microorganisms living on your skin are then able to enter your body. They pass into the bloodstream and pass throughout your body. Some of these microorganisms are pathogenic, that is, they may cause illness and even death. As soon as those microorganisms enter your body, its immune system begins to identify them as foreign to your body and to produce defenses that will protect your body against any diseases they may cause.

The study of the immune system is known as immunology and scientists engaged in this field of research are immunologists. Our understanding of the way in which the immune system functions in animals has made possible the prevention of various diseases by means of immunizations. The term immunization refers to the protection of an individual animal against a disease by the introduction of killed or weakened disease-causing organisms into its bloodstream.

Words to Know

Antibody response: The specific immune response that utilizes B cells to kill certain kinds of antigens.

Antigen: Anything that causes an immune response in an animal.

B cell (or B lymphocyte): A lymphocyte that participates in the antibody response.

Helper T cell: A kind of T cell with many functions in the immune system, including the stimulation of the development of B cells.

Histamine: A chemical that causes blood vessels to dilate (become wider), thus increasing blood flow to an area.

Inflammatory response: A nonspecific immune response that causes the release of histamine into an area of injury; also prompts blood flow and immune cell activity at injured sites.

Lymphocyte: White blood cell.

Memory cell: The T and B cells that remain behind after a primary immune response and that respond swiftly to subsequent invasions by the same microorganism.

Nonspecific defenses: Immune responses that generally target all foreign cells.

Phagocytosis: The process by which one cell engulfs another cell.

Plasma cell: A B cell that secretes antibodies.

Proteins: Large molecules that are essential to the structure and functioning of all living cells.

Specific defenses: Immune responses that target specific antigens.

Vaccination: Introducing antigens into the body in order to make memory cells, thereby reducing the likelihood of contracting future diseases caused by those antigens.

Levels of defense

The immune system consists of three levels of response: external barriers; nonspecific responses; and specific responses. Included among the external barriers are the skin and mucous membranes. An animal's skin acts something like a protective wrapping that keeps diseasecausing organisms out of the body. Normally, the skin is covered with

Interferons

One of the most exciting new disease-fighting agents is a class of compounds known as interferons. Interferons were first discovered in 1957 by Alick Isaacs and Jean Lindenmann. Isaacs and Lindenmann found that chick embryos injected with the influenza virus released very small amounts of a protein that destroyed the virus. The protein also prevented the growth of any other viruses in the embryos. Isaacs and Lindenmann suggested the name interferon for the protein because of its ability to interfere with viral growth.

Further research showed that interferon was produced within hours of a viral invasion and that most living things (including plants) make the protective protein. Scientists realized that interferons were the first line of defense against viral infection in a cell. They realized that interferons might be effective in treating a number of viral diseases in humans, such as some forms of cancer, genital warts, and multiple sclerosis.

Interferons are classified into two general categories, Type I and Type II. Type I interferons are made by every cell in the body, while Type II interferons are made only by T cells and natural killer (NK) cells. Interferons are also classified according to their molecular structure as alpha, beta, gamma, omega, and tau interferons.

In 1986, interferon-alpha became the first interferon to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of disease, in this case, for hairy-cell leukemia. In 1988, this class of interferons was also approved for the treatment of genital warts, proving effective in nearly 70 percent of patients who do not respond to standard therapies. In that same year, it was approved for treatment of Kaposi's sarcoma, a form of cancer that appears frequently in patients suffering from AIDS.

In 1993, another class of interferon, interferon-gamma, received FDA approval for the treatment of one form of multiple sclerosis characterized by the intermittent appearance and disappearance of symptoms. Interferon-gamma may also have therapeutic value in the treatment of leishmaniasis, a parasitic infection that is prevalent in parts of Africa, North and South America, Europe, and Asia.

untold numbers of organisms, some that are harmless, but others that can cause disease. Virtually none of these organisms has the ability to penetrate the skin. Only when the skin has been broken, as in a cut, can the organisms pass into the body.

Mucous membranes are tissues that excrete a thick, sticky liquid known as mucus. All openings that lead to the interior of the bodythe mouth, nose, anal tract, and digestive tractare covered with mucous membranes. Organisms that try to enter the body through one of these openings tend to become trapped in the mucus, preventing them from entering the body.

Nonspecific immune system. Organisms that manage to penetrate the body's first line of defense then encounter another hurdle: the body's nonspecific immune system. The term nonspecific means that this line of defense goes into operation whenever any kind of foreign material enters the body. The immune systems of animals have developed the ability to tell the difference between its own cells, that is, cells produced by the body, and any other kind of material. The foreign matter might be another kind of organism, such as a bacterium or virus; cells from another animal; or inanimate matter, such as coal dust, pollen, cigarette smoke, or asbestosis fibers. Anything that causes an immune response in an animal is said to be an antigen.

Identification of foreign particles as "not-me" cells is made by a group of white blood cells known lymphocytes. Lymphocytes search out antigens in the bloodstream and destroy them by phagocytosis. Phagocytosis is the process by which one cell surrounds a second cell and engulfs it. Once the foreign cell has been swallowed up by the lymphocyte, it is digested by enzymes released from the lymphocyte.

The invasion of antigens can also produce an inflammatory response. Suppose you cut your finger on a tin can. The cut soon becomes red, swollen, and warm. These signs are evidence of the inflammatory response. Injured tissues send out signals to immune system cells, which quickly migrate to the injured area. These immune cells perform different functions. Some destroy bacteria by phagocytosis. Others release enzymes that kill the bacteria. Still other cells release a substance called histamine. Histamine causes blood vessels to dilate (become wider), thus increasing blood flow to the area. All of these activities promote healing in the injured tissue.

Allergic reactions are examples of an inappropriate inflammatory response. When a person is allergic to pollen, the body's immune system is reacting to pollen (a harmless substance) as if it were a bacterium and an immune response is

prompted. When pollen is inhaled, it stimulates an inflammatory response in the nasal cavity and sinuses. Histamine is released, which dilates blood vessels and causes large amounts of mucous to be produced, leading to a "runny nose." In addition, histamine stimulates the release of tears and is responsible for the watery eyes and nasal congestion typical of allergies.

To combat these reactions, many people take drugs that deactivate histamine. These drugs, called antihistamines, are available over the counter and by prescription. Some allergic reactions result in the production of large amounts of histamine, which impairs breathing and necessitates prompt emergency care. People prone to these extreme allergic reactions must carry a special syringe with epinephrine (adrenalin), a drug that quickly counteracts this severe respiratory reaction.

Specific immune system. The body's third line of defense against invasion by foreign organisms is the specific immune system. The specific immune system consists of two kinds of lymphocytes known as T lymphocytes and B lymphocytes. The two kinds of cells are sometimes known simply as T cells and B cells. Both kinds of cells are produced in bone marrow. T cells then migrate to the thymus (which gives them the T in their names), where they mature. No one knows where B cells mature.

T cells and B cells differ from nonspecific lymphocytes in that they attack only very specific antigens. For example, the blood and lymph of humans have T cell lymphocytes that specifically target the chicken pox virus, T cell lymphocytes that target the diphtheria virus, and so on. When T cell lymphocytes specific for the chicken pox virus encounters a body cell infected with this virus, the T cell multiplies rapidly and destroys the invading virus.

Two kinds of T cells exist: killer T cells and helper T cells. Killer T cells go directly to the target antigen and attack it. Helper T cells have many different functions, including to help in the development of B cells. Another function is to stimulate the formation of other T cells and the release of various chemicals that aid in the destruction of antigens.

Helper T cells have an especially crucial role in the immune system. Thus, any disease that destroys helper T cells has a devastating effect on the immune system as a whole. HIV (human immunodeficiency virus, which causes AIDS [acquired immunodeficiency syndrome]), for example, infects and kills helper T cells, thus disabling the immune system and leaving the body helpless to stave off infection.

Memory cells. After an invader has been destroyed, some T cells remain behind. These cells are called memory cells. Memory cells give an animal immunity to future attacks by the original invader. Once a person has had chicken pox, memory cells are created. If the person is later exposed to the chicken pox virus again, the virus is quickly destroyed. This secondary immune response, involving memory cells, is much faster than the primary immune response.

The procedure known as vaccination makes use of the above process. Vaccination is the process by which a killed microorganism (or parts thereof) are injected into a person's bloodstream. The presence of these particles prompts the formation of memory cells without a person's having to actually develop the disease.

B cells and the antibody response. When helper T cells recognize the presence of an invading antigen, they stimulate B cells in the blood and lymph to start reproducing. As the B cells reproduce, they also undergo a change in structure and become known as plasma cells. Those plasma cells then begin to secrete compounds known as antibodies. Antibodies are chemicals released by B cells that attach themselves to the surface of an antigen. The presence of an antibody helps other cells in the immune system recognize the antigen and mark it for destruction.

[See also AIDS (acquired immunodeficiency syndrome); Allergy; Antibody and antigen; Lymphatic system; Vaccine ]

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immune system

immune system Have you ever wondered why you are resistant to the colds that plague your friends, even though you have been exposed to the same environment? This is because you have an efficient immune system which is working overtime to identify and mount a reaction to ‘invaders’, including microorganisms capable of causing disease and foreign macromolecules like polysaccharides and proteins — a phenomenon known as immunity.

Historically, immunity referred to protection from infectious diseases, and the term was derived from the Latin word immunitas, meaning the exemption from civic duties and prosecution extended to Roman senators. However the concept of immunity existed long before, especially in the Chinese custom of making children inhale powders of crust of skin lesions of patients recovering from small pox. The first scientifically documented evidence of inducing immunity was the landmark work of Dr Edward Jenner, an English physician. He noticed that milkmaids who had recovered from cowpox were resistant to contracting small pox. When he injected the material from a cowpox pustule into a young boy, the boy did not develop small pox even when intentionally inoculated. Jenner published his findings in 1798 and laid the foundation for the future development of ‘vaccination’ (the Latin word vacinus means of or from cows) and other forms of immunization.

Two basic levels of immunity exist in healthy individuals to confer protection against microbes and other foreign bodies; the less perfect natural immunity and the more specific acquired immunity.

Natural immunity

Those defence mechanisms that exist prior to exposure to foreign substances, that are not enhanced by subsequent exposures, and that cannot discriminate between most foreign molecules, are categorized as natural or innate immunity. This includes the first line of defence — the protective barriers like the skin and the mucous membranes lining the body tracts, which secrete acids and enzymes capable of digesting bacterial cell walls. Often a failure at this level may lead to fatal complications (such as in cystic fibrosis, where the mucus formed is not protective).

If this protective barrier is breached, the next lines of defence involve two components of natural immunity — the humoral (mediated by substances free in the body fluids) and the cellular (mediated by cells). A number of humoral agents are rapidly produced or activated to exert non-specific effects: that is, they are equally effective against multiple microbes. They include acute phase proteins, serum complements, and interferons. Interferons are vital mainly in controlling viral infections. At this time the cellular component also comes into play. Two types of phagocytic cells ‘eat up’ and destroy the foreign molecules. The first of these are the polymorphonuclear neutrophil leucocytes (white blood cells), which circulate in blood and migrate to sites of microbial invasion; the second are called monocytes in the blood and macrophages in the tissues (they migrate between the two) — collectively, the macrophage–monocyte system. Humoral and cellular mechanisms interact: serum complements bind to the surface of the foreign molecule and increase the efficiency of phagocytosis by the cells.

Acquired immunity

By the time the components of natural immunity perform their act, more specific defence mechanisms are also mounted. These mechanisms are induced by exposure to the foreign molecules which are known as antigens. Besides amplifying the protective mechanisms of innate immunity, the specific immune system also ‘memorizes’ each encounter with a particular antigen such that subsequent exposure to that antigen leads to the development of ‘active immunity’. Specific immunity can also be induced in an individual by transferring cells or serum (depending on the type of immune response, see later) from a specifically immunized individual, so that the recipient becomes immune to the particular antigen without getting an actual exposure to it. This form of immunity is called ‘passive immunity’, and often is a useful method for rapid conferring of immunity. This technique has helped in saving lives following potentially lethal snake bites, by the administration of antibodies from immunized individuals. Much more commonly, anti-tetanus serum has been widely used to confer passive immunity after potentially contaminated minor injuries.

Lymphocytes are the primary players in specific immunity. These are cells that are present throughout the body, circulating in the blood and lymph and organized in lymphoid tissues. They are produced in primary lymphoid organs — the liver in the fetus, the thymus, and the bone marrow. Some lymphocytes pass through the thymus after release from the bone marrow, re-enter the circulation and then settle in secondary lymphoid organs like the spleen and the lymph nodes. During passage through the thymus these lymphocytes acquire antigen specificity, properties which equip them to act against a particular invader, and are thereafter known as T-cells. Other lymphocytes do not pass through the thymus, but settle directly in the secondary lymphoid organs where they mature and develop antigen specificity. These cells are called B-lymphocytes or B-cells; they carry on their surface a ‘recognition molecule’ or antibody, which acts as a receptor for an antigen.

Antibodies belong to a group of proteins called immunoglobulins. They are similar in their overall Y-shaped structure. The 2 arms form the part known as ‘Fab’, which binds with the antigen. Here the amino acid sequence varies widely; these regions determine the specificity of the antibody and also account for the diversity of immunity. In fact there are between 10 and 1000 million structurally different antibodies in an individual, each with unique amino acid sequences in the Fab region. The stem of the antibody determines its biological function, and its properties are used in classifying the immunoglobulins (IgG, IgM, IgA, IgD, and IgE.)

Humoral immunity is mediated by antibodies that are released into the circulation from B-lymphocytes, and can therefore be transferred to non-immunized individuals by cell-free components of blood. It is the principal defence mechanism against extra-cellular foreign molecules or their toxins because the antibodies bind to these and lead to their destruction. Intracellular antigens are handled by cell-mediated immunity, of which the main component is T-lymphocytes. This form of immunity can be transferred only through the cells of the blood. Humoral and cellular immunity are thus the two types of acquired or specific immunity.

Following exposure to an antigen, the specific immune response is brought about in a sequential manner, which can be divided into three phases: ‘cognitive’, ‘activation’ and ‘effector’. During the cognitive phase, the antigen binds to specific receptors on mature lymphocytes of both types. The antibody on B-lymphocytes recognizes and binds foreign proteins, polysaccharides, or lipids in soluble form. Receptors on T-lymphocytes, on the other hand, can recognize only short peptide sequences in protein antigens present on the surface of other cells. In the technical jargon of immunology, the portion of an antigen that is specifically recognized by the antibody is called an ‘epitope’.

Next, in the activation phase, the antigen-specific lymphocytes of both types proliferate by cloning, thus amplifying the immune response. Lymphocytes develop into cells whose primary function is to eliminate the antigen. All clonal B-cells secrete the same antibody, which combines with the antigen and initiates a sequence of events leading to destruction of that antigen. Subsets of the antigen-specific T-cell clones develop different functions; some activate phagocytes; others, called T-cytotoxic cells, directly break down cells that produce viral antigens; some regulate the production of antibody by B-cells. Those T-cells, which promote the immune response, are called T-helper cells, while others that inhibit it as part of the self-limiting capability of the immune response, are called T-suppressor cells. Another subset, the Tdth cells (delayed type hypersensitivity) produce factors that modulate the functions of lymphocytes and macrophages.

A set of membrane proteins that are products of genes determining (in)compatibility of tissues between individuals are known as HLA (called human lymphocyte antigens, because they were first recognized on these cells, but they occur on other cells also). They regulate the T-cell activity in such a way that T-cells recognize other antigens only when they are associated with the HLA molecules. This system is highly variable in the human population and it is rare for two individuals to have the same HLA products. This is often the reason for transplant rejection due to an immune response, when the donor's proteins serve as antigens in the recipient. HLA typing and matching is thus an essential step before any transplant surgery to minimize the chances of an immune response.

Once the lymphocytes have been activated and the antigen has been presented to them, the immune response enters the effector phase. Few antigens bind directly to antigen-reactive T- or B-cells but are presented to the lymphocytes bound to other ‘antigen presenting cells’ such as macrophages. The effector phase requires the participation also of other non-lymphoid ‘effector cells’ such as mast cells, eosinophils, or natural killer (NK) cells, which act also as components of natural immunity. Antibodies bind to the antigen, and this promotes phagocytosis by neutrophils or other phagocytes. Antibodies can also activate the ‘complement system’, generating proteins that cause inflammation, cell breakdown, and phagocytosis of the antigen. Some antibodies, like IgA released from mucous membranes, coat the antigen and prevent its docking on the epithelial lining of body tracts. T-cells also secrete chemicals called cytokines, which stimulate an inflammatory response and enhance the function of natural immunity. The antigen thus faces a barrage of defence mechanisms' which leads to its destruction.

Once the antigenic stimulation is removed, lymphocytes become quiescent and only some remain viable as memory cells. On a subsequent exposure to the same antigen these become rapidly activated and can mount a faster response than the first time, called the secondary immune response. A series of feedback controls also come into play, which makes the immune response self limiting.

One of the distinguishing and essential features of the immune system is its ability to discriminate between foreign and ‘self-antigens’. Immunity is unresponsive to molecules present in the individual that would be antigenic in another. This arises due to an acquired process called self-tolerance. Thus during the early stages of development, functionally immature ‘self-recognizing’ lymphocytes come in contact with self-antigens and are prevented from developing to a stage where they can respond to self-antigens. However, in certain unfortunate conditions, abnormalities in induction or maintenance of self-tolerance may occur, which leads to the immune system acting against a normal component of the same body. This leads to the development of autoimmune diseases.

Shiladitya Sengupta, and Tai-Ping Fan


See also allergy; autoimmune diseases.

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Immune System

Immune system

The immune system is the body's biological defense mechanism that protects against foreign invaders. Only in the last century have the components of that system and the ways in which they work been discovered, and more remains to be clarified.

The true roots of the study of the immune system date from 1796 when an English physician, Edward Jenner , discovered a method of smallpox vaccination . He noted that dairy workers who contracted cowpox from milking infected cows were thereafter resistant to smallpox. In 1796, Jenner injected a young boy with material from a milkmaid who had an active case of cowpox. After the boy recovered from his own resulting cowpox, Jenner inoculated him with smallpox; the boy was immune. After Jenner published the results of this and other cases in 1798, the practice of Jennerian vaccination spread rapidly.

It was Louis Pasteur who established the cause of infectious diseases and the medical basis for immunization . First, Pasteur formulated his germ theory of disease , the concept that disease is caused by communicable microorganisms . In 1880, Pasteur discovered that aged cultures of fowl cholera bacteria lost their power to induce disease in chickens but still conferred immunity to the disease when injected. He went on to use attenuated (weakened) cultures of anthrax and rabies to vaccinate against those diseases. The American scientists Theobald Smith (18591934) and Daniel Salmon (18501914) showed in 1886 that bacteria killed by heat could also confer immunity.

Why vaccination imparted immunity was not yet known. In 1888, Pierre-Paul-Emile Roux (18531933) and Alexandre Yersin (18631943) showed that diphtheria bacillus produced a toxin that the body responded to by producing an antitoxin. Emil von Behring and Shibasaburo Kitasato found a similar toxin-antitoxin reaction in tetanus in 1890. Von Behring discovered that small doses of tetanus or diphtheria toxin produced immunity, and that this immunity could be transferred from animal to animal via serum. Von Behring concluded that the immunity was conferred by substances in the blood, which he called antitoxins, or antibodies. In 1894, Richard Pfeiffer (18581945) found that antibodies killed cholera bacteria (bacterioloysis). Hans Buchner (18501902) in 1893 discovered another important blood substance called complement (Buchner's term was alexin), and Jules Bordet in 1898 found that it enabled the antibodies to combine with antigens (foreign substances) and destroy or eliminate them. It became clear that each antibody acted only against a specific antigen . Karl Landsteiner was able to use this specific antigen-antibody reaction to distinguish the different blood groups.

A new element was introduced into the growing body of immune system knowledge during the 1880s by the Russian microbiologist Elie Metchnikoff. He discovered cell-based immunity: white blood cells (leucocytes), which Metchnikoff called phagocytes, ingested and destroyed foreign particles. Considerable controversy flourished between the proponents of cell-based and blood-based immunity until 1903, when Almroth Edward Wright brought them together by showing that certain blood substances were necessary for phagocytes to function as bacteria destroyers. A unifying theory of immunity was posited by Paul Ehrlich in the 1890s; his "side-chain" theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until this time, immune responses were seen as purely beneficial. In 1902, however, Charles Richet and Paul Portier demonstrated extreme immune reactions in test animals that had become sensitive to antigens by previous exposure. This phenomenon of hypersensitivity, called anaphylaxis , showed that immune responses could cause the body to damage itself. Hypersensitivity to antigens also explained allergies , a term coined by Pirquet in 1906.

Much more was learned about antibodies in the mid-twentieth century, including the fact that they are proteins of the gamma globulin portion of plasma and are produced by plasma cells; their molecular structure was also worked out. An important advance in immunochemistry came in 1935 when Michael Heidelberger and Edward Kendall (18861972) developed a method to detect and measure amounts of different antigens and antibodies in serum. Immunobiology also advanced. Frank Macfarlane Burnet suggested that animals did not produce antibodies to substances they had encountered very early in life; Peter Medawar proved this idea in 1953 through experiments on mouse embryos.

In 1957, Burnet put forth his clonal selection theory to explain the biology of immune responses. On meeting an antigen, an immunologically responsive cell (shown by C. S. Gowans (1923 ) in the 1960s to be a lymphocyte) responds by multiplying and producing an identical set of plasma cells, which in turn manufacture the specific antibody for that antigen. Further cellular research has shown that there are two types of lymphocytes (nondescript lymph cells): B-lymphocytes, which secrete antibody, and T-lymphocytes , which regulate the B-lymphocytes and also either kill foreign substances directly (killer T cells ) or stimulate macrophages to do so (helper T cells). Lymphocytes recognize antigens by characteristics on the surface of the antigen-carrying molecules. Researchers in the 1980s uncovered many more intricate biological and chemical details of the immune system components and the ways in which they interact.

Knowledge about the immune system's role in rejection of transplanted tissue became extremely important as organ transplantation became surgically feasible. Peter Medawar's work in the 1940s showed that such rejection was an immune reaction to antigens on the foreign tissue. Donald Calne (1936 ) showed in 1960 that immunosuppressive drugs, drugs that suppress immune responses, reduced transplant rejection, and these drugs were first used on human patients in 1962. In the 1940s, George Snell (19031996) discovered in mice a group of tissue-compatibility genes, the MHC , that played an important role in controlling acceptance or resistance to tissue grafts. Jean Dausset found human MHC, a set of antigens to human leucocytes (white blood cells), called HLA . Matching of HLA in donor and recipient tissue is an important technique to predict compatibility in transplants. Baruj Benacerraf in 1969 showed that an animal's ability to respond to an antigen was controlled by genes in the MHC complex.

Exciting new discoveries in the study of the immune system are on the horizon. Researchers are investigating the relation of HLA to disease; certain types of HLA molecules may predispose people to particular diseases. This promises to lead to more effective treatments and, in the long run, possible prevention. Autoimmune reaction, in which the body has an immune response to its own substances, may also be a cause of a number of diseases, like multiple sclerosis, and research proceeds on that front. Approaches to cancer treatment also involve the immune system. Some researchers, including Burnet, speculate that a failure of the immune system may be implicated in cancer. In the late 1960s, Ion Gresser (1928 ) discovered that the protein interferon acts against cancerous tumors. After the development of genetically engineered interferon in the mid-1980s finally made the substance available in practical amounts, research into its use against cancer accelerated. The invention of monoclonal antibodies in the mid-1970s was a major breakthrough. Increasingly sophisticated knowledge about the workings of the immune system holds out the hope of finding an effective method to combat one of the most serious immune system disorders, AIDS .

Avenues of research to treat AIDS includes a focus on supporting and strengthening the immune system. (However, much research has to be done in this area to determine whether strengthening the immune system is beneficial or whether it may cause an increase in the number of infected cells.) One area of interest is cytokines , proteins produced by the body that help the immune system cells communicate with each other and activate them to fight infection. Some individuals infected with the AIDS virus HIV (human immunodeficiency virus ) have higher levels of certain cytokines and lower levels of others. A possible approach to controlling infection would be to boost deficient levels of cytokines while depressing levels of cytokines that may be too abundant. Other research has found that HIV may also turn the immune system against itself by producing antibodies against its own cells.

Advances in immunological research indicate that the immune system may be made of more than 100 million highly specialized cells designed to combat specific antigens. While the task of identifying these cells and their functions may be daunting, headway is being made. By identifying these specific cells, researchers may be able to further advance another promising area of immunologic research, the use of recombinant DNA technology, in which specific proteins can be mass-produced. This approach has led to new cancer treatments that can stimulate the immune system by using synthetic versions of proteins released by interferons .

See also Antibody and antigen; Antibody formation and kinetics; Antibody, monoclonal; Antibody-antigen, biochemical and molecular reactions; B cells or B lymphocytes; Bacteria and bacterial infection; Germ theory of disease; Immunity, active, passive and delayed; Immunity, cell mediated; Immunity, humoral regulation; Immunochemistry; Immunodeficiency; Immunogenetics; Immunologic therapies; Immunological analysis techniques; Immunology, nutritional aspects; Immunology; Immunosuppressant drugs; Infection and resistance; Invasiveness and intracellular infection; Major histocompatibility complex (MHC); T cells or T-lymphocytes; Transmission of pathogens; Transplantation genetics and immunology; Viruses and responses to viral infection

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Immune System Genetics

Immune System Genetics

The immune system is the set of cells and glands that protects the body from invasion and infection by viruses, bacteria, and other pathogens . The immune system must be able to recognize any foreign target, or antigen, of which there are potentially millions. Pathogenic organisms change over time, and new antigens evolve that must also be targeted. At the same time, the immune system must distinguish pathogenic antigens from the body's own tissues, attacking the former and sparing the latter. The key to the scope and specificity of the immune system response is in the genes that give rise to it.

Overview of the Immune System

The immune system includes several interacting components. Nonspecific immunity (protection against any invasion) is provided by the barriers of the skin and mucous membranes lining the lungs and gut. Additional non-specific defenses are provided by the inflammatory response and the complement proteins in the bloodstream. We shall not deal further with these defenses.

Specific immunity is the set of defenses mounted against a specific invader. It involves the action of three major types of cells: B cells, T cells, and macrophages. In broad, somewhat oversimplified terms, B cells make proteins called antibodies that attach to foreign antigens, serving as warning flags. T cells coordinate the immune attack and destroy virus-infected cells. Macrophages consume flagged antigens and clean up the debris from a T cell attack on infected cells.

An antibody binds to an invader when its shape fits some shape (the antigen) on the invader's surface. Any particular invader, such as a bacterial cell, may have dozens of such antigens.

The Puzzle of Antibody Diversity

B cells are created in the bone marrow. Many millions of different B cells are made, each containing a unique gene for the specific antibody that it (and all its descendants) will make. A group of B cells with all its descendants is called a clone. Thus, the antibody made by one B cell clone differs from that made by any other B cell clone. T cells develop along a slightly different pathway but also contain a unique protein, called the T cell receptor, which is coded for by a gene unique to that T cell clone.

Antibodies are proteins, and like all of the body's proteins, must be encoded by genes. However, the number of distinct antibodies each of us makes (many millions) is vastly greater than the total number of genes in our entire genome (30,000-70,000). How is all this diversity encoded? To understand the answer, it is helpful to look at the structure of an antibody.

Antibody Structure

The antibody is formed from four polypeptides that link up in the shape of a Y. There are two identical long heavy (H) chains and two identical short light (L) chains. The tips of each branch of the Y form a pocket, and it is here the antibody binds antigen. Thus, these twin pockets are called the antigen-binding regions of the antibody.

By comparing the amino acid sequences of antibodies from different B cell clones, several important features can be discovered. Light chains, for instance, have a constant region, with amino acid sequences that differ little from clone to clone, and a variable region, with sequences that differ considerably. The constant region comes in two different forms, termed "kappa" and "lambda." The amino acid sequence of one kappa constant sequence differs little or not at all from clone to clone; similarly, all lambda constant sequences are essentially identical. The variable region does differ considerably between clones. The heavy chain also has a constant region (of which there are five forms) and a variable region.

The constant regions of all the chains are found toward the bottom of the Y, while the variable regions are found toward the tip. Furthermore, within each variable region, there are three hypervariable regions, whose five to ten amino acids differ even more than the other portions of the variable region. These hypervariable regions form the actual points of contact between antibody and antigen.

Gene Segments Combine Randomly to Generate Diversity

The fundamental principle governing antibody generation is combinatorial diversity. A large number of genes are generated by choosing from among a smaller pool of differing gene segments and combining them in different ways. This process, known as somatic recombination, is similar in principle to constructing words. The alphabet's twenty-six letters can be combined to make 676 (262) two-letter words and almost 12 million five-letter words.

To understand the molecular details of somatic recombination, let us focus on the creation of a kappa-type light chain. The process is similar for lambda light chains and only marginally more involved for a heavy chain.

We noted that the light chain has both a variable and a constant region. There are forty gene segments that can code for the variable (V) region and a single segment that codes for the constant (C) region. In addition, there are five possible coding segments for the J region, a short region that is also present on light chains. All of these genes and segments are located in sequence on chromosome 2. Each V and J segment is flanked by special noncoding sequences that facilitate the next stage, in which specific segments are joined.

Somatic recombination begins when special recombining proteins randomly bring together the downstream end of one V segment and the upstream end of one J segment. They do this by attaching to the flanking sequences and bending the intervening DNA into a loop. The loop is cut out and degraded, and the remaining DNA is spliced together. The product is the mature antibody gene.

Note in the diagram on the right that the resulting gene may still have some extra upstream V segments. An ingenious mechanism prevents such segments from being transcribed to make messenger RNA, however.

Each V segment contains a promoter , the region to which RNA polymerase binds to start transcription. The promoter is inactive, though, until it is brought close to an "enhancer" region between the J and C segments. Thus, transcription will begin at the V segment closest to the enhancer, and only this one V segment is transcribedthe others are too far from the enhancer. The gene may also have extra downstream J segments and intron sequences between J and C. These are transcribed, but they are removed by RNA processing.

Other Sources of Diversity

The random combination of V and J segments alone can produce millions of possible combinations. More diversity arises because the joining of V and J chains is done imprecisely, with the possible loss or gain of several nucleotides, resulting in added or deleted amino acids.

Remember also that each antibody includes both light and heavy chains. Heavy chains are produced by a similar combinatorial process, using a different, larger set of gene segments. The combination of a randomly produced light chain with a randomly produced heavy chain produces even more diversity. Finally, when a B cell multiplies in response to antigens, the rearranged gene can mutate, making some members of the clone different from others. The number of possible antibodies available through all these processes is in the trillions.

T Cell Receptors

As mentioned above, T cells help control the immune response and kill infected cells. Infected cells are recognized because they chop up foreign proteins from the invader and display the bits on their surface. These bits, which are antigens, are held aloft by surface proteins, called MHC (major histocompatibility complex) proteins. The MHC-antigen complex is recognized by the T cell receptor, in cooperation with one or more other T cell surface molecules.

When a T cell discovers a cell whose MHC proteins contain foreign antigens, it marks the cell for destruction. The T cell receptor interacts with antigens in much the same way as an antibody does, although the size of the antigen it recognizes is smaller. T cell receptors come in as many diverse forms as antibodies do, and, while the details differ, their diversity is generated in much the same way, with random recombination of gene segments.

The Major Histocompatibility Complex

The T cell-MHC interaction serves another, related function: It confirms that the cell is part of the self that the immune system should be protecting. Thus, MHCs serve as self-recognition markers. When a T cell recognizes foreign MHCs, as would occur in an organ transplant, it sets in motion an immune attack to reject the foreign tissue. Indeed, "histocompatibility" means compatibility of tissues, and these proteins control that process.

There are two major classes of MHC proteins, called class I and II, with different functions in antigen presentation. Class I contains three members, each coded for by different genes, and class II contains four members. For almost every gene, there are multiple alleles . The number of alleles per gene ranges from a handful to more than 100. Since each person will inherit and express a unique set of MHC alleles, once again we can see the combinatorial possibilities: There are millions of different combinations of MHC alleles, and very few people are likely to have exactly the same set. This is what makes organ transplants so difficult. Matching MHC types is the key to success, but even close relatives may have different allele sets.

Richard Robinson

Bibliography

Alberts, Bruce, et al. Molecular Biology of the Cell, 4th ed. New York: Garland Science, 2002.

Janeway, Charles A., Jr., et al. Immunobiology: The Immune System in Health and Disease, 5th ed. New York: Garland Publishing, 2001.

The MHC genes are believed to be the most allelically diverse of all human genes.

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Immune Globulin

Immune globulin

Definition

Immune globulin is a concentrated solution of antibodies, pooled from donated blood, which is sometimes given to cancer patients whose own immune systems are either not working or are suppressed as a side effect of treatment. Immune globulin can also be called gamma globulin; in the United States some of the brand names are Gamimune, Gammagard, Gammar-P, Iveegam, Polygam, Sandoglobulin, and Venoglobulin.

Purpose

A healthy human body produces proteins called antibodies that act to destroy microorganisms (bacteria and viruses) that invade the body. Some cancer patients, due to the illness itself or side effects of treatment, become depleted of these proteins and therefore susceptible to serious infections. Immune globulin is given to these patients to restore their body's immunity. The use of immune globulin in this way is also called passive immunization. For example, immune globulin is given to bone marrow transplant recipients to prevent the development of severe bacterial infections while their own immune system is not functioning, and chronic lymphocytic leukemia patients (of the type whose antibody-producing cells are the malignant cells) are given immune globulin to prevent the recurrent infections these patients sometimes suffer. Use in this disorder also allows the use of aggressive chemotherapy that will destroy the patient's own cancerous antibody-producing cells.

Immune globulin is also used to treat other diseases such as Eaton-Lambert Syndrome , a rare neurological disorder that sometimes occurs in association with small cell lung cancer called Eaton-Lambert syndrome, an autoimmune disease in which a patient's own antibodies attack nerve cells. The use of immune globulin appears to cause the body to reduce its own production of antibody, thereby improving the neurological disorder.

Description

Immune globulin primarily consists of antibody proteins of the type called IgG or gamma, although the solution may contain small amounts of other antibody types as well as sugars, proteins, and salt.

It is produced by pooling donated blood from at least 1000 people who have been tested to be free of blood-borne diseases like HIV or hepatitis. The antibody proteins are then separated out of the whole blood, and the pH of the immune globulin solution is adjusted to match the normal pH of blood. The preparation is also treated to remove any contaminants, including infectious bacteria or viruses.

Recommended dosage

The dose of immune globulin used varies with the specific problem that it is being used for. When immune gobulin is used in patients with Eaton-Lambert Syndrome, the effective dose is usually about 1 g/kg of body weight/day. (One gram equals 0.035274 ounce; one kilogram equals 2.2046 pounds.) When used to counteract immunodeficiency, the dose is designed to produce an antibody level that stays at an effective threshold over a period of time.

When immune globulin is given to bone marrow transplant recipients, it is usually begun at the time of the transplant and continued for 100 days thereafter, with the objective of maintaining the level of IgG in the patient's blood above 400 mg per deciliter. (A deciliter equals 3.38 fluid ounces.) In patients with chronic lymphocytic leukemia (B-cell type) the target threshold for antibodies in the patient's blood is usually about 600 mg/dL. Although the amount required to maintain these levels varies from patient to patient (because different patients metabolize the drug at different rates) a dose between 10 and 200 mg/kg of body weight, given every 3-4 weeks, is usually sufficient.

Immune globulin is usually given intravenously, although intramuscular shots are available.

Precautions

Some people may have experienced severe reactions, including allergy-type reactions, to other antibody preparations. Generally these people should not be given intravenous immune globulin. Patients with deficiency of antibody IgA, specifically, should also avoid the use of immune globulin. People with a tendency to form blood clots, or those with kidney problems should also avoid the use of this product, especially if elderly. While many pregnant women have been treated with immune globulin for different problems that have occurred during their pregnancy, since the method of action and specific effects on the fetus are not completely understood, pregnant women should avoid the use of immune globlulin unless it is clearly necessary. Any patient who is given immune globulin should be watched carefully, and epinephrine should be kept available in case a severe allergic reaction is experienced. Immune globulin which was made to be given through intramuscular injection should never be administered intravenously.

Side effects

Administration of intramuscular immune globulin may result in tenderness, swelling, and possibly hives at the site of the injection.

Intravenous immune globulin may cause more severe reactions related to rapid introduction into the blood system. Possible side effects include headache, backache, aching muscles, fever , low blood pressure, and chest pain. More commonly, fever accompanied by chills or nausea and vomiting may be experienced. If these side effects occur, they are usually related to the immune globulin being administered too rapidly. If the rate of infusion is reduced, or if the infusion is stopped temporarily, negative effects will generally disappear. Rare, but potentially serious, side effects observed have been kidney failure and aseptic meningitis.

Interactions

Use of immune globulin may reduce the effectiveness of vaccinations (for example, measles, mumps, and rubella) for a few months following the use of the immune globulin preparation. Patients who have been given immune globulin should notify their doctors before any vaccinations are given. In addition, in some situations patients may need to have antibody levels measured to determine whether or not they have had previous infection with a specific microorganism. Use of immune globulin can create the false impression of prior exposure to the organism due to the donated antibodies in their blood.

See Also Immunologic therapies

Wendy Wippel, M.S.

KEY TERMS

Autoimmune disease

A disease in which the body produces an immunologic reaction against itself.

Epinephrine

A medication used to treat heart failure and severe allergic reactions.

Immunoglobulins

An antibody of a specific type. Five main types are produced, known as IgA, IgD, IgE, Ig G, and IgM. Most antibody in the blood is IgG.

Intramuscular administration

A shot usually in the hip or arm, in which medication is delivered into a muscle.

Intravenous administration

Introduction of medication straight into a vein (commonly called IV).

Neurologic

Involving the nervous system.

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Immune System

Immune System

A staple in forensic investigations is the use of antibodies to detect a target antigen . Blood typing and the detection of bacteria, or their elaborated toxins , rely on the recognition of antigens by their corresponding antibodies. The production of antibodies is one aspect of the immune system, the body's biological defense mechanism that protects against foreign invaders.

The true roots of the study of the immune system date from 1796, when English physician Edward Jenner discovered a method of smallpox vaccination. He noted that dairy workers who contracted cowpox from milking infected cows were thereafter resistant to smallpox. In 1796, Jenner injected a young boy with material from a milkmaid who had an active case of cowpox. After the boy recovered from his own resulting cowpox, Jenner inoculated him with smallpox; the boy was immune. After Jenner published the results of this and other cases in 1798, the practice of Jennerian vaccination spread rapidly.

Louis Pasteur established the cause of infectious diseases and the medical basis for immunization. Pasteur formulated the germ theory of disease, the concept that disease is caused by communicable microorganisms. In 1880, Pasteur discovered that aged cultures of fowl cholera bacteria lost their power to induce disease in chickens but still conferred immunity to the disease when injected. He went on to use attenuated (weakened) cultures of anthrax and rabies to vaccinate against those diseases. The American scientists Theobald Smith (18591934) and Daniel Salmon (18501914) showed in 1886 that bacteria killed by heat could also confer immunity.

In 1888, Pierre-Paul-Emile Roux (18531933) and Alexandre Yersin (18631943) showed that diphtheria bacillus produced a toxin that the body responded to by producing an antitoxin. Emil von Behring and Shibasaburo Kitasato found a similar toxin-antitoxin reaction in tetanus in 1890, and von Behring discovered that small doses of tetanus or diphtheria toxin produced immunity, which could be transferred from animal to animal via serum . He concluded that the immunity was conferred by substances in the blood, which he called antitoxins, or antibodies. In 1894, Richard Pfeiffer (18581945) found that antibodies killed cholera bacteria (bacterioloysis). Hans Buchner (18501902) in 1893 discovered another important blood substance called complement (Buchner's term was alexin), and Jules Bordet in 1898 found that it enabled the antibodies to combine with antigens (foreign substances) and destroy or eliminate them. It became clear that each antibody acted only against a specific antigen. Karl Landsteiner exploited this specific antigen-antibody reaction to distinguish the different blood groups.

In the 1880s Russian microbiologist Elie Metchnikoff discovered cell-based immunity: white blood cells (leucocytes), which Metchnikoff called phagocytes, ingested and destroyed foreign particles. Considerable controversy flourished between the proponents of cell-based and blood-based immunity until 1903, when Almroth Edward Wright brought them together by showing that certain blood substances were necessary for phagocytes to function as bacteria destroyers. A unifying theory of immunity was posited by Paul Ehrlich in the 1890s; his "side-chain" theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until now, immune responses were seen as purely beneficial. In 1902, however, Charles Richet and Paul Portier demonstrated extreme immune reactions in test animals that had become sensitive to antigens by previous exposure. This phenomenon of hypersensitivity, called anaphylaxis, showed that immune responses could cause the body to damage itself. Hypersensitivity to antigens also explained allergies, a term coined by Pirquet in 1906.

Much more was learned about antibodies in the mid-twentieth century, including the fact that they are proteins of the gamma globulin portion of plasma and are produced by plasma cells; their molecular structure was also determined. An important advance in immunochemistry came in 1935 when Michael Heidelberger and Edward Kendall (18861972) developed a method to detect and measure amounts of different antigens and antibodies in serum. Immunobiology also advanced. Frank Macfarlane Burnet suggested that animals did not produce antibodies to substances they had encountered very early in life; Peter Medawar proved this idea in 1953 through experiments on mouse embryos.

In 1957, Burnet put forth his clonal selection theory to explain the biology of immune responses. On meeting an antigen, an immunologically responsive cell (shown by C. S. Gowans [1923] in the 1960s to be a lymphocyte) responds by multiplying and producing an identical set of plasma cells, which in turn manufacture the specific antibody for that antigen. Further cellular research has shown that there are two types of lymphocytes (non-descript lymph cells): B-lymphocytes, which secrete antibody, and T-lymphocytes, which regulate the B-lymphocytes and also either kill foreign substances directly (killer T cells) or stimulate macrophages to do so (helper T cells). Lymphocytes recognize antigens by characteristics on the surface of the antigen-carrying molecules. Researchers in the 1980s uncovered many more intricate biological and chemical details of the immune system components and the ways in which they interact.

see also Antibody; Antigen; Homogeneous enzyme immunoassay (EMIT); Vaccines.

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Immune Synapse

Immune synapse

Before they can help other immune cells respond to a foreign protein or pathogenic organism, helper T cells must first become activated. This process occurs when an antigen-presenting cell submits a fragment of a foreign protein, bound to a Class II MHC molecule (virus-derived fragments are bound to Class I MHC molecules) to the helper T cell. Antigen-presenting cells are derived from bone marrow, and include both dendritic cells and Langerhans cells, as well as other specialized cells. Because T cell responses depend upon direct contact with their target cells, their antigen receptors, unlike antibodies made by B cells , exist bound to the membrane only. In the intercellular gap between the T cell and the antigen-presenting cell, a special pattern of various receptors and complementary ligands forms that is several microns in size. This patterned collection of receptors is called the immune synapse.

The immune synapse can be compared to a molecular machine that controls T cell activation. Physically it consists of a group of T cell receptors surrounded by a ring of integrin-like adhesion molecules as well as other accessory proteins like the CD3 complex. Integrins are a family of cell-surface proteins that are involved in binding to extracellular matrix components. This specialized cell-cell junction was named the immunological synapse because it is thought to be involved in the transfer of information across the T cell-APC junction. Specifically, the immune synapse appears to play an essential role in organizing the immune response, the level of control, and the nature of that response. The formation of the synapse requires several minutes and it appears to be stable for several hours. The structural protein actin seems to have an important role in that stability as T-cell activation is blocked by disruption of actin filaments. There also appears to be a temporal spatial component in that signals that modulate T-cell maturity and functions are received in a serial manner as well as simultaneously. Further clarification of the structure of the immune synapse will help develop further insights into T cell recognition as well as the mechanism of T cell receptor signalinghow information transfer occurs across the synapse. The duration of signaling in immature T cells may control CD4 and CD8 lineage decisions. This would be useful in determining the degree to which different types and developmental stages rely on alternative signaling mechanisms.

See also Antibody and antigen; Antibody formation and kinetics; Antibody-antigen, biochemical and molecular reactions; T cells or T-lymphocytes

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Immune System

Immune System

The immune system is made up of cells, tissues, organs, and processes that identify a substance as abnormal or foreign and prevent it from harming the body. Primary defenses include the white blood cells , but skin, mucosa , normal bacteria , enzymes , and proteins also provide protection. During times of stress and malnutrition , immune function may be decreased, meaning that susceptibility to illness is increased. Proper nutrition , including adequate protein, calories , and antioxidants (such as vitamin C, vitamin E, and beta-carotene, which are all found in fruits and vegetables) may help to improve immune response and reduce the risk of illness.

see also Infection.

Catherine Christie

Bibliography

Shils, Maurice, et al. (1999). Modern Nutrition in Health and Disease, 9th edition. Baltimore, MD: Williams & Wilkins.

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Immune Deficiencies

Immune Deficiencies

What Are Immune Deficiencies?

Overview of the Immune System

Primary Immune Deficiencies

Secondary Immune Deficiencies

What Are the Signs and Symptoms of Immune Deficiencies?

How Do Doctors Make the Diagnosis?

How Are Immune Deficiencies Treated?

Resources

Immune deficiencies (ih-MYOON dih-FIH-shen-seez) are conditions that impair the bodys immune system so that it is less capable of fighting infection.

KEYWORDS

for searching the Internet and other reference sources Acquired immunodeficiency syndrome (AIDS)

Human immunodeficiency virus (HIV) Hypogammaglobulinemia Immune response Immune system Primary immune deficiencies Secondary immune deficiencies Selective IgA deficiency Severe combined immunodeficiency disease (SCID)

X-linked agammaglobulinemia

What Are Immune Deficiencies?

Immune deficiencies arise when one or more of the parts of the immune system are missing or not working correctly, leaving the body less able to fight disease-causing agents. There are two types of these deficiencies: primary, or inherited, immune deficiencies and secondary, or acquired, immune deficiencies.

The immune system has many parts that work together to protect the body from foreign invaders, such as microorganisms* and toxins*. When any segment of the immune system is absent or breaks down, it can lead to an immune deficiency. With so many elements of the immune system, there are more than 80 different types of primary immune deficiencies. They range from those that have severe and sometimes fatal effects to mild diseases that cause people few, if any, problems. About half a million people in the United States have some type of primary immune deficiency, with more boys than girls affected by these conditions.

*microorganisms
are tiny organisms that can be seen only using a microscope. Types of microorganisms include fungi, bacteria, and viruses.
*toxins
are poisons that harm the body.

Secondary immune deficiencies are much more common than inherited deficiencies. Unlike patients with primary immune deficiencies, people with secondary immune deficiencies are born with a healthy immune system, but sometime later in life the system becomes weakened or damaged. Both primary and secondary deficiencies typically lead to frequent infections and sometimes to additional medical problems, including certain cancers. These people often experience a variety of skin, respiratory, and bone problems as well, and they are more likely to have autoimmune diseases*.

*autoimmune
(aw-toh-ih-MYOON) diseases are diseases in which the bodys immune system attacks some of the bodys own normal tissues and cells.

Overview of the Immune System

The immune system consists of a group of organs, cells, and a specialized system called the lymphatic (lim-FAH-tik) system that helps clear infectious agents from the body. Together, they guard the body against infectious diseases. The lymphatic system is a key part of the immune system: it consists of lymphatic vessels, lymph nodes*, and the thymus (THY-mus) and spleen. Lymph nodes and lymphatic vessels transport lymph, a clear fluid that contains white blood cells called lymphocytes (LIM-fo-sites), throughout the body. The lymphocytes mature in the thymus, a gland located behind the breastbone. The spleen, an organ that is the center of certain immune system activities, is found in the upper-left side of the abdomen. Lymphatic tissue also is found in other locations throughout the body, including the tonsils* and the appendix*.

*lymph
(LIMF) nodes are small, bean-shaped masses of tissue that contain immune system cells that fight harmful microorganisms. Lymph nodes may swell during infections.
*tonsils
are paired clusters of lymph tissues in the throat that help protect the body from bacteria and viruses that enter through a persons nose or mouth.
*appendix
(ah-PEN-diks) is thenarrow, finger-shaped organ that branches off the part of the large intestine in the lower right side of the abdomen. Although the organ is not known to have any vital function, the tissue of the appendix is populated by cells of the immune system.

When a foreign substance or microorganism enters the body, phagocytes (FAH-go-sites) often are the first cells on the scene. These large scavenger white blood cells patrol the bloodstream, looking for possible invaders. When they find one, they engulf, digest, and destroy the intruder.

Other components of the immune response react when presented with specific antigens*. The most important players in this fight are two types of lymphocytes that learn to recognize and destroy the foreign invaders.

*antigens
(AN-tih-jenz) are substances that are recognized as a threat by the bodys immune system, which triggers the formation of specific antibodies against the substances.

B cells, the first type, are white blood cells that produce antibodies*, which circulate in the blood and lymph streams. The first time B cells encounter a new foreign substance, they make antibodies in response to the intruders antigens. When the antibodies come across that specific antigen again, they attach themselves to it, marking it (and with it, the entire foreign substance or microorganism) for destruction by other cells. Antibodies also summon phagocytes and body chemicals, such as complement proteins*, to the site of an infection and move them into action against the antigens.

*antibodies
(AN-tih-bah-deez) are protein molecules produced by the bodys immune system to help fight specific infections caused by microorganisms, such as bacteria and viruses.
*complement proteins
are proteins that circulate in the blood and play a role in the immune systems response to infections. More than 20 complement proteins have been identified.

T cells, the second type, are specialized white blood cells that have several roles. They monitor and coordinate the entire immune response, which includes recruiting many different cells to take part in that response. Some T cells, the T helper cells, signal the B cells to start making antibodies. Other T cells, the T killer cells, attack and destroy substances that they recognize as foreign. Once the foreign antigens have been defeated, cleanup crews of scavenger phagocytes called neutrophils (NU-tro-fils), a type of white blood cell that can surround and destroy invading organisms, and macrophages (MAH-kro-fay-jez), another form of engulf-and-destroy cell, arrive to clear up remains of the infection.

Primary Immune Deficiencies

A genetic* abnormality in any type of cell of the immune system can lead to a primary immune deficiency. Some of these deficiencies produce no symptoms, whereas others cause severe symptoms and may even be fatal. Although primary immune deficiencies are present at birth, some patients do not begin to show signs of the condition until later in childhood or even beyond childhood.

*genetic
(juh-NEH-tik) refers to heredity and the ways in which genes control the development and maintenance of organisms.

There are several well-known primary immune deficiencies. About 1 person in 600 is born with selective IgA deficiency, a mild disease that most often affects those of European ancestry. People with this condition lack immunoglobulin (ih-myoo-no-GLAH-byoo-lin) A (IgA), a class of antibodies that fight organisms that can infect the mucous membranes that line the mouth, airways, and digestive system*. Many patients with this disorder experience few symptoms, but some may have frequent infections.

*digestive system
is the system that processes food. It includes the mouth, esophagus, stomach, intestines, colon, rectum, and other organs involved in digestion, including the liver and pancreas.

The SCID Mouse

To gain a better understanding of the human immune system, scientists developed a laboratory mouse that lacks an enzyme* necessary for its immune system to function properly. Like people with severe combined immunodeficiency disease, these SCID mice cannot fight infections.

*enzyme
(EN-zime) is a protein that helps speed up a chemical reaction in the body.

Another very useful mouse model was developed in the 1980s, when scientists transplanted parts of the human immune system into the mouse. This gave an opportunity to researchers to study the workings of the human immune response more easily, as well as the impact of drugs and viruses on the immune system. This mouse has been described as a living test tube.

The effects of common variable immunodeficiency, also known as hypogammaglobulinemia (hi-po-gah-muh-gloh-byoo-lih-NEE-me-uh), can range from mild to severe. Its symptoms occasionally affect infants but often do not appear until early adulthood. Those symptoms include frequent bacterial infections of the ears, sinuses*, bronchi*, or lungs brought on by low levels of various immunoglobulins, including IgA and IgG.

*sinuses
(SY-nuh-ses) are hollow, air-filled cavities in the facial bones.
*bronchi
(BRONG-kye) are the larger tube-like airways that carry air in and out of the lungs.

Caused by defective genes on the X chromosome*, X-linked agammaglobulinemia (a-gah-muh-gloh-byoo-lih-NEE-me-uh) is uncommon and affects only males. Patients have very low levels of mature B cells as well as low levels of immunoglobulins, which can result in pus* collections in the lungs, sinuses, and ears in addition to other infections.

*chromosome
is a unit or strand of DNA, the chemical substance that contains the genetic code to build and maintain a living being. Humans have 23 pairs of chromosomes, for a total of 46.
*pus
is a thick, creamy fluid, usually yellow or greenish in color, that forms at the site of an infection. Pus contains infection-fighting white cells and other substances.

Severe combined immunodeficiency (ih-myoo-no-dih-FIH-shen-see), also known as SCID or the bubble boy disease, strikes about 1 in a million people. This group of immune disorders is marked by major deficiencies in B cells and T cells, low levels of white blood cells, and decreased levels of IgA, IgG, and IgM antibodies. Such massive defects in the immune system can leave patients open to many serious infections, including pneumonia*, sepsis*, and meningitis*, which can lead to death.

*pneumonia
(nu-MO-nyah) is inflammation of the lung.
*sepsis
is a potentially serious spreading of infection, usually bacterial, through the bloodstream and body.
*meningitis
(meh-nin-JY-tis) is an inflammation of the meninges, the membranes that surround the brain and the spinal cord. Meningitis is most often caused by infection with a virus or a bacterium.

Organisms that typically do not cause problems in a person with a healthy immune system may produce an opportunistic infection in a person with an immune deficiency. A person particularly at risk for such infections might be placed in isolation in a sterile environment. Custom Medical Stock Photo, Inc.

Other primary immune deficiency diseases may involve other components of the immune system, including neutrophils and phagocytes. There may be fewer of these cells produced, as occurs in a condition known as neutropenia (nu-tro-PEE-nee-uh) that is marked by low levels of neutrophils in the blood. Chronic* granulomatous (gran-yoo-LO-muhtus) disease is an immune disorder in which bacteria-fighting phagocytes are present but do not work properly. Genetic defects also can impair the complement system, a series of 20 or more proteins that come together during the bodys immune response to complement, or support, the work of antibodies. These conditions and defects in other parts of the complex immune system cause problems with the bodys immune response, often making a person more susceptible to a variety of infections.

*chronic
(KRAH-nik) means continuing for a long period of time.

Secondary Immune Deficiencies

Secondary immune deficiencies are acquired, rather than inherited, disorders. Many chronic conditions, such as diabetes*, cancer, and cirrhosis* of the liver, make a person more likely to have infections. Patients who have had their spleens removed or whose spleens do not work properly, as occurs in sickle-cell disease*, for example, are especially vulnerable to infection by certain bacteria that the spleen normally fights. In addition, some medications, particularly corticosteroids* and drugs used to treat cancer, may limit the immune system. Malnutrition, especially when there is a lack of protein in the diet, also may weaken a persons immune response.

*diabetes
(dye-uh-BEE-teez) is a condition in which the bodys pancreas does not produce enough insulin or the body cannot use the insulin it makes effectively, resulting in increased levels of sugar in the blood. This can lead to increased urination, dehydration, weight loss, weakness, and a number of other symptoms and complications related to chemical imbalances within the body.
*cirrhosis
(sir-O-sis) is a condition that affects the liver, involving long-term inflammation and scarring, which can lead to problems with liver function.
*sickle-cell disease
is a hereditary condition in which the red blood cells, which are usually round, take on an abnormal crescent shape and have a decreased ability to carry oxygen throughout the body.
*corticosteroids
(kor-tih-ko-STIR-oyds) are chemical substances made by the adrenal glands that have several functions in the body, including maintaining blood pressure during stress and controlling inflammation. They can also be given to people as medication to treat certain illnesses.

The human immunodeficiency virus (HIV), a virus that attacks the immune system and is the cause of acquired immunodeficiency syndrome (AIDS), is responsible for a sharp increase in the number of people with secondary immune deficiencies. HIV destroys T cells, which are crucial to the normal functioning of the human immune system. This can lead to overwhelming infections. People can contract the virus through contact with blood, semen*, vaginal* secretions, and breast milk.

*semen
(SEE-men) is the sperm-containing whitish fluid produced by the male reproductive tract.
*vaginal
(VAH-jih-nul) refers to the vagina, the canal in a woman that leads from the uterus to the outside of the body.

What Are the Signs and Symptoms of Immune Deficiencies?

Immune deficiencies may be characterized by frequent, recurrent, or prolonged infections. In some cases, there may be an overwhelming or unusual infection. In others, organisms that typically do not cause problems in a person with a healthy immune system may produce an opportunistic infection* in a person with an immune deficiency. These infections are seen in people infected with HIV and often mark the onset of AIDS.

*opportunistic infections
are infections caused by infectious agents that usually do not produce disease in people with healthy immune systems but can cause widespread and severe illness in patients with weak or faulty immune systems.

Other immune deficiencies are characterized by chronic opportunistic infections. Depending on the condition, patients may experience recurrent lung and sinus infections, weakness, tiredness, a lingering cough, diarrhea (dye-uh-REE-uh), skin rashes, and hair loss. Many patients simply look sick. Signs of immune deficiencies also include poor response to treatments, incomplete or slow recovery from illness, fungal or yeast infections that keep coming back, and certain specific infections, such as pneumonia caused by Pneumocystis carinii (nu-mo-SIS-tis kah-RIH-nee-eye).

How Do Doctors Make the Diagnosis?

Although symptoms of opportunistic infections may suggest an immune deficiency, laboratory tests are needed to diagnose the specific deficiency. These include blood tests to measure levels of white blood cells, red blood cells, and platelets* and to measure the presence of specific types of cells, such as B cells and T cells. Other blood tests can measure the levels or function of antibodies (such as IgA, IgG, and IgM) and complement proteins. Skin tests may be done to check the responses of T cells. Other, more specific tests of the immune systems competency depend on the type of deficiency suspected.

*platelets
(PLATE-lets) are tiny disk-shaped particles within the blood that play an important role in clotting.

How Are Immune Deficiencies Treated?

The primary goal of treating immune deficiencies is to prevent infections. Although it is a good idea for some people who have immune deficiencies to avoid contact with people who have infections, this is not always practical. Many patients take daily medication to prevent certain infections, and patients with antibody deficiencies may receive regular doses of the immunoglobulins they lack. People who have HIV or AIDS take combinations of drugs to keep the virus from making more copies of itself and destroying more T cells. Bone marrow* transplantation, to replace the absent or poorly functioning immune system cells of the affected person, is necessary for some patients with severe immune deficiencies, such as SCID. Prompt recognition and treatment of infections, including opportunistic infections, is essential.

*bone marrow
is the soft tissue inside bones where blood cells are made.

See also

AIDS and HIV Infection

Body Defenses

Meningitis

Pneumonia

Sepsis

Resources

Organizations

Immune Deficiency Foundation, 40 W. Chesapeake Avenue, Suite 308, Towson, MD 21204. The Immune Deficiency Foundation offers information on primary immune deficiencies and an overview of the immune system just for kids at its website.

Telephone 800-296-4433 http://www.primaryimmune.org

Jeffrey Modell Foundation, 747 Third Avenue, New York, NY 10017. The Jeffrey Modell Foundation is a nonprofit research foundation devoted to primary immune deficiencies.

Telephone 212-819-0200 http://www.jmfworld.org

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immune system

immune system System by which the body defends itself against disease. It involves many kinds of leucocytes (white blood cells) in the blood, lymph and bone marrow. Some of the cells (B-cells) make antibodies against invading microbes and other foreign bodies (antigens), or neutralize toxins produced by pathogens, while other antibodies encourage two types of leucocytes, phagocytes and macrophages, to attack and digest invaders. T-cells also provide a variety of functions in the immune system. See also interferon

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immune system

immune system Series of defence mechanisms of the body. There are two major parts: humoral, mediated through antibodies secreted into the circulation (immunoglobulins); and cell‐mediated. Lymphocytes produce antibodies against, and bind to, the antigens of foreign cells, leading to death of the invading organisms; other white blood cells are phagocytic and engulf the invading organisms.

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Immune System

Immune System

History

Organs of the immune system

Overview of the immune system

The nonspecific defenses

Specific immune defenses

A closer look at antibodies

How antibodies work to destroy invaders

T cells and the cell-mediated response

How is the immune response turned off?

Current research

Resources

The immune system protects the body from disease-causing microorganisms. It consists of two levels of protection, the non-specific defenses and the specific defenses. The non-specific defenses, such as the skin and mucous membranes, prevent microorganisms from entering the body. The specific defenses are activated when microorganisms evade the non-specific defenses and invade the body. Only starting in the nineteenth century and continuing into the twentieth century have the components of the immune system and the ways in which it works been discovered. More remains to be clarified in the twenty-first century.

The human body is constantly bombarded with microorganisms, many of which can cause disease. Some of these microorganisms are viruses, such as those that cause colds and influenza; other microorganisms are bacteria, such as those that cause pneumonia and food poisoning. Still other microorganisms are parasites or fungi. Usually, the immune system is so efficient that most people are unaware of the battle that takes place almost everyday, as the immune system rids the body of harmful invaders. However, when the immune system is injured or destroyed, the consequences are severe. For instance, acquired immune deficiency syndrome (AIDS) is caused by a virus human immunodeficiency virus (HIV)that attacks a key immune system cell, the helper T-cell lymphocyte. Without these cells, the immune system cannot function. People with AIDS cannot fight off the microorganisms that constantly bombard their bodies, and eventually succumb to infections that a healthy immune system would effortlessly neutralize.

History

Since ancient times, medical observers had noticed that the body seemed to have powers to protect itself and resist disease. In particular, people who survived some infectious diseases did not suffer from those diseases again during their lifetime. This led to the practice of variolation in Asia, whereby people were injected with a mild case of smallpox to prevent the later development of a severe case of the disease. Lady Mary Wortley-Montague (16891762) introduced variolation to Britain from the Ottoman Empire in 1720. The procedure was rather dangerous, however, because the injected person could develop an acute rather than mild case of smallpox, which could lead to an epidemic.

The true roots of immunology-or the study of the immune system-date from 1796 when English physician

Edward Jenner (17491823) discovered a method of smallpox vaccination. He noted that dairy workers who contracted cowpox from milking infected cows were thereafter resistant to smallpox. In 1796, Jenner injected a young boy with material from a milkmaid who had an active case of cowpox. After the boy recovered from his own resulting cowpox, Jenner inoculated him with smallpox; the boy was immune. After Jenner published the results of this and other cases in 1798, the practice of Jennerian vaccination spread rapidly.

It was French microbiologist Louis Pasteur (18221895) who established the cause of infectious diseases and the medical basis for immunization. First, Pasteur formulated his germ theory of diseasethe concept that disease is caused by communicable microorganisms. In 1880, Pasteur discovered that aged cultures of fowl cholera bacteria lost their power to induce disease in chickens but still conferred immunity to the disease when injected. He went on to use attenuated (weakened) cultures of anthrax and rabies to vaccinate against those diseases. American scientists Theobald Smith (18591934) and Daniel Salmon (18501914) showed in 1886 that bacteria killed by heat could also confer immunity.

Why vaccination imparted immunity was not yet known. In 1888, Pierre-Paul-Emile Roux (18531933) and Alexandre Yersin (18631943) showed that diphtheria bacillus produced a toxin that the body responded to by producing an antitoxin. German bacteriologist Emil von Behring (18541917) and Japanese

physician Shibasaburo Kitasato (18521931) found a similar toxin-antitoxin reaction in tetanus in 1890. They discovered that small doses of tetanus or diphtheria toxin produced immunity, and that this immunity could be transferred from animal to animal via serum. Von Behring concluded that the immunity was conferred by substances in the blood, which he called antitoxins, or antibodies. In 1894, Richard Pfeiffer (18581945) found that antibodies killed cholera bacteria (bacterioloysis). German bacteriologist Hans Buchner (18501902) in 1893 discovered another important blood substance called complement (Buchners term was alexin), and Belgian bacteriologist Jules Bordet (18701961) in 1898 found that it enabled the antibodies to combine with antigens (foreign substances) and destroy or eliminate them. It became clear that each antibody acted only against a specific antigen. Austrian American immunologist and pathologist Karl Landsteiner (18681943) was able to use this specific antigen-antibody reaction to distinguish the different blood groups.

A new element was introduced into the growing body of immune system knowledge during the 1880s by the Russian microbiologist Elie Metchnikoff (18451916). He discovered cell-based immunity: white blood cells (leucocytes), which Metchnikoff called phagocytes, ingested and destroyed foreign particles. Considerable controversy flourished between the proponents of cell-based and blood-based immunity until 1903, when British bacteriologist and immunologist Sir Almroth Edward Wright (18611947) brought them together by showing that certain blood substances were necessary for phagocytes to function as bacteria destroyers. A unifying theory of immunity was posited by German scientist Paul Ehrlich (18541915) in the 1890s; his side-chain theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until now, immune responses were seen as purely beneficial. In 1902, however, French physiologist Charles Richet (18501935) and French physiologist Paul Portier (18661962), demonstrated extreme immune reactions in test animals that had become sensitive to antigens by previous exposure. This phenomenon of hypersensitivity, called anaphylaxis, showed that immune responses could cause the body to damage itself. Hypersensitivity to antigens also explained allergies, a term coined by Austrian physician Clemens von Pirquet in 1906.

By the early 1900s immunology had become an established medical field with its own journals, first in Germany in 1909 and then in the United States in 1916 (the latter published by the worlds first immunology society, founded in 1913).

Much more was learned about antibodies in the mid-twentieth century, including the fact that they are proteins of the gamma globulin portion of plasma and are produced by plasma cells; their molecular structure was also worked out. An important advance in immunochemistry came in 1935 when Michael Heidelberger (18811991) and Edward Kendall (18861972) developed a method to detect and measure amounts of different antigens and antibodies in serum. Immunobiology also advanced. Australian biologist Sir Frank Macfarlane Burnet (18991985) suggested that animals did not produce antibodies to substances they had encountered very early in life; Brazilian-born British zoologist Peter Medawar (19151987) proved this idea in 1953 through experiments on mouse embryos.

In 1957, Burnet put forth his clonal selection theory to explain the biology of immune responses. On meeting an antigen, an immunologically responsive cell (shown by C.S. Gowans [1923] in the 1960s to be a lymphocyte) responds by multiplying and producing an identical set of plasma cells, which in turn manufacture the specific antibody for that antigen. Further cellular research has shown that there are two types of lymphocytes (nondescript lymph cells): B-lymphocytes, which secrete antibody, and T-lymphocytes, which regulate the B-lymphocytes and either kill foreign substances directly (killer T cells) or stimulate macrophages to do so (helper T cells). Lymphocytes recognize antigens by characteristics on the surface of the antigen-carrying molecules. Researchers in the 1980s uncovered many more intricate biological and chemical details of the immune system components and the ways in which they interact.

Knowledge about the immune systems role in rejection of transplanted tissue became extremely important as organ transplantation became surgically feasible. Peter Medawars work in the 1940s showed that such rejection was an immune reaction to antigens on the foreign tissue. Canadian neurologist Donald Calne (1936) showed in 1960 that immunosuppressive drugsdrugs that suppress immune responsesreduced transplant rejection, and these drugs were first used on human patients in 1962. In the 1940s, American geneticist George D. Snell (19031996) discovered in mice a group of tissue-compatibility genes that played an important role in controlling acceptance or resistance to tissue grafts. French immunologist Jean Dausset (1916) found human MHC (major histocompatability complex), a set of antigens to human leucocytes (white blood cells), called HLA (human leucocyte antigen). Matching of HLA in donor and recipient tissue is an important technique to predict compatibility in transplants. Venezuelanborn American immunologist Baruj Benacerraf (1920) in 1969 showed that an animals ability to respond to an antigen was controlled by genes in the MHC complex.

In the late 1960s, Ion Gresser (1928) discovered that the protein interferon acts against cancerous tumors. After the development of genetically engineered interferon in the mid1980s finally made the substance available in practical amounts, research into its use against cancer accelerated. The invention of monoclonal antibodies in the mid1970s was a major breakthrough. Increasingly sophisticated knowledge about the workings of the immune system holds out the hope of finding an effective method to combat one of the most serious immune system disorders, AIDS (acquired immune deficiency syndrome).

Organs of the immune system

The organs of the immune system either make the cells that participate in the immune response or act as sites for immune function. These organs include the lymphatic vessels, lymph nodes, tonsils, thymus, Peyers patch, and spleen. The lymph nodes are small aggregations of tissues interspersed throughout the lymphatic system. White blood cells (lymphocytes) that function in the immune response are concentrated in the lymph nodes. Lymphatic fluid circulates through the lymph nodes via the lymphatic vessels. As the lymph filters through the lymph nodes, foreign cells of microorganisms are detected and overpowered.

The tonsils contain large numbers of lymphocytes. Located at the back of the throat and under the tongue, the tonsils filter out potentially harmful bacteria that may enter the body via the nose and mouth. Peyers patches are lymphatic tissues that perform this same function in the digestive system. Peyers patches are scattered throughout the small intestine and the appendix. They are also filled with lymphocytes that are activated when they encounter disease-causing microorganisms.

The thymus gland is another site of lymphocyte production. Located within the upper chest region, the thymus gland is most active during childhood when it makes large numbers of lymphocytes. The lymphocytes made here do not stay in the thymus, however; they migrate to other parts of the body and concentrate in the lymph nodes. The thymus gland continues to grow until puberty; during adulthood, however, the thymus shrinks in size until it is sometimes impossible to detect in x rays.

Bone marrow, found within the bones, also produces lymphocytes. These lymphocytes migrate out of the bone marrow to other sites in the body. Because bone marrow is an integral part of the immune system, certain bone cancer treatments that require the destruction of bone marrow are extremely risky, because without bone marrow, a person cannot make lymphocytes. People undergoing bone marrow replacement must be kept in strict isolation to prevent exposure to viruses or bacteria.

The spleen acts as a reservoir for blood and any rupture to the spleen can cause dangerous internal bleeding, a potentially fatal condition. The spleen also destroys worn-out red blood cells. Moreover, the spleen is also a site for immune function, since it contains lymphatic tissue and produces lymphocytes.

Overview of the immune system

For the immune system to work properly, two things must happen: First, the body must recognize that it has been invaded by foreign microorganisms. Second, the immune response must be quickly activated before many body tissue cells are destroyed by the invaders.

How the immune system recognizes foreign invaders

The cell membrane of every cell is studded with various proteins that protrude from the surface of the membrane. These proteins are a kind of name tag called the major histocompatibility complex (MHC). They identify all the cells of the body as belonging to the self. An invading microorganism, such as a bacterium, does not have the self MHC on its surface. When an immune system cell encounters this non-self cell, it alerts the body that it has been invaded by a foreign cell. Every person has their own unique MHC. For this reason, organ transplants are often unsuccessful because the immune system interprets the transplanted organ as foreign, since the transplanted organ cells have a non-self MHC. Organ recipients usually take immunosuppressant drugs to suppress the immune response, and every effort is made to transplant organs from close relatives, who have genetically similar MHCs.

In addition to a lack of the self MHC, cells that prompt an immune response have foreign molecules (called antigens) on their membrane surfaces. An antigen is usually a protein or polysaccharide complex on the outer layer of an invading microorganism. The antigen can be a viral coat, the cell wall of a bacterium, or the surface of other types of cells. Antigens are extremely important in the identification of foreign microorganisms. The specific immune response depends on the ability of the immune lymphocytes to identify the invader and create immune cells that specifically mark the invader for destruction.

How the two defenses work together

The immune system keeps out microorganisms with nonspecific defenses. Nonspecific defenses do not involve identification of the antigen of a microorganism; rather the nonspecific defenses simply react to the presence of a non-self cell. Oftentimes, these nonspecific defenses effectively destroy microorganisms. However, if they are not effective and the microorganisms manage to infect tissues, the specific defenses are activated. The specific defenses work by recognizing the specific antigen of a microorganism and mounting a response that targets the microorganism for destruction by components of the non-specific system. The major difference between the non-specific defenses and the specific defenses is that the former impart a general type of protection against all kinds of foreign invaders, while the specific defenses create protection that is tailored to match the particular antigen that has invaded the body.

The nonspecific defenses

The nonspecific defenses consist of the outer barriers, the lymphocytes, and the various responses that are designed to protect the body against invasion by any foreign microorganism.

Barriers: skin and mucous membranes

The skin and mucous membranes act as effective barriers against harmful invaders. The surface of the skin is slightly acidic, which makes it difficult for many microorganisms to survive. In addition, the enzyme lysozyme, which is present in sweat, tears, and saliva, kills many bacteria. Mucous membranes line many of the bodys entrances, such as those that open into the respiratory, digestive, and uro-genital tract. Bacteria become trapped in the thick mucous layers and are thus prevented from entering the body. In the upper respiratory tract, the hairs that line the nose also trap bacteria. Any bacteria that are inhaled deeper into the respiratory tract are swept back out again by the cilia-tiny hairs-that line the trachea and bronchii. One reason why smokers are more susceptible to respiratory infections is that hot cigarette smoke disables the cilia, slowing the movement of mucus and bacteria out of the respiratory tract. Within days of quitting smoking, the cilia regenerate and new non-smokers then cough and bring up large amounts of mucus, which eventually subsides.

Nonspecific immune cells

Nonspecific lymphocytes carry out search-and-destroy missions within the body. If these cells encounter a foreign microorganism, they will either engulf the foreign invader or destroy the invader with enzymes. The following is a list of non-specific lymphocytes:

Macrophages are large lymphocytes that engulf foreign cells. Because macrophages ingest other cells, they are also called phagocytes (phagein, to eat; kytos, cell).

Neutrophils are cells that migrate to areas where bacteria have invaded, such as entrances created by cuts in the skin. Neutrophils phagocytize microorganisms and release microorganism-killing enzymes. Neutrophils die quickly; pus is an accumulation of dead neutrophils.

Natural killer cells kill body cells infected with viruses, by punching a hole in the cell membrane, causing the cell to lyse, or break apart.

The inflammatory response

The inflammatory response is an immune response confined to a small area. When a finger is cut, the area becomes red, swollen, and warm. These signs are evidence of the inflammatory response. Injured tissues send out signals to immune system cells, which quickly migrate to the injured area. These immune cells perform different functions: some engulf bacteria, while others release bacteria-killing chemicals. Other immune cells release a substance called histamine, which causes blood vessels to become wider (dilate), thus increasing blood flow to the area. All of these activities promote healing in the injured tissue.

An inappropriate inflammatory response is the cause of allergic reactions. When a person is allergic to pollen, the bodys immune system is reacting to pollen (a harmless substance) as if it was a bacterium and an immune response is prompted. When pollen is inhaled it stimulates an inflammatory response in the nasal cavity and sinuses. Histamine is released that dilates blood vessels, and also causes large amounts of mucous to be produced, leading to a runny nose. In addition, histamine stimulates the release of tears and is responsible for the watery eyes and nasal congestion typical of allergies.

To combat these reactions, many people take drugs that deactivate histamine. These drugs, called antihistamines, are available over-the-counter and by prescription. Some allergic reactions, involve the production of large amounts of histamine that impairs breathing and necessitates prompt emergency care. People prone to these extreme allergic reactions must carry a special syringe with epinephrine (adrenalin), a drug that quickly counteracts this severe respiratory reaction.

Complement

The complement system is a group of more than 20 proteins that complement other immune responses. When activated, the complement proteins perform a variety of functions: they coat the outside of microorganisms, making them easier for immune cells to engulf; they stimulate the release of histamine in the inflammatory response; and they destroy virus-infected cells by puncturing the plasma membrane of the infected cell, causing the cell to burst open.

Specific immune defenses

The specific immune response is activated when microorganisms evade the nonspecific defenses. Two types of specific defenses destroy microorganisms in the human body: the cell-mediated response and the antibody response. The cell-mediated response attacks cells that have been infected by viruses. The antibody response attacks both free viruses that have not yet penetrated cells, and bacteria, most of which do not infect cells. However, some bacteria, such as the myco-bacteria that cause tuberculosis, do infect cells.

Specific immune cells

Two kinds of lymphocytes operate in the specific immune response: T lymphocytes and B lymphocytes, (T lymphocytes are made in the thymus gland, while B lymphocytes are made in bone marrow). The T and B lymphocytes migrate to other parts of the lymphatic system, such as the lymph nodes, Peyers patches, and tonsils. Non-specific lymphocytes attack any foreign cell, while B and T lymphocytes are individually configured to attack a specific antigen. In other words, the blood and lymph of humans have T-cell lymphocytes that specifically target the chickenpox virus, T-cell lymphocytes that target the diphtheria virus, and so on. When T-cell lymphocytes specific for the chickenpox virus encounter a body cell infected with this virus, the T cell multiplies rapidly and destroying the invading virus.

Memory cells

After the invader has been neutralized, some T cells remain behind. These cells, called memory cells, impart immunity to future attacks by the virus. Once a person has had chickenpox, memory cells quickly stave off subsequent infections. This secondary immune response, involving memory cells, is much faster than the primary immune response.

Some diseases, such as smallpox, are so dangerous that it is better to artificially induce immunity rather than to wait for a person to create memory cells after an infection. Vaccination injects whole or parts of killed viruses or bacteria into the bloodstream, prompting memory cells to be made without a person developing the disease.

Helper T cells

Helper T cells are a subset of T-cell lymphocytes that play a significant role in both the cell-mediated and antibody immune responses. Helper T cells are present in large numbers in the blood and lymphatic system, lymph nodes, and Peyers patches. When one of the bodys macrophage cells ingests a foreign invader, it displays the antigen on its membrane surface. These antigen-displaying-macrophages, or APCs, are the immune systems distress signal. When a helper T cell encounters an APC, it immediately binds to the antigen on the macrophage. This binding unleashes several powerful chemicals called cytokines. Some cytokines, such as interleukin I, stimulate the growth and division of T cells. Other cytokines play a role in the fever response, another nonspecific immune defense. Still another cytokine, called interleukin II, stimulates the division of cytotoxic T cells, key components of the cell-mediated response. The binding also turns on the antibody response. In effect, the helper T cells stand at the center of both the cell-mediated and antibody responses.

Any disease that destroys helper T cells destroys the immune system. HIV infects and kills helper T cells, so disabling the immune system and leaving the body helpless to stave off infection.

B cells and the antibody response

B-cell lymphocytes, or B cells, are the primary players in the antibody response. When an antigen-specific B cell is activated by the binding of an APC to a helper T cell, it begins to divide. These dividing B cells are called plasma cells. The plasma cells, in turn, secrete antibodies, proteins that attach to the antigen on bacteria or free viruses, marking them for destruction by macrophages or complement. After the infection has subsided, a few memory B cells persist that confer immunity.

A closer look at antibodies

Antibodies are made when a B cell specific for the invading antigen is stimulated to divide by the binding of an APC to a helper T cell. The dividing B cells, called plasma cells, secrete proteins called antibodies. Antibodies are composed of a special type of protein called immunoglobin (Ig). An antibody molecule is Y-shaped and consists of two light chains joined to two heavy chains. These chains vary significantly between antibodies. The variable regions make antibodies antigen-specific. Constant regions, on the other hand, are relatively the same between antibodies. All antibody molecules, whether made in response to a chickenpox virus or to a Salmonella bacterium, have some regions that are similar.

How antibodies work to destroy invaders

An antibody does not itself destroy microorganisms. Instead, the antibody that has been made in response to a

KEY TERMS

Antibody response The specific immune response that utilizes B cells to neutralize bacteria and free viruses.

Antigen-presenting cell (APC) A macrophage that has ingested a foreign cell and displays the antigen on its surface.

B lymphocyte Immune system white blood cell that produces antibodies.

Cell mediated response-The specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria.

Complement system A series of 20 proteins that complement the immune system; complement proteins destroy virus-infected cells and enhance the phagocytic activity of macrophages.

Cytotoxic T cell A T lymphocyte that destroys virus-infected cells in the cell-mediated immune response.

Helper T lymphocyte The lynch pin of specific immune responses; helper T cells bind to APCs (antigen-presenting cells), activating both the antibody and cell-mediated immune responses.

Inflammatory response A non-specific immune response that causes the release of histamine into an area of injury; also prompts blood flow and immune cell activity at injured sites.

Lymphocyte White blood cell.

Macrophage An immune cell that engulfs foreign cells.

Major histocompatibility complex (MHC) The proteins that protrude from the surface of a cell that identify the cell as self.

Memory cell The T and B cells that remain behind after a primary immune response; these cells swiftly respond to subsequent invasions by the same microorganism.

Natural killer cell An immune cell that kills infected tissue cells by punching a hole in the cell membrane.

Neutrophil An immune cell that releases a bacteria-killing chemical; neutrophils are prominent in the inflammatory response.

Nonspecific defenses Defenses such as barriers and the inflammatory response that generally target all foreign cells.

Phagocyte A cell that engulfs another cell.

Plasma cell A B cell that secretes antibodies.

Primary immune response The immune response that is elicited when the body first encounters a specific antigen.

Secondary immune response The immune response that is elicited when the body encounters a specific antigen a second time; due to the presence of memory cells, this response is usually much swifter than the primary immune response.

Specific defenses Immune responses that target specific antigens; includes the antibody and cell-mediated responses.

Suppressor T cell T lymphocytes that deactivate T and B cells.

T cells Immune-system white blood cells that enable antibody production, suppress antibody production, or kill other cells.

Vaccination Inducing the body to make memory cells by artificially introducing antigens into the body.

specific microorganism binds to the specific antigen on its surface. With the antibody molecule bound to its antigen, the microorganism is targeted by destructive immune cells like macrophages and NK cells. Antibody-tagged microorganisms can also be destroyed by the complement system.

T cells and the cell-mediated response

T-cell lymphocytes are the primary players in the cell-mediated response. When an antigen-specific helper T cell is activated by the binding of an APC, the cell multiplies. The cells produced from this division are called cytotoxic T cells. Cytotoxic T cells target and kill cells that have been infected with a specific microorganism. After the infection has subsided, a few memory T cells persist, so conferring immunity.

How is the immune response turned off?

Chemical signals activate the immune response and other chemical signals must turn it off. When all the invading microorganisms have been neutralized, special T cells (called suppressor T cells) release cyto-kines that deactivate the cytotoxic T cells and the plasma cells.

Current research

For many years it was believed that the immune system responded only to invading antigens and was not influenced by psychological events. However, building on research that began in the mid1960s, scientists have determined that the immune system is also affected by a persons psychological health, or state of mind. This branch of research is referred to as pscyhoimmunology, or psychoneuroimmunology (the study of the relationship among psychology, neurology, and immunology). A complex network of nerves, hormones, and neuropeptides appear to link the immune system and an individuals psyche. For example, extreme psychological stress has been shown to suppress the immune system and accelerate disease in people with HIV (human immunodeficiency virus). (Short-term stress is believed to have certain benefits to the body.) Other psychosocial factorssuch as a fixation on dying, clinical depression, a lack of purpose in life, inability to be assertive, and lack of a supportive network of friends and familymay also affect the immune system. Research into pscyhoim-munology focuses on treatments that can impact stress levels and other psychological factors.

Advances in immunological research indicate that the immune system may be made of more than 100 million highly specialized cells designed to combat specific antigens. While the task of identifying these cells and their functions may be daunting, headway is being made. By identifying these specific cells, researchers may be able to further advance another promising area of immunological researchthe use of recombinant DNA technology, in which specific proteins can be mass produced. This approach has led to new cancer treatments that can stimulate the immune system by using synthetic versions of proteins released by interferons.

See also Allergy; Antibody and antigen; Cyclosporine; Immunology; Inflammation; Vaccine.

Resources

BOOKS

Parham, Peter. The Immune System. New York: Garland Science, 2005.

Richman, D.D., and R.J. Whitley. Clinical Virology. 2nd ed. Washington, DC: American Society for Microbiology, 2002.

Sompayrac, Lauren. How the Immune System Works. Malden, MA: Blackwell Pub., 2003.

PERIODICALS

Travis, John. Tracing the Immune Systems Evolutionary History. Science 261 (9 July 1993): 164.

Kathleen Scogna

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Immune System

Immune System

Definition

The immune system is composed of cells, organs, tissues, and molecules that protect the body from disease. The term "immunity" comes from the Latin word immunitas. It is roughly divided into two branches, "innate immunity" and "acquired (adaptive) immunity". These two branches may interact to produce an immune response to protect the body from attack by infectious bacteria, viruses, parasites, or fungi, as well as abnormal conditons that may arise, such as cancer. Innate immunity refers to immunity that does not require prior contact with the attacking pathogen (organism that causes disease) in order to quickly initiate protective measures, rather, this type of immunity may be thought of as a defense system that is waiting on "stand-by" for attack by an unknown enemy, attempting to identify and destroy it. The other type of immunity, specific acquired immunity or adaptive immunity, acts somewhat like a "special forces unit" that develops in response to a specific, recognized enemy. Acquired immunity may arise as a result of previous exposure to a pathogen (ie. the immunity one would obtain from a vaccination) or called into action by the innate immune sytstem. Though very specific, acquired immunity requires time for development. Both branches of immunity, innate and acquired, work together in a coordinated effort to mount an amazingly orchestrated immune response to pathogenic attack, injury, and disease.

Description

Innate Immunity

Some form of innate immunity can be found in a wide variety of organisms, ranging from plants, worms and fruit flies all the way to animals and humans. This ancient form of immunity has evolved as the first line of defense in the protection from disease. In humans, this type of immune response was once thought to be a non-specific, and was previously referred to as "non-specific immunity". It is now known, however, to involve specialized molecules (pattern recognition receptors) that have evolved over time that recognize specific molecular patterns on the surfaces of pathogens. In this regard, innate immunity is very efficient and works rapidly (within minutes) to develop an immune response. Innate immunity is involved in the protection of the body by preventing the offending pathogen from spreading by capturing it in phagocytic cells where they can be destroyed. It also assists in the recognition of molecules that are considered to be "non-self " (not part of the body) and presents them to the acquired immune system. The innate immune system is comprised of several elements that work in a coordinated fashion: physical barriers, phagocytic cells, pattern recognition receptors, immune pathways (complement and lectin), chemical messagers (ie. cytokines, chemokines, interferons). Clearly, the interactions between all of these players are highly complex, and many details await discovery with critical implications for the prevention and management of disease.

PHYSICAL BARRIERS. Anatomic barriers provide the first line of protection against invading bacterial and viral pathogens. Layers of epithelial cells form a protective, physical barrier between the body and the world of harmful pathogens that lies outside. Epithelial cells are found in the skin, and line the openings of the body that permit entrance air and food, and passage of waste; the respiratory, gastrointestinal, and urogenital tracts. The skin is composed primarily of keratin, which cannot be digested by most microorganisms. The skin is usually dry with a high salt concentration due to sweat, and this environment may not be condusive for the growth of most types of bacteria. Sweat and sebaceous skin secretions also contain substances that kill bacteria and viruses. Some examples are lysozyme (an enzyme found in saliva, sweat, and tears), fatty acids, and lactic acid, which generates a low ph in which some bacteria can not survive. Further, the fluid nature of saliva, sweat, tears, and urine helps to wash away harmful invading pathogens. Other bodily fluids kill bacteria, such as the acidic gastric juices produced in the stomach, bile salts in the gastrointestinal tract, lactoperoxidase found in milk, and substances called defensins that are found in the gastrointestinal, urogenital, and respiratory tracts. Taken together, such secreted factors inhibit the growth of most kinds of bacteria.

Often, the invading pathogens first encounter the mucosal epithelia surfaces that are are found in areas such as lungs, respiratory, gastrointestinal, and urogenital tracts. These areas are lined with epithelial cells and a mucus layer that prevents the attachment of the pathogens. Epithelial cells may be rapidly shed in areas such as the intestine, quickly eliminating infected cells from the system. The mucosal surfaces may secrete lysozyme and other substances such as lactoferrin, a protein which binds to iron and traps it so that it can not be used by invading bacteria for growth. The cilia of the lung lungs are small, fine projections that help to move bacteria trapped in mucus out of the lungs and nose during coughing and sneezing, transporting secretions to the throat where they can be swallowed and destroyed by stomach acid. The lungs also produce surfactant proteins that help special cells of the immune system, the macrophages, engulf and destroy pathogens.

There are some types of bacteria, the "microflora", that inhabit the skin surface, yet do not cause disease under normal conditions. The microflora may produce substances that kill other more harmful, pathogenic bacteria and fungi. The microflora may also consume some of the nutrients required by other pathogens. This gives rise to a competitive relationship between the microflora and the pathogens that limits the growth of the pathogens. In this regard, the microflora provide a helpful, delicate balance that helps to protect the body from disease.

molecules and cells involved in innate immunity.

Pattern Recognition Receptors

Upon initial invasion into the body, as when the skin is broken due to injuries or burns, harmful bacteria may enter and establish a site of infection. Bacteria, viruses fungi, and parasites may be recognized by special molecules of the innate immune system called "pattern recognition receptors" (PRR). These receptors, found on a variety of cells in the body, recognize specific, common molecular patterns on pathogens that are required for their growth and survival (pathogen-associated molecular patterns or PAMPs). This highly efficient strategy allows the cells of the immune system to recognize a variety of harmful pathogens using a smaller pool receptors, thus greatly simplifying the process. Pattern recognition receptors (PPRs) are of several basic types, including acute phase proteins, transmembrane proteins (those that span the membrane of the host cell), as well as intracellular PRR that can identify bacteria and viruses. During the course of an infection, several types of PRR may be used to fight an infection. The acute phase proteins are involved in the inflammatory reaction that results in the development of a fever during an infection or an injury. One such acute phase protein, CRP (C-reactive protein), acts as a antibacterial protein, and high levels of this protein in the blood may indicate the presence of an infection or a chronic disease. Another acute phase protein, Mannan Binding Lectin (MBL), recognizes a pattern of sugar molecules found in bacteria and viruses and assists in their destruction without affecting the host cells. Additional acute phase proteins include clotting factors and fibrinogen, which helps to prevent the pathogens from spreading through the bloodstream, some components of the complement proteins (see below), protease inhibitors, proteins involved in transport, and proteins such as alpha-1 glycogprotein and serum amyloid A. Of the transmembrane proteins, one particularily well-studied group is the Toll-like receptors. These receptors, named after receptors with similar structure identified in fruit flies (Drosophila melanogaster), are involved in the production of antimicrobial peptides. The Toll-like receptors in mammals, including humans, are found in many tissues on the surfaces of immune cells such as dendritic cells and macrophages (see below). Once the Toll-like receptors recognize PAMPs on the pathogens, they may quickly jump-start a more specific immune response by causing the activation of special cells, the antigen presenting cells (APC), to display portions of the foreign pathogens to the aquired immune system. The Toll-like receptors also cause phagocytic cells, such as macrophages and dendritic cells, to produce substances called cytokines and chemokines.

Cytokines, Chemokines, and Interferons

Cytokines are special proteins that are secreted by activated cells that influence the behavior of the cells that have secreted them (an autocrine activity) or act on other cells (a paracrine activity). If they are able to enter the circulatory system and remain stable in the blood, they may act on cells farther away in the body (an endocrine activity). In general, cytokines may be thought of as the "communicators" of the immune system, working in both innate and acquired immunity. Some roles of cytokines include the activation of lymphocytes, increasing the vascular permeability (leaking) of the endothelial cells in the blood vessels, increasing the production of antibodies, recruitment of immune cells, activation of Natural Killer cells, and affecting the differention of T cells (see below). Cytokines are also involved in the generation of a fever, which helps the body by genrating a more intensive acquired (adaptive) immune response and makes it more difficult for some pathogens to grow. Chemokines are special types of proteins that affect other cells and attract them to sites of infection, and are involved in wound healing and affect the growth of tumors. Chemokines may also help to link the innate and adaptive immune systems together so that they can work in a coordinated way to eliminate the pathogens. Cytokines and chemokines, working together, constitute an immune response known as inflammation, which may be clinically observed by redness, swelling, pain, and heat. Interferons (Interferon alpha and beta) are proteins that are produced when a cell is attacked and infected by a virus, and may prevent the spread of the virus to healthy cells. Interferons also activate the Natural Killer Cells (NK), a type of immune cell that can kill cells that are infected with viruses and those that harbor microbes within them.

Complement

The complement system is a group of proteins in the plasma or on cell surfaces that work together to cause inflammation and help to opsonize pathogens (coating them to enhance their uptake by immune cells for phagocytosis). The complement proteins become activated in areas of infection and initiate a series of enzymatic reactions that promote inflammation and lysis of the pathogens. Some parts of the complement proteins draw phagocytic cells (see below) to the site of infections, while other parts of complement may form membrane-attack complexes that damage bacteria by putting holes (pores)in their membranes.

Phagocytic Cells

If a microrganism or other particle is able to invade the physical barriers of the body, there are a number of cells in the circulation that will recognize the pathogen, using pattern recognition receptors, and will respond to the attack. The polymorphonuclear leukocytes (PMNs) are a group of cells that display a characteristic staining of granules in blood smears. These cells have a short life span in the blood (about two or three days), and make up the majority of the white blood cells under normal conditions (approximately 40-75% of the blood). The neutrophils are some of the first responders to the site of an infection and are critical in the development of the immune response to pathogens. In response to cytokines produced by other cells, the neutrophil progenitor cells in the bone marrow rapidly produced large numbers of neutrophils that enter the bloodstream. The neutrophils can then migrate from the blood into the tissues during infection by a process known as chemotaxis (the movement of cells in response to and external chemical stimulation). Once they encounter a pathogen or particle and recognize it, they may engulf it by a process known as phagocytosis, whereby a part of the neutrophils cell membrane engulfs the pathogen or particle and encloses it inside the cell within a vesicle called a phagosome where it may be destroyed by molecules that can kill it, such as lysozyme, myeloperoxidase, defensins, and lactoferrin. Neutrophils that have phagocytized a pathogen and destroyed it die shortly thereafter, and they are a large amount of the pus that is formed during some bacterial infections.

Special types of cells, the myeloid progenitor cells, reside within the bone marrow. These cells develop into monocytes that enter the blood stream where they compose 2-10% of the blood. After approximately one or two days, the monocytes then migrate into the tissues and become macrophages, where they may survive for long periods of time. The macrophages take on certain traits that depend on the type of tissue in which they are residing (alveolar macrophagesin the lung, Kupffer cells in the liver, microglial cells in the brain, spleen, lymph nodes, etc). This distribution of macrophages throughout the body is called the mononuclear phagocyte system, which acts somewhat like a giant "filter", assisting in the removal and destruction of harmful pathogens such as bacteria and fungi, as well as particles, dead cells, dust, etc. Like neutrophils, macrophages are capable of removing and ingesting microorganisms by a process phagocytosis. Macrophages may destroy phagocytized pathogens they have entrapped with lysosomal enzymes and special molecules called ROI (reactive oxygen intermediates), nitric oxide, and lysosomal proteases. Macrophages also produce cytokines, help heal injured tissue, and cause other types of acquired immune cells, the T cells, to become active.

Other Cells With a Role in Innate Immunity

Dendritic cells are potent stimulators of immune responses. These cells engulf the pathogen, become activated, and travel to the lymph nodes where they become antigen presenting cells (APC), and help to initiate an acquired immune response. The dendritic cells also play an important role in the increased immune response upon a second exposure to an antigen, and are distributed throughout the body, especially in the T-cell areas of lymphoid organs. In the lymphoid tissue, dendritic cells are involved in the stimulation of T-cell responses. Dendritic cells also produce cytokines that may play a role in both innate and acquired immunity

The Natural Killer cells (NK) are a type of lym-phocyte and comprise approximately 3% of normal blood circulation. Natural Killer cells can kill cells that are infected with viruses, as well as those that may harbor microbes within. Viruses cannot replicate with-out the help of the host cell. An infected cell must be recognized and destroyed before it can multiply within the host cell. One way in which Natural Killer cells can attack their targets with one of the components found in their granules, perforin, that creates a pore in the cell membrane of the target that allows destruction. NK cells can also induce their target to undergo a process called apoptosis (programmed cell death). Cells that are infected with viruses also secrete interferons that enhance the killing activities of the NK cells. Natural Killer cells are also capable of killing some tumor cells.

Mast cells are distributed in the connective tissues, especially in the skin and mucosal surfaces of the respiratory, gastrointestinal, and urogenital tract, in the blood vessels, as well as in the eye. Mast cells contain granules that contain histamine, leukotrienes, and prostoglandin. Histamine causes dilation of the smaller blood vessels and increases vascular permeability, and leukotrienes cause contraction of smooth muscle. Mast cells also release cytokines and chemokines. These cells are involved in defenses against parasitic and bacterial infections, and are also highly active in the allergic response.

There are several other cell type involved in the innate immune response. The eosinophils are mainly involved in an immune response to parasitic infection (worms) and also play a role in the allergic response, and comprise only 1-6% of the blood. The basophils, normally present in low numbers in the circulation (less than 1% of the blood), are thought to play a role in the inflammation and damage to tissue associated with allergic reactions. Platelets are cell fragments in the blood that are involved in blood clotting and inflammation.

Aquired (Adaptive) Immunity

The adaptive immunity is called into action when the innate system is unable to keep the invaders in check, and some pathogens may be able to "fly under the radar" and escape detection by the innate immune system. This requires a more advanced strategy with specific recognition abilities and the means to prevent reinfection with immunological memory. This role is met by the acquired (adaptive) immune system, which may be likened to the "guided missle" of the immune response. This is dependent upon two broad divisions of special cells, the T and B cells (lymphocytes), which comprise 20-50% of the white blood cells in normal adult human circulation. It also involves coordination with the cells of the innate immune system, the specialized substances produced to facilitate the cellular interactions, such as cytokines, chemokines, and complement, as well as lymphatic systems, organs, and tissues of the immune system.

cells involved in acquired immunity.

T cells

A type of lymphocyte, T cells derive from stem cells in the bone marrow, but mature and differentiate in the thymus gland (hence the "T" designation). T cells assist in cellular immune responses, primarily detecting those host cells that have been infected and carry foreign material within them (intracellular infections) These recognize the presence of foreign antigens (materials that are not part of "self " that give rise to an immune response ). The T cell may produce cytokines and toxic substances that may cause the infected cell to be killed, or possibly produce substances that activate other cell types, such as macrophages and B cells, to be become activated so that they can assist in the response. There are three broad categories of T cells that are classified according to their function: cytotoxic T cells (Tc) that kill abnormal cells that contain pathogens (within viruses), helper T cells (Th) that enhance an immune responses by helping other immune cells through the secretion of cytokines, and suppressor T cells (Ts) that diminish the immune responses causing them to subside. To carry out these activities, the T cells need to recognize the host cells of the body, and be able to distinguish those that are normal from those which are not. To do this this, they are able to detect special molecules found on host cells that produced from the genes of Major Histocompatibility Complex (MHC), somewhat like a "sign" that designates the cell as "part of the family". When this "sign" is accompanied by the display of parts of foreign invaders recognized by the T cell, it serves as a signal to the T cells that something is wrong and action is required. The importance of the MHC (or HLA for "human leucotye antigen" in humans) in recognition is apparent during the rejection of grafts in a transplant, as two identical twins will have the same HLA, but unrelated people may not, hence the reason that successful grafts often come from a close relative or close match. This also is involved in the differences between individuals when responding to an infection or abnormality in the body.

B cells

The B cells mature in the bone marrow, and each B cell is designed to make a specific type of antibody that works against an antigen of the invader. B cells can recognize antigens with the help of T cells. Upon activation, B cells give rise to plasma cells, found in the lymph nodes, spleen, and bone marrow, which may rapidly produce more antibodies (immunoglobulins) at rates up to approximately 100,000 molecules per minute. The cells which recognize the antigen produce more cells of the same type to make antibody by a process called clonal selection. This builds up the antibody over a period of a few days so that a sufficient amount of antibody is generated to fight the infection. Different types of antibodies are involved in specific activities, and they are incredibly diverse in their ability to recognize antigens. Antibodies can recognize almost any foreign invader or even synthetically produced molecules generated in the laboratory, which is very useful for drug development and biomedical research. There are several broad ways that antibodies work to help in immune responses. Antibodies may neutralize toxins that are produced by bacteria, Antibodies bind with pathogen proteins or antigens, and then the antibodies can be recognized by other cells and molecules of the innate immune system, such as macrophages and complement, to help remove the invader from the system. The B cells also give rise to memory cells that remain alive for long periods of time and assist in a more effective immune response upon the next exposure to the same antigen that is more pronounced, faster, and more specific. This is the principal behind the concept of vaccination, which makes use of immunological memory and B an T cell interactions to prepare an individual to mount an effective immune response when exposed to a pathogen.

Lymphatic Systems, Organs, and Tissues Involved in Immunity

CENTRAL LYMPHOID TISSUES. The central lymphoid organs include the bone marrow and thymus. At these sites, the lymphocytes interact with other cells to enhance their development or increase their ability to assist in an immune response. They also acquire the ability to recognize specific antigens before they actually become exposed to them, and are antigen-independent. At this stage the lymphocytes are called naive lymphocytes because they have not yet been exposed to antigens. The bone marrow is the site of hematopoiesis. Both B-lymphocytes and T-lymphocytes come from this site, but only the B cells undergo maturation in this area.

PERIPHERAL LYMPHOID TISSUES. The peripheral lymphoid tissues include the lymphatic vessels, lymph nodes, various lymphoid tissues, and spleen. The events that occur in these areas require exposure to an antigen, and are called antigen-dependent events.

LYMPHATIC VESSELS. The filtration of the blood results in the production of extracellular fluid called lymph. The lymphatic vessels that carry the fluid back to the bloodstream also carries cells that will present antigens. These antigens come from other sites within the body where infection may be present. The fluid passes through the lymph nodes. This fluid is eventually returned to the blood via lymphatic vessels. All the lymph from the body is carried back to the heart by way of the thoracic duct.

LYMPH NODES AND LYMPHOID TISSUE. Lymph nodes are distributed along lymphatic vessel pathways and act as a filter for the lymph. The lymph nodes are distributed throughout the lymphatic system, and are especially prominent in the neck, axilla (underarm), and groin. These fibrous nodes contain immune cells such as lymphocytes, macrophages, and dendritic cells. Dendritic cells have long, filamentous cytoplasmic processes. These processes have the ability to bind antibodies such that the antibodies can also bind with their specific antigens. This creates a web that traps antigens. The macrophages in the lymph nodes degrade debris and extract material that contains antigens, such as those from pathogenic bacteria. The structure of the lymph nodes is such that both T and B cells are exposed to this antigenic material. The cells that recognize this material are held in the lymphoid nodes and tissues where they multiply and differentiate. These cells become effector cells that are capable of fighting disease. The lymph node may enlarge during this process, giving rise to the clinical observation of swollen glands.

Lymphocytes can also be found in several other areas throughout the body. The gut-associated lymphoid tissue is a broad term that describes lymphoid tissue found in the Peyer's patches of the intestine, appendix, adenoids, and tonsils. Cells that protect the respiratory tract are called bronchial-associated lymphoid tissue (BALT). Other mucosal areas are protected as well, and are collectively known as mucosal-associated lymphoid tissue (MALT).

SPLEEN. Blood is filtered in the spleen, where damaged or dead red blood cells are removed from the blood as well as antigens. This organ also serves as a site for storage of erythrocytes and platelets. In the fetus, it is the site of erythropoiesis (formation of red blood cells). Within this organ reside B cells, T cells, macrophages, and dendritic cells. As in the lymph nodes, lymphocytes are trapped in this organ. Antibodies and effector cells are produced in the spleen.

Common disorders and diseases

Hypersensitivity reactions result from an immune-mediated inflammatory response to an antigen that would normally be innocuous (causing no harm to the body). Examples include allergic reactions, such as hay fever, asthma, reactions to insect bites, and the systemic anaphylactic shock that occurs in response to bee stings, allergies to antibiotics, and foods.

Delayed-type hypersensitivity reactions are due to the release of lymphokines. These lymphokines are small polypetides produced by lymphocytes that have been stimulated by an antigen, affecting other cells. This hypersensitivity reaction may occur as part of the normal immune response to infection by bacteria and viruses. This effect is responsible for the tissue damage in the lungs due to tuberculosis, the skin lesions that occur in leprosy and herpes, and rashes associated with chicken pox and measles. This may also occur via skin exposure to cosmetics, poison ivy, and allergy to metals in jewelry, resulting in contact dermatitis.

Autoimmune diseases occur when the immune system begins to attack the body or "self." In Grave's disease, antibodies are produced against the thyroid-stimulating hormone (TSH) receptor. In multiple sclerosis (MS), antibodies are produced against elements of the myelin sheaths in the brain and spinal cord. The effects of myasthenia gravis are traced to antibodies directed against the acetylcholine receptor. Following a heart attack, antibodies may form against heart muscle antigens resulting in autoimmune myocarditis. Rheumatoid arthritis (RA) develops from complexes pf antibodies to immunoglobulin G (IgG) in the joints and connective tissue. In systemic lupus erythematosus, the body produces antibodies directed against nuclear antigens and DNA.

In acquired immunodeficiency syndrome (AIDS ), the HIV retrovirus attacks T cells (CD4), dendritic cells, and macrophages. The number of CD4 T cell in the blood eventually declines and the body can no longer resist the HIV infection. With the immune system compromised, constitutional disease can develop with fever, weight loss, or diarrhea. Neurological disease can occur, resulting in dementia and effects to the peripheral nervous system. Pathogenic microorganisms may cause opportunistic infections in this compromised immune state, such as pneumonia, diarrhea, skin and mucous membrane infections, and central nervous system infections. Cancers may also arise, such as lymphomas. Death from HIV is due to one of these complications or a combination of effects.

There is considerable research interest in understanding the role of the immune system in a variety of clinical situations that affect public health. The under-lying mechanisms of septic shock, a major cause of death, are currently the subject of intense research efforts. The link between sleep and immunity is under investigation, as well as the role of immunity in psychological disorders such as depression. The issue of defense against possible bioterrorism poses unique questions with regard to immunity. The problem of combatting the spread of avian flu is the subject of much investigation, with difficulties due to the different subtypes of the antigens and ability of the virus to mutate and change over time. Though understanding of immune system has grown considerably, it is clear that investigation will always be needed to combat the next challenge on the horizon.

KEY TERMS

Antibodies (immunoglobulins)— Proteins that bind to their corresponding specific antigen.

Antigen— A material that gives rise to an immune response.

Autoimmune disease— An immune response that occurs when the immune system begins to attack the body or self.

B lymphocyte— A lymphocyte that contains an immunoglobulin on the surface (the B-cell receptor). B cells mature in the bone marrow.

Effector cells— Mature lymphocytes that assist in the removal of pathogens from the system and do not require further differentiation to perform this function.

Hypersensitivity— An immune reaction that results from an immune mediated inflammatory response to an antigen that would normally be innocuous.

Macrophages— Cells that are capable of ingesting microorganisms by phagocytosis and have a critical role in the host defense to pathogens.

Pathogen— A microorganism that has the potential to cause a disease.

T cytotoxic cells (Tc)— T lymphocytes that kill abnormal cells.

T helper cells (Th)— T lymphocytes that enhance an immune response.

T lymphocyte— A lymphocyte that matures in the thymus and has receptors related to CD3 complex proteins.

T suppressor cells (Ts)— T lymphocytes that diminish the immune response.

Resources

BOOKS

Abbas, Abul K., and Andrew H. Lichtman Basic Immunology: Functions and Disorders of the Immune System. Philadelphia, W.B. Saunders Company, 2001.

Anderson, William L. Immunology. West Sussex: John Wiley & Sons Ltd, 2003.

Eales, Lesley-Jane. Immunology for Life Scientists. Madison, CT: Fence Creek Publishing, 1999.

Janeway, Charles A., et al. Immunobiology: The Immune System in Health and Disease. New York: Garland Publishing, 2005.

Playfair, John, and Gregory Bancroft. Infection and Immunity New York: Oxford University Press, 2004.

Roitt, Ivan M., and Peter J. Delves. Essential Immunology. Malden: Blackwell Science, 2001.

Roitt, Ivan, and Arthur Rabson. Really Essential Medical Immunology. Malden: Blackwell Science, 2000.

Sharon, Jacqueline. Basic Immunology. Baltimore: Williams and Wilkins, 1998.

Widmann, Frances K., and Carol A. Itatani. An Introduction to Clinical Immunology and Serology. Philadelphia: F. A. Davis Company, 1998.

Wier, Donald M., and John Stewart. Immunology. New York: Churchchill Linvingstone, Inc., 1997.

PERIODICALS

Hargreaves, Diana, C., and Ruslan Medzhitov. "Innate Sensors of Microbial Infection." Journal of Clinical Immunology, November 2005 v25 No.6 p503-510.

Majde, Jeannine A., and James M. Kruger. "Links between the Innate Immune System and Sleep." Journal of Allergy and Clinical Immunology, December 2005 v116 No.6 p1188-1198.

Staros, Eric B. "Innate Immunity: New Approaches to Understanding Its Clinical Significance." American Journal of Clinical Pathology, 2005 v123 p305-312.

Suarez, D.L., and S. Schultz-Cherry. "Immunology of Avian Influenza Virus: A Review." Developmental and Comparative Immunology, 2000 v24 p269-283.

ORGANIZATIONS

American Autoimmune Related Disease Association. 〈http://www.aarda.org〉.

OTHER

Mayo Clinic 〈http://www.mayoclinic.com〉.

Med Web, Emory University. 〈http://www.medweb.emory.edu/MedWeb/〉.

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Immune System

Immune system

Definition

The immune system is a complex network of cells, tissues and organs that function cooperatively to protect the body from invasion by bacteria, viruses , parasites, fungi, toxins and tumor cells. When an immune system is healthy and works as it is designed to, it keeps out or destroys “foreign” invaders or destroys, keeping humans from getting sick. However, the immune system itself can develop disorders. When the immune system lacks any of its component parts (immune deficiency) or becomes overactive or attacks wrong targets, it can fail to fight foreign cells or organisms properly, or it can mistakenly fight cells and tissues that belong to the body it is supposed to protect (autoimmune disease).

Description

A healthy immune system protects the body from invasion from outside sources because of its innate ability to identify the body's own cells (self-cells) and distinguish them from foreign cells (non-self-cells). Identification of self- and non-self-cells depends on recognizing tiny protein structures (antigens) on cell surfaces that are unique to the cells of each organism, including cells of each individual. When immune system cells come across antigens they don't recognize as belonging to the body, they mobilize other immune system components and attack the cells identified as foreign. Certain immune cells produce antibodies against antigens on the foreign cells; these antibodies usually remain in the bloodstream and continue to protect the individual from the particular bacteria or virus if it is encountered again. This means that the body has developed “natural immunity” to a particular organism. Immunization with vaccines (acquired immunity) mimics this function of the body's immune system by purposefully exposing the body to a tiny amount of a foreign substance so that antibodies are developed against it to prevent infection.

Immune System Organization

Immune system organs, vessels, nodes, and cells are found throughout the body. Highly specialized immune system cells are found in the lymphoid organs and, through a complex system of communication and cell movement, these cells become foot soldiers that attack when needed to protect the body from invasion. During immune response, immune cells are transported by the two main fluids in the body: lymph, a milky fluid produced by the lymphatic system, and blood. The main components of the immune system include:

  • Lymphoid organs—bone marrow in the center of bones where cells are produced, and the thymus gland, an organ behind the breastbone where lymphocytes mature and become T cells.
  • Lymphoid vessels—vein-like tubules that connect organs of the immune system and allow passage of immune system cells to monitor for foreign antigens and travel to infected sites.
  • Lymph nodes—found under the arms, in the throat, abdomen and groin, these nodes house immune cells and are control centers for immune system activity; lymphocytes go in and out tiny lymph node blood vessels continuously, prospecting for foreign antigens.
  • Lymphocytes—small white blood cells (leukocytes) produced in the bone marrow to eventually become immune cells. Other white cells (neutrophils, monocytes, basophils, and eosinophils) may also be mobilized as part of immune response.
  • T-cells, B-cells, phagocytes and macrophages—examples of an array of powerful specialized immune cells, each with specific functions designed to attack a vast number of targets either by direct contact or through the release of chemical substances. All immune cells begin as stem cells; chemical messengers (cytokines) from the immune system coordinate immune cell development and determine how they will function to produce appropriate immune responses. B cells and plasma cells produce antibodies against surface antigens on foreign cells; T cells directly attack foreign cells that have abnormal surface antigens; and phagocytes are large white cells in the blood that actually swallow and digest bacteria and foreign substances; macrophages are groups of cells such as monocytes found in the brain, lungs, kidneys and liver, that can surround a foreign organism and destroy it.
  • Immune antibodies—produced by B cells and large plasma cells, these large molecules are known as “immunoglobulins” (IgG, IgM, IgA, IgE, and IgD); they can attack antigens on cell surfaces but cannot enter foreign cells. Each type of immunoglobulin fights specific kinds of bacteria, viruses, or parasites.
  • Spleen—a flat organ in the upper abdomen where immune cells collect in preparation for providing immune defense against foreign antigens, and where bacteria and viruses are filtered from blood.
  • Lymphoid tissue—tonsils, adenoids and the appendix are bundles of lymphoid tissue in which foreign antigens can be trapped and attacked. Lymphoid tissue is also found in the lungs and digestive tract. A tonsil infection or appendicitis may begin as an attack against a foreign invader, helping to prevent infection in the rest of the body.

Other parts of the body support immune system defenses. The skin provides a tough barrier against many organisms, but not against objects that may break the skin and allow organisms to enter. The skin also secretes acids on its surface that retards growth of bacteria; the ears produce offensive wax to deter bacteria from entering, and hair follicles produce lactic and fatty acids that prevent growth of bacteria and fungi. Mucus membranes of the nose, throat and lungs are equipped with cilia, little hairs that move unwanted material along that can be ejected through coughing or sneezing. Tears, saliva and urine also remove material and organisms in the flow of fluid. Saliva, tears, secretions of the nose, and sweat contain an enzyme that can destroy harmful Gram positive bacteria. Mucus in the digestive and respiratory tracts can trap microscopic organisms for eventual removal. Besides having “friendly” bacteria, the stomach secretes concentrated hydrochloric acid and enzymes that digest proteins, helping to kill harmful organisms and chemical intruders.

Demographics

Anyone of any age, race or gender can develop immune system disorders. Certain genetic disorders of the immune system, such as lack of a specific immunoglobulin, may be present at birth. Half a million individuals of all ages in the U.S. have primary immunodeficiency, which is usually diagnosed in childhood. Autoimmune diseases occur primarily in young to middle-aged adults, women more than men, but the chronic effects may continue progressively into senior years.

Causes and symptoms

The immune system's defenses against many thousands of potentially harmful organisms, allergens and environmental substances can be weakened through constant response to repeated assaults on the body from infectious organisms, environmental sources such as chemical pollutants found in household cleaners and industrial waste, and by exposure to toxins such as food additives, certain medications and pesticides. Stress is another burden on immune system function, placing repeated demands on the adrenal glands, depleting nutrients, and suppressing normal white cell function. All of these factors, as well as other types of genetic or acquired immune system deficiency, can reduce the body's natural defenses against infection and its overall healing ability, leaving the affected individual open to a wide range of illnesses and infections.

Immune system disorders are of several main types: allergic conditions, autoimmune diseases and immune deficiency diseases, which are each caused by failure of the immune system to operate normally. Symptoms of immune system disorders vary according to organs, body systems or mechanisms involved.

Allergic diseases

Allergic diseases usually develop as an overly aggressive immune response to a relatively harmless substance such as dust, ragweed pollen or food constituent; antibodies are developed against the foreign substance and histamine is produced in a somewhat hysterical reaction to the presence of the substance interpreted as foreign, until the individual has repeated allergic responses each time this substance is encountered. Allergies can manifest as sneezing, coughing, stuffy noses and tearing eyes if an airborne allergen is involved. Contact allergies may involve rashes and tissue swelling. Food allergies can produce rashes, headaches or digestive system disturbances.

Autoimmune diseases

Autoimmune diseases develop when the immune system is not able to distinguish self cells from non-self-cells and begins to attack a certain part of the body. The mechanism that causes the immune system to fail to recognize self-cells is not entirely understood but is believed to be failure of a built-in self-tolerance mechanism that normally helps the immune system distinguish self-cells from foreign. Examples of autoimmune diseases are rheumatoid arthritis in which joint tissue is attacked, fibromyalgia in which muscles and soft tissue are attacked, and multiple sclerosis in which the nervous system is attacked. Diabetes may even have an autoimmune component because certain antibodies are produced in the pancreas of individuals with diabetes. In autoimmune diseases, autoantibodies are produced such as the rheumatoid factor (RF) found in rheumatoid arthritis; autoantibodies attack self-cells and destroy tissue as though it were foreign.

Autoimmune diseases typically involve symptoms in the part of the body that is being attacked, such as swollen, inflamed joints in rheumatoid arthritis and lupus , aching muscles and soft tissue in fibromyalgia, and loss of balance and limb weakness in multiple sclerosis because of nerve destruction. Autoimmune diseases may have systemic symptoms such as fever, fatigue or general malaise, weight loss , aches and pains or reduced mobility, and progressive reduction in functioning of the system affected; autoimmune diseases are typically chronic with flareups of symptoms. Although inflammation is a normal immune system response, in chronic autoimmune disease it can become a source of ongoing tissue damage, which can in turn damage affected organs.

Immune deficiency diseases

Immune deficiency refers to the absence or functional failure of certain immune system components. Common variable immunodeficiency (CVID) is an immune system disorder with low levels of immunoglobulin G (IgG), resulting in diminished immune response and recurring infections. The absence or reduced amounts of any immunoglobulins results in reduced immunity and can lead to development of autoimmune disease. Acquired immunodeficiency syndrome (AIDs) is an extremely aggressive and complex disease caused by a powerful virus (HIV) that immobilizes the immune system by infecting primarily T cells and using immune system cytokines to help the virus reproduce itself. AIDs exposes the individual to a range of serious infections.

Individuals with a weakened immune system or immune deficiency of any kind will typically experience repeated and prolonged bacterial or viral infections. Colds and viruses may occur regularly rather than once or twice a year. Wounds may be slow to heal. Urinary tract infections, including kidney infection, may be recurrent. Individuals with compromised lung function are especially subject to bronchial infection.

Diagnosis

count , blood chemistry profile, and tests for immunoglobulins, among other tests used to evaluate immune system function, nervous system function and current health status. Allergy tests may be conducted to identify specific allergens causing symptoms. Blood serum may be tested for the presence of specific antibodies common to autoimmune diseases. A bone marrow sample may be obtained for evaluation of cell production in some cases. Sources of infection may be identified by bacterial cultures and tests may be performed to identify specific viruses. Diagnostic imaging may be needed to identify the presence of tumors or tissue damage in affected parts of the body.

Treatment

Because immune disorders are chronic and progressive, treatment for immune system disorders focuses on treating the resulting infection or disease and avoiding repeat infection or flare-ups. Treatment for allergies may involve the use of specific allergy medications or antihistamines to relieve symptoms. Treatment for infections may include antibiotic therapy, steroid therapy or gamma globulin injections. Treatment for autoimmune diseases may involve the use of immunosuppressive medications to reduce exaggerated immune response.

Nutrition/Dietetic concerns

Maintaining a healthy immune system means providing the body with the nutrients needed to support the system and also to help the body reduce damage caused by normal aging, free radicals from unwanted substances, and regular exposure to environmental pollutants. Certain vitamins , antioxidants and food sources provide nutrients that can help boost immune system function, including:

  • Acidophilus to restore normal bacteria in the intestinal tract
  • Coenzyme Q10 to support immune system function and oxygenate cells and tissue
  • Echinacea, an herb known to boost the immune system by enhancing lymphatic function
  • Essential fatty acids (Omega 3 and 6) to aid immune system function and reduce inflammation
  • Garlic, with natural antibiotic properties, stimulates the immune system
  • Kelp to provide essential minerals for immune function
  • Vitamins C and E, antioxidants that help reduce threat of infection
  • Vitamin A with carotenoid complex, a powerful free radical scavenger and immune system booster
  • Quercetin to help prevent reactions to food and pollen allergens
  • Selenium, an essential mineral and destroyer of free radicals
  • Zinc, a mineral essential to immune system function

QUESTIONS TO ASK YOUR DOCTOR

  • Is my immune system able to prevent or fight infection?
  • What can I do to support my immune system?
  • How can I avoid infection?
  • How can I avoid allergic reactions?
  • Can antibiotics effectively treat my infection?
  • What other options are available?

Prognosis

Immune system dysfunction may lead to recurrent infections such as sinusitis, upper respiratory infections, pneumonia, bacteremia , bronchiectasis, urinary tract infections, and diarrhea . Chronic infections may develop in individuals who do not have full immune response to fight the causative bacteria or virus. Infections can sometimes be treated effectively with antibiotics , however lack of immune response by the individual can lead to systemic infection, sepsis and death .

Prevention

The immune system needs regular care such as obtaining good nutrition with fresh, whole foods, regular sleep and regular exercise to help the immune system generate cells needed for immune response. Avoiding environmental pollutants that may overwork and depress immune function is essential as well. Similarly, avoiding or reducing stress is essential for maintaining an effectively functioning immune system. Individuals with known immune deficiency must reduce the threat of infection by avoiding crowds and contact with individuals who have active bacterial or viral infections, including colds and flu, and by practicing good hygiene.

KEY TERMS

Antigen —A type of protein found on cell surfaces that uniquely identifies the cellular organism.

Cytokines —Chemical messengers in the immune system (interferons, interleukins, and growth factors) that coordinate immune system response and turn immune cell activity on and off.

Free radicals —Atoms of specific elements that are uncombined with other elements and can be present in body tissue as unwanted foreign or harmful agents.

Gamma globulin —One of a family of proteins that have a protective function against some types of infectious agents.

Sepsis —The presence of infective organisms in the blood throughout the body; systemic infection.

Caregiver concerns

Individuals with compromised immune systems or who are taking prescribed immunosuppressant drugs are especially subject to infection. Exposure to colds, viruses such as flu, and other possible infections should be prevented. Good hygiene should be practiced, including frequent and thorough hand washing. Caretakers should provide and encourage drinking water and other clear fluids. Adequate hydration is needed at all times to maintain fluid balance in the body and to prevent urinary tract infection as a result of dehydration .

Resources

BOOKS

“Understanding the Immune System: How it Works.” National Institutes of Health. NIH Publication No. 03-5423, U.S. Department of Health and Human Services, 2003. (Available at niaid.nih.gov/Publications/immune/the_immune_system.pdf) Accessed March 11, 2008.

Balch P A. “Weakened Immune System.” Prescription for Nutritional Healing. Garden City Park, NY: Avery, 1997.

PERIODICALS

Chaplin DD. “Overview of the human immune response.”Journal of Allergy and Clinical Immunology. 117(2) Suppl 2. 2006.

ORGANIZATIONS

National Institute of Allergy and Infectious Diseases, 6610 Rockledge Drive MSC 6612, Bethesda, MD, 20817-1811, 301-496-5717, 866-284-4107, 301-402-3573, www3.niaid.nih.gov.

L. Lee Culvert

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Immune System

Immune system

Definition

The immune system is composed of cells, organs, tissues, and molecules that protect the body from disease. The term "immunity" comes from the Latin word immunitas.

Description

Physical barriers

Anatomic barriers provide protection against invading bacterial and viral pathogens. The skin is composed primarily of keratin, which cannot be digested by most microorganisms. The skin is usually dry with a high salt concentration due to sweat. These conditions are not favorable for bacterial growth. Sweat and sebaceous skin secretions also contain substances that kill bacteria . Some types of bacteria inhabit the skin surface and do not cause disease under normal conditions (microflora). These bacteria may produce substances that kill other more pathogenic bacteria. The microflora may also consume nutrients required by pathogens. This gives rise to a competitive relationship that limits the growth of the pathogens. If the skin is broken, due to injuries or burns , harmful bacteria may enter and give rise to infection . The cilia of the lungs protect this organ from inhaled pathogens, transporting secretions to the throat so that they can be swallowed and destroyed by stomach acid. Secretions in the nose, saliva, and components of tears also contain substances that protect against bacteria and viruses .

Cells of the immune system

LYMPHOCYTES. There are two major types of lymphocytes, the T-cells and B-cells, which comprise 20–50% of the white blood cells in normal adult human circulation. T-cells mature and differentiate in the thymus gland and assist in cellular immune responses. These cells are responsible for the recognition of antigens (materials that give rise to an immune response , such as components of pathogenic bacteria). There are three major types of T-cells that are classified according to their function: cytotoxic T cells (Tc) that kill abnormal cells, helper T cells (Th) that enhance an immune response, and suppressor T-cells (Ts) that diminish the immune response. The B-cells mature in the bone marrow and recognize antigens with the help of T-cells. Upon activation, these cells give rise to plasma cells, which produce antibodies (immunoglobulins). Antibodies bind with toxic pathogen proteins or antigens and interact with other cells to remove the invader from the system. Plasma cells are found in the lymph nodes, spleen and bone marrow. B-cells also give rise to memory cells that remain alive for long periods of time and assist in a more effective immune response upon the next exposure to the same antigen.

The natural killer cells (NK) are a third type of lymphocyte and comprise approximately 3% of normal blood circulation. These large cells are responsible for the killing of some tumors and virus-infected cells. Additionally, some cells can be induced to kill their targets in a non-specific manner under the appropriate conditions. These cells are called lymphokine activated killer (LAK) cells.

GRANULOCYTES. The granulocytes or polymorphonuclear leukocytes (PMNs) are a group of cells that display a characteristic staining of granules in blood smears, hence their name. These cells have a short life span in the blood (about two or three days), and make up the majority of the white blood cells under normal conditions. They are usually found in greater numbers during an immune response to injury or infection. The neutrophils are a very important type of granulocyte and demonstrate phagocytosis (ingestion of particles by cells, such as particles of bacteria, with ultimate destruction by lysosomal enzymes). These cells are critical in the development of the immune response to pathogens and can migrate from the blood to the tissues during infection by a process known as chemotaxis (the movement of cells in response to and external chemical stimulation). They comprise approximately 40–75% of the blood. The eosinophils are mainly involved in an immune response to parasitic infection and also play a role in the allergic response, and comprise only 1–6% of the blood. The basophils, normally present in low numbers in the circulation (less than 1% of the blood), are thought to play a role in the inflammation and damage to tissue associated with allergic reactions.

MONOCYTES, MACROPHAGES, AND MAST CELLS. Monocytes are a type of cell that circulates in the bloodstream, comprising 2–10% of the blood. Upon migration into the tissues, these cells differentiate into macrophages that are capable of ingesting microorganisms by phagocytosis and have a critical role in the host defense to pathogens. They also produce substances called monokines that are a type of secreted protein (cytokine) that affects the actions of other cells.

Mast cells are distributed in the connective tissues, especially in the skin and mucosal surfaces of the respiratory, gastrointestinal, and urogenital tracts as well as the eye. These cells are also involved in the allergic response.

PLATELETS. Platelets are cell fragments in the blood that are involved in blood clotting and inflammation.

DENDRITIC CELLS. Dendritic cells are potent stimulators of immune responses. These cells play an important role in the increased immune response upon a second exposure to an antigen. Dendritic cells are distributed throughout the body, especially in the T-cell areas of lymphoid organs. In the lymphoid tissue, dendritic cells are involved in the stimulation of T-cell responses.

Central lymphoid tissues

The central lymphoid organs include the bone marrow and thymus. At these sites, the lymphocytes interact with other cells to enhance their development or increase their ability to assist in an immune response. They also acquire the ability to recognize specific antigens before they actually become exposed to them, and are antigen independent. At this stage the lymphocytes are called naïve lymphocytes because they have not yet been exposed to antigens. The bone marrow is the site of hematopoiesis. Both B-lymphocytes and T-lymphocytes come from this site, but only the B cells undergo maturation in this area (hence the name B-cell T-cell).

Peripheral lymphoid tissues

The peripheral lymphoid tissues include the lymphatic vessels, lymph nodes, various lymphoid tissues, and spleen. The events that occur in these areas require exposure to an antigen, and are called antigen-dependent events.

Lymphatic vessels

The filtration of the blood results in the production of extracellular fluid called lymph. The lymphatic vessels that carry the fluid back to the bloodstream also carries cells with antigens. These antigens come from other sites within the body where infection may be present. The fluid passes through the lymph nodes. This fluid is eventually returned to the blood via lymphatic vessels. All the lymph from the body is carried back to the heart by way of the thoracic duct.

Lymph nodes and lymphoid tissue

Lymph nodes are distributed along lymphatic vessel pathways and act as a filter for the lymph. The lymph nodes are distributed throughout the lymphatic system , and are especially prominent in the neck, axilla (underarm), and groin. These fibrous nodes contain immune cells such as lymphocytes, macrophages, and dendritic cells. Dendritic cells have long, filamentous cytoplasmic processes. These processes have the ability to bind antibodies such that the antibodies can also bind with their specific antigens. This creates a web that traps antigens. The macrophages in the lymph nodes degrade debris and

extract material that contains antigens, such as those from pathogenic bacteria. The structure of the lymph nodes is such that both T-and B-cells are exposed to this antigenic material. The cells that recognize this material are held in the lymphoid nodes and tissues where they multiply and differentiate. These cells become effector cells that are capable of fighting disease. The node may enlarge during this process, giving rise to the clinical observation of swollen glands.

Lymphocytes can also be found in several other areas throughout the body. The gut-associated lymphoid tissue is a broad term that describes lymphoid tissue found in the Peyer's patches of the intestine, appendix, adenoids, and tonsils. Cells that protect the respiratory tract are called bronchial-associated lymphoid tissue (BALT). Other mucosal areas are protected as well, and are collectively known as mucosal-associated lymphoid tissue (MALT).

Spleen

Blood is filtered in the spleen, where damaged or dead red blood cells are removed from the blood as well as antigens. This organ also serves as a site for storage of erythrocytes and platelets. In the fetus, it is the site of erythropoiesis (formation of red blood cells). Within this organ reside B-cells, T-cells, macrophages, and dendritic cells. As in the lymph nodes, lymphocytes are trapped in this organ. Antibodies and effector cells are produced in the spleen.

Common disorders and diseases

Hypersensitivity reactions result from an immunemediated inflammatory response to an antigen that would normally be innocuous (causing no harm to the body). Examples include allergic reactions, such as hay fever , asthma , reactions to insect bites, and the systemic anaphylactic shock that occurs in response to bee stings, allergies to antibiotics , and foods.

Delayed-type hypersensitivity reactions are due to the release of lymphokines. These lymphokines are small polypetides produced by lymphocytes that have been stimulated by an antigen, affecting other cells. This hypersensitivity reaction may occur as part of the normal immune response to infection by bacteria and viruses. This effect is responsible for the tissue damage in the lungs due to tuberculosis , the skin lesions that occur in leprosy and herpes, and rashes associated with chicken pox and measles. This may also occur via skin exposure to cosmetics, poison ivy, and allergy to metals in jewelry, resulting in contact dermatitis.

Autoimmune diseases occur when the immune system begins to attack the body or "self." In Grave's disease, antibodies are produced against the thyroid-stimulating hormone (TSH) receptor. In multiple sclerosis (MS), antibodies are produced against elements of the myelin sheaths in the brain and spinal cord . The effects of myasthenia gravis are traced to antibodies directed against the acetylcholine receptor. Following a heart attack, antibodies may form against heart muscle antigens resulting in autoimmune myocarditis. Rheumatoid arthritis (RA) develops from complexes pf antibodies to immunoglobulin G (IgG) in the joints and connective tissue. In systemic lupus erythematosus, the body produces antibodies directed against nuclear antigens and DNA.

In acquired immunodeficiency syndrome (AIDS ), the HIV retrovirus attacks T-cells (CD4), dendritic cells, and macrophages. The number of CD4 T-cell in the blood eventually declines and the body can no longer resist the HIV infection. With the immune system compromised, constitutional disease can develop with fever, weight loss, or diarrhea . Neurological disease can occur, resulting in dementia and effects to the peripheral nervous system. Pathogenic microorganisms may cause opportunistic infections in this compromised immune state, such as pneumonia , diarrhea, skin and mucous membrane infections, and central nervous system infections. Cancers may also arise, such as lymphomas. Death from HIV is due to one of these complications or a combination of effects.


KEY TERMS


Antibodies (immunoglobulins) —Proteins that bind to their corresponding specific antigen.

Antigen —A material that gives rise to an immune response.

Autoimmune disease —An immune response that occurs when the immune system begins to attack the body or self.

B lymphocyte —A lymphocyte that contains an immunoglobulin on the surface (the B-cell receptor). B cells mature in the bone marrow.

Effector cells —Mature lymphocytes that assist in the removal of pathogens from the system and do not require further differentiation to perform this function.

Hypersensitivity —An immune reaction that results from an immune mediated inflammatory response to an antigen that would normally be innocuous.

Macrophages —Cells that are capable of ingesting microorganisms by phagocytosis and have a critical role in the host defense to pathogens.

Pathogen —A microorganism that has the potential to cause a disease.

T cytotoxic cells (Tc) —T lymphocytes that kill abnormal cells.

T helper cells (Th) —T lymphocytes that enhance an immune response.

T lymphocyte —A lymphocyte that matures in the thymus and has receptors related to CD3 complex proteins.

T suppressor cells (Ts) —T lymphocytes that diminish the immune response.


Resources

BOOKS

Anderson, William L. Immunology. Madison, CT: Fence Creek Publishing, 1999.

Janeway, Charles A., et al. Immunobiology: The Immune System in Health and Disease. New York: Elsevier Science London/Garland Publishing, 1999.

Roitt, Ivan, and Arthur Rabson. Really Essential Medical Immunology. Malden: Blackwell Science, 2000.

Sharon, Jacqueline. Basic Immunology. Baltimore: Williams and Wilkins, 1998.

Widmann, Frances K., and Carol A. Itatani. An Introduction to Clinical Immunology and Serology. Philadelphia: F. A. Davis Company, 1998.

Wier, Donald M., and John Stewart. Immunology. New York: Churchchill Linvingstone, Inc., 1997.

ORGANIZATIONS

American Autoimmune Related Disease Association. <http://www.aarda.org>.

OTHER

Mayo Clinic <http://www.mayoclinic.com>.

Med Web, Emory University. <http://www.medweb.emory.edu/MedWeb/>.

Jill Ilene Granger, M.S.

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Immune System

Immune system

The immune system protects the body from diseasecausing microorganisms . It consists of two levels of protection, the non-specific defenses and the specific defenses. The non-specific defenses, such as the skin and mucous membranes, prevent microorganisms from entering the body. The specific defenses are activated when microorganisms evade the non-specific defenses and invade the body.

The human body is constantly bombarded with microorganisms, many of which can cause disease . Some of these microorganisms are viruses, such as those that cause colds and influenza ; other microorganisms arebacteria , such as those that cause pneumonia and food poisoning . Still other microorganisms are parasites or fungi . Usually, the immune system is so efficient that most of us are unaware of the battle that takes place almost everyday, as the immune system rids the body of harmful invaders. However, when the immune system is injured or destroyed, the consequences are severe. For instance, Acquired Immune Deficiency Syndrome (AIDS ) is caused by a virus—Human Immunodeficiency Virus (HIV)—that attacks a key immune system cell , the helper T-cell lymphocyte. Without these cells, the immune system cannot function. People with AIDS cannot fight off the microorganisms that constantly bombard their bodies, and eventually succumb to infections that a healthy immune system would effortlessly neutralize.


Organs of the immune system

The organs of the immune system either make the cells that participate in the immune response or act as sites for immune function. These organs include the lymphatic vessels, lymph nodes, tonsils, thymus, Peyer's patch, and spleen. The lymph nodes are small aggregations of tissues interspersed throughout the lymphatic system . White blood cells (lymphocytes) that function in the immune response are concentrated in the lymph nodes. Lymphatic fluid circulates through the lymph nodes via the lymphatic vessels. As the lymph filters through the lymph nodes, foreign cells of microorganisms are detected and overpowered.

The tonsils contain large numbers of lymphocytes. Located at the back of the throat and under the tongue, the tonsils filter out potentially harmful bacteria that may enter the body via the nose and mouth. Peyer's patches are lymphatic tissues which perform this same function in the digestive system . Peyer's patches are scattered throughout the small intestine and the appendix. They are also filled with lymphocytes that are activated when they encounter disease-causing microorganisms.

The thymus gland is another site of lymphocyte production. Located within the upper chest region, the thymus gland is most active during childhood when it makes large numbers of lymphocytes. The lymphocytes made here do not stay in the thymus, however; they migrate to other parts of the body and concentrate in the lymph nodes. The thymus gland continues to grow until puberty ; during adulthood, however, the thymus shrinks in size until it is sometimes impossible to detect in x-rays.

Bone marrow, found within the bones, also produces lymphocytes. These lymphocytes migrate out of the bone marrow to other sites in the body. Because bone marrow is an integral part of the immune system, certain bone cancer treatments that require the destruction of
bone marrow are extremely risky, because without bone marrow, a person cannot make lymphocytes. People undergoing bone marrow replacement must be kept in strict isolation to prevent exposure to viruses or bacteria.

The spleen acts as a reservoir for blood and any rupture to the spleen can cause dangerous internal bleeding, a potentially fatal condition. The spleen also destroys worn-out red blood cells. Moreover, the spleen is also a site for immune function, since it contains lymphatic tissue and produces lymphocytes.


Overview of the immune system

For the immune system to work properly, two things must happen: First, the body must recognize that it has been invaded by foreign microorganisms. Second, the immune response must be quickly activated before many body tissue cells are destroyed by the invaders.


How the immune system recognizes foreign invaders

The cell membrane of every cell is studded with various proteins that protrude from the surface of the membrane. These proteins are a kind of name tag called the Major Histocompatibility Complex (MHC). They identify all the cells of the body as belonging to the "self." An invading microorganism, such as a bacterium, does not have the "self" MHC on its surface. When an immune system cell encounters this "non-self" cell, it alerts the body that it has been invaded by a foreign cell. Every person has their own unique MHC. For this reason,organ transplants are often unsuccessful because the immune system interprets the transplanted organ as "foreign," since the transplanted organ cells have a "non-self" MHC. Organ recipients usually take immunosuppressant drugs to suppress the immune response, and every effort is made to transplant organs from close relatives, who have genetically similar MHCs.

In addition to a lack of the "self" MHC, cells that prompt an immune response have foreign molecules (called antigens) on their membrane surfaces. An antigen is usually a protein or polysaccharide complex on the outer layer of an invading microorganism. The antigen can be a viral coat, the cell wall of a bacterium, or the surface of other types of cells. Antigens are extremely important in the identification of foreign microorganisms. The specific immune response depends on the ability of the immune lymphocytes to identify the invader and create immune cells that specifically mark the invader for destruction.


How the two defenses work together

The immune system keeps out microorganisms with non-specific defenses. Non-specific defenses do not involve identification of the antigen of a microorganism; rather the non-specific defenses simply react to the presence of a "non-self" cell. Oftentimes, these non-specific defenses effectively destroy microorganisms. However, if they are not effective and the microorganisms manage to infect tissues, the specific defenses are activated. The specific defenses work by recognizing the specific antigen of a microorganism and mounting a response that targets the microorganism for destruction by components of the non-specific system. The major difference between the non-specific defenses and the specific defenses is that the former impart a general type of protection against all kinds of foreign invaders, while the specific defenses create protection that is tailored to match the particular antigen that has invaded the body.


The non-specific defenses

The non-specific defenses consist of the outer barriers, the lymphocytes, and the various responses that are designed to protect the body against invasion by any foreign microorganism.


Barriers: skin and mucous membranes

The skin and mucous membranes act as effective barriers against harmful invaders. The surface of the skin is slightly acidic which makes it difficult for many microorganisms to survive. In addition, the enzyme lysozyme, which is present in sweat, tears, and saliva, kills many bacteria. Mucous membranes line many of the body's entrances, such as those that open into the respiratory, digestive, and uro-genital tract. Bacteria become trapped in the thick mucous layers and are thus prevented from entering the body. In the upper respiratory tract, the hairs that line the nose also trap bacteria. Any bacteria that are inhaled deeper into the respiratory tract are swept back out again by the cilia—tiny hairs—that line the trachea and bronchii. One reason why smokers are more susceptible to respiratory infections is that hot cigarette smoke disables the cilia, slowing the movement of mucus and bacteria out of the respiratory tract. Within days of quitting smoking, the cilia regenerate and new quitters then cough and bring up large amounts of mucus, which eventually subsides.

Non-specific immune cells

Non-specific lymphocytes carry out "search and destroy" missions within the body. If these cells encounter a foreign microorganism, they will either engulf the foreign invader or destroy the invader with enzymes. The following is a list of non-specific lymphocytes:

Macrophages are large lymphocytes which engulf foreign cells. Because macrophages ingest other cells, they are also called phagocytes (phagein, to eat + kytos, cell).

Neutrophils are cells that migrate to areas where bacteria have invaded, such as entrances created by cuts in the skin. Neutrophils phagocytize microorganisms and release microorganism-killing enzymes. Neutrophils die quickly; pus is an accumulation of dead neutrophils.

Natural killer cells kill body cells infected with viruses, by punching a hole in the cell membrane, causing the cell to lyse, or break apart.


The inflammatory response

The inflammatory response is an immune response confined to a small area. When a finger is cut, the area becomes red, swollen, and warm. These signs are evidence of the inflammatory response. Injured tissues send out signals to immune system cells, which quickly migrate to the injured area. These immune cells perform different functions: some engulf bacteria, others release bacteria-killing chemicals. Other immune cells release a substance called histamine , which causes blood vessels to become wider (dilate), thus increasing blood flow to the area. All of these activities promote healing in the injured tissue.

An inappropriate inflammatory response is the cause of allergic reactions. When a person is "allergic" to pollen, the body's immune system is reacting to pollen (a harmless substance) as if it were a bacterium and an immune response is prompted. When pollen is inhaled it stimulates an inflammatory response in the nasal cavity and sinuses. Histamine is released which dilates blood vessels, and also causes large amounts of mucous to be produced, leading to a "runny nose." In addition, histamine stimulates the release of tears and is responsible for the watery eyes and nasal congestion typical of allergies.

To combat these reactions, many people take drugs that deactivate histamine. These drugs, called antihistamines , are available over the counter and by prescription. Some allergic reactions, involve the production of large amounts of histamine which impairs breathing and necessitates prompt emergency care. People prone to these extreme allergic reactions must carry a special syringe with epinephrine (adrenalin), a drug that quickly counteracts this severe respiratory reaction.

Complement

The complement system is a group of more than 20 proteins that "complement" other immune responses. When activated, the complement proteins perform a variety of functions: they coat the outside of microorganisms, making them easier for immune cells to engulf; they stimulate the release of histamine in the inflammatory response; and they destroy virus-infected cells by puncturing the plasma membrane of the infected cell, causing the cell to burst open.


Specific immune defenses

The specific immune response is activated when microorganisms evade the non-specific defenses. Two types of specific defenses destroy microorganisms in the human body: the cell-mediated response and the antibody response. The cell-mediated response attacks cells which have been infected by viruses. The antibody response attacks both "free" viruses that haven't yet penetrated cells, and bacteria, most of which do not infect cells. However, some bacteria, such as the Mycobacteria that cause tuberculosis , do infect cells.


Specific immune cells

Two kinds of lymphocytes operate in the specific immune response: T lymphocytes and B lymphocytes, (T lymphocytes are made in the thymus gland, while B lymphocytes are made in bone marrow). The T and B lymphocytes migrate to other parts of the lymphatic system, such as the lymph nodes, Peyer's patches, and tonsils. Non-specific lymphocytes attack any foreign cell, while B and T lymphocytes are individually configured to attack a specific antigen. In other words, the blood and lymph of humans have T-cell lymphocytes that specifically target the chickenpox virus, T-cell lymphocytes that target the diphtheria virus, and so on. When T-cell lymphocytes specific for the chickenpox virus encounter a body cell infected with this virus, the T cell multiplies rapidly and destroying the invading virus.


Memory cells

After the invader has been neutralized, some T cells remain behind. These cells, called memory cells, impart immunity to future attacks by the virus. Once a person has had chickenpox, memory cells quickly stave off subsequent infections. This secondary immune response, involving memory cells, is much faster than the primary immune response.

Some diseases, such as smallpox , are so dangerous that it is better to artificially induce immunity rather than to wait for a person to create memory cells after an infection . Vaccination injects whole or parts of killed viruses or bacteria into the bloodstream, prompting memory cells to be made without a person developing the disease.

Helper T cells

Helper T cells are a subset of T-cell lymphocytes which play a significant role in both the cell-mediated and antibody immune responses. Helper T cells are present in large numbers in the blood and lymphatic system, lymph nodes, and Peyer's patches. When one of the body's macrophage cells ingests a foreign invader, it displays the antigen on its membrane surface. These antigen-displaying-macrophages, or APCs, are the immune system's distress signal. When a helper T cell encounters an APC, it immediately binds to the antigen on the macrophage. This binding unleashes several powerful chemicals called cytokines. Some cytokines, such as interleukin I, stimulate the growth and division of T cells. Other cytokines play a role in the fever response, another non-specific immune defense. Still another cytokine, called interleukin II, stimulates the division of cytotoxic T cells, key components of the cell-mediated response. The binding also "turns on" the antibody response. In effect, the helper T cells stand at the center of both the cell-mediated and antibody responses.

Any disease that destroys helper T cells destroys the immune system. HIV infects and kills helper T cells, so disabling the immune system and leaving the body helpless to stave off infection.


B cells and the antibody response

B-cell lymphocytes, or B cells, are the primary players in the antibody response. When an antigen-specific B cell is activated by the binding of an APC to a helper T cell, it begins to divide. These dividing B cells are called plasma cells. The plasma cells, in turn, secrete antibodies, proteins that attach to the antigen on bacteria or free viruses, marking them for destruction by macrophages or complement. After the infection has subsided, a few memory B cells persist that confer immunity.


A closer look at antibodies

Antibodies are made when a B cell specific for the invading antigen is stimulated to divide by the binding of an APC to a helper T cell. The dividing B cells, called plasma cells, secrete proteins called antibodies. Antibodies are composed of a special type of protein called immunoglobin (Ig). An antibody molecule is Y-shaped and consists of two light chains joined to two heavy chains. These chains vary significantly between antibodies. The variable regions make antibodies antigen-specific. Constant regions, on the other hand, are relatively the same between antibodies. All antibody molecules, whether made in response to a chickenpox virus or to a Salmonella bacterium, have some regions that are similar.


How antibodies work to destroy invaders

An antibody does not itself destroy microorganisms. Instead, the antibody that has been made in response to a specific microorganism binds to the specific antigen on its surface. With the antibody molecule bound to its antigen, the microorganism is targeted by destructive immune cells like macrophages and NK cells. Antibodytagged microorganisms can also be destroyed by the complement system.

T cells and the cell-mediated response

T-cell lymphocytes are the primary players in the cell-mediated response. When an antigen-specific helper T cell is activated by the binding of an APC, the cell multiplies. The cells produced from this division are called cytotoxic T cells. Cytotoxic T cells target and kill cells that have been infected with a specific microorganism. After the infection has subsided, a few memory T cells persist, so conferring immunity.

How is the immune response "turned off?"

Chemical signals activate the immune response and other chemical signals must turn it off. When all the invading microorganisms have been neutralized, special T cells (called suppressor T cells) release cytokines that deactivate the cytotoxic T cells and the plasma cells.

See also Allergy; Antibody and antigen; Cyclosporine; Immunology; Inflammation; Vaccine.

Kathleen Scogna

Resources

books

Richman, D. D., and R. J. Whitley. Clinical Virology. 2nd ed. Washington: American Society for Microbiology, 2002.

Schindler, Lydia Woods. The Immune System: How It Works. Bethesda, MD: U.S. National Institutes of Health, 1993.

periodicals

Engelhard, Victor H. "How Cells Process Antigens." Scientific American 271 (August 1994): 54.

Kedzierski, Marie. "Vaccines and Immunization (sic)." New Scientist 133 (8 February 1992): S1.

Kisielow, Pavelrod. "Self-Nonself Discrimination by T Cells." Science 248 (June 15, 1990): 1369.

"Life, Death, and the Immune System." Special Issue, Scientific American 269 (September 1993).

Miller, Jacques. "The Thymus: Maestro of the Immune System." BioEssays 16 (July 1994): 509.

Radesky, Peter. "Of Parasites and Pollens." Discover 14 (September 1993): 54.

Travis, John. "Tracing the Immune System's Evolutionary History." Science 261 (July 9, 1993): 164.

KEY TERMS

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antibody response

—The specific immune response that utilizes B cells to neutralize bacteria and "free viruses."

Antigen-presenting cell (APC)

—A macrophage that has ingested a foreign cell and displays the antigen on its surface.

B lymphocyte

—Immune system white blood cell that produces antibodies.

Cell-mediated response

—The specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria.

Complement system

—A series of 20 proteins that "complement" the immune system; complement proteins destroy virus-infected cells and enhance the phagocytic activity of macrophages.

Cytotoxic T cell

—A T lymphocyte that destroys virus-infected cells in the cell-mediated immune response.

Helper T lymphocyte

—The "lynch pin" of specific immune responses; helper T cells bind to APCs (antigen-presenting cells), activating both the antibody and cell-mediated immune responses.

Inflammatory response

—A non-specific immune response that causes the release of histamine into an area of injury; also prompts blood flow and immune cell activity at injured sites.

Lymphocyte

—White blood cell.

Macrophage

—An immune cell that engulfs foreign cells.

Major Histocompatibility Complex (MHC)

—The proteins that protrude from the surface of a cell that identify the cell as "self."

Memory cell

—The T and B cells that remain behind after a primary immune response; these cells swiftly respond to subsequent invasions by the same microorganism.

Natural Killer cell

—An immune cell that kills infected tissue cells by punching a hole in the cell membrane.

Neutrophil

—An immune cell that releases a bacteria-killing chemical; neutrophils are prominent in the inflammatory response.

Non-specific defenses

—Defenses such as barriers and the inflammatory response that generally target all foreign cells.

Phagocyte

—A cell that engulfs another cell.

Plasma cell

—A B cell that secretes antibodies.

Primary immune response

—The immune response that is elicited when the body first encounters a specific antigen.

Secondary immune response

—The immune response that is elicited when the body encounters a specific antigen a second time; due to the presence of memory cells, this response is usually much swifter than the primary immune response.

Specific defenses

—Immune responses that target specific antigens; includes the antibody and cell-mediated responses.

Suppressor T cell

—T lymphocytes that deactivate T and B cells.

T cells

—Immune-system white blood cells that enable antibody production, suppress antibody production, or kill other cells.

Vaccination

—Inducing the body to make memory cells by artificially introducing antigens into the body.

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Immune system

Immune system


The immune system is the body's biological defense mechanism and protects it against foreign invaders, such as bacteria and viruses. The system is a collection of cells and tissues in the body that protect it against disease-causing organisms. It works by using a simple system in which it distinguishes self (acceptable) from nonself (nonacceptable), and then it attacks and attempts to destroy anything nonself. Nearly all animals, simple and complex, have an immune system based on this self/nonself mechanism.

NATURAL IMMUNITY

The immune system has two different types of defense. The first is called natural immunity and is composed of the basic physical and chemical barriers that every body has at its disposal to fight a foreign invasion. The body's skin is its first line of natural defense since healthy, unbroken skin acts as a physical barrier against microorganisms. If, however, these tiny organisms try to get into the body through normal openings, like the nose and eyes, the body is prepared. These passages are lined with sticky mucus that catches the microorganisms, and with hairlike cilia that sweep them back out of the body. The body also uses secretions, like tears and saliva to protect itself. These secretions contain an enzyme called lysozyme that breaks down the walls of invading bacteria. If after these three defenses, microorganisms still manage to get into the body, the blood contains certain types of white cells called phagocytes that literally swallow up and destroy foreign cells or substances. The body then activates its complement system, which releases proteins that cause an inflammatory response. With this response, the body releases a fluid called histamine that helps fight the invader and results in local swelling.

ACQUIRED IMMUNITY

Sometimes the phagocytes, which make a general attack and attempt to destroy anything detected as foreign, cannot cope with the invader. When this happens, the body's acquired immunity goes into action. If natural immunity is the body's "nonspecific defense," meaning it will attack anything detected as foreign, then acquired immunity is its "specific defense."

Acquired immunity allows the body to "remember" and link past infections to a particular bacteria or virus. The body is then able to respond more quickly the next time it encounters the invader (now called an antigen). Only vertebrates (animals with a backbone) have acquired immunity. Acquired immunity enables the immune system to produce certain types of white cells called antibodies to fight a particular type of pathogen (disease-producing organism). It also enables the immune system to "remember" that pathogen and to respond more quickly the next time it appears. The body produces three types of white blood cells, macrophages, T lymphocytes, and B lymphocytes, that work together and carry out a complex series of events known as the immune response. (Macrophages alert the immune system that specific foreign agents are present.) The primary immune response involves the B-cell lymphocytes producing antibodies that capture and kill the invading antigen. However, when a virus invades a cell, the virus is safe from antibodies, so the T-cell lymphocytes begin what is called cell-mediated immunity. The T-cell is able to recognize any infected cell, and when it does, it kills the cell. Lymphocytes are transported throughout the body via the lymphatic system, a type of secondary circulatory system that acts as a bridge to the immune system.

EDWARD JENNER DEVELOPS IMMUNIZATION

The natural ability of the immune system to be able to recognize a particular antigen is the basis for immunization. Since ancient times, medical observers had noticed that the body seemed to have powers to protect itself and resist disease. In particular, people who had survived a certain infectious disease did not suffer from that disease again during their lifetime. In 1796, the English physician Edward Jenner (1749–1823) discovered that it was possible to make people immune to a disease they never had. First, he gave a person an injection of a dead or weakened microorganism (called a vaccine) that caused a certain disease (like cowpox). The vaccine was not strong enough to give the person cowpox, but still the patient's body would react by producing antibodies against the disease. Jenner found that immunization protected his patients from the dreaded smallpox disease. Eventually, successful methods of immunization were developed against such diseases as diphtheria, whooping cough, mumps, measles, rubella, polio, rabies, anthrax, typhoid fever, typhus, yellow fever, cholera, and the plague.

PAUL EHRLICH

German bacteriologist (a person specializing in the study of bacteria) Paul Ehrlich (1854–1915) is the founder of chemotherapy, which is the use of a chemical substance to treat a disease. He also identified substances that could be used as drugs to destroy bacteria in the body, and made important contributions to the understanding of immunity (the body's natural resistance to a foreign substance).

Paul Ehrlich was born in Strehlin, Silesia (then part of Germany, now part of Poland). His family was educated and well-off, and although young Ehrlich did not do well in school at first, he came to be very interested in both chemistry and biology. He attended German universities and received his medical degree in 1878. Throughout his medical education, Ehrlich was always interested in its chemical aspects, and he became especially interested in the new dyes that were being introduced. Ehrlich was particularly fascinated by the staining (dyeing) of cells and tissues and their reactions to dyes. For his graduate thesis he discovered several practical stains for bacteria and even wrote his thesis on that subject. After working with the famous German bacteriologist Robert Koch (1843–1910) studying tuberculosis, he was appointed a professor at the University of Berlin in 1890.

There he began work with others on the study of immunity, or the body's own defense against disease. The group he joined was trying to find a cure for diphtheria, a childhood respiratory disease that killed many. Ehrlich was searching for a substance that would give immunity against diphtheria by using antitoxins. Antitoxins are antibodies produced by the body's immune system to fight poisons invading the body. An antibody is a special protein in the blood that locks on to a specific foreign substance and kills it. By 1892, Ehrlich had worked out an antitoxin for diphtheria that could be used medically. He obtained the right antitoxin from large animals that had been immunized against diphtheria. He then concentrated and purified it and administered it to 220 children with success. For his work on immunity, Ehrlich later won the 1908 Nobel Prize for Physiology and Medicine. After this achievement, Ehrlich returned to studying dyes and stains, and decided to pursue a fascinating idea. He knew that stains were useful because they colored some cells but not others, thereby making the stained ones stand out. He also knew that a stain would not color a bacterium (plural, bacteria) unless it combined with something in the bacterium. Knowing also that when this happened the bacterium usually died, he theorized that if he could find a dye that stained bacteria but not ordinary cells, then maybe it was also a chemical that killed bacteria without harming the host (the human being). He described such a chemical as a "magic bullet," saying that it would seek and destroy only the invader. Eventually, he did discover one dye, called trypan red, that worked against such diseases as sleeping sickness. Much later, he discovered a dye he named Salvarsan that would kill the microorganism that caused syphilis, a sexually transmitted disease. These two chemicals marked the beginning of modern chemotherapy. Ehrlich proved to be a pioneer not only in the field of immunology, but in the newer field of chemotherapy as well.

HIV AND AIDS

The last few decades of the twentieth century witnessed not a new disease to fight, but the emergence of a disorder of the human immune system itself called AIDS (Acquired Immune Deficiency Syndrome). Infection by this new Human Immunodeficiency Virus (HIV) caused the immune system to collapse, leaving the body defenseless. Specifically, the HIV virus attacked certain T-cells and made them unable to do their job helping B-cells make antibodies. The result was that once a person's natural immune system shut down, they became host to a number of devastating infectious organisms. AIDS is not a single disease but a syndrome of symptoms that are caused by infectious invaders taking advantage of an immune system that cannot function. HIV can remain dormant in the body for some time without producing any signs. There is still no cure for AIDS, although great progress has been made in coping and managing this disease and prolonging the lives of its victims.

Also in the last few decades, biologists have discovered that the immune system can be affected by a person's psychological health or state of mind. Apparently there exists a complex network of nerves, hormones, and brain chemicals that link the immune system to a person's mental state, and it has been demonstrated that extreme psychological stress can suppress the immune system and accelerate certain diseases. Recent immunological research indicates that the mind/body connection is more significant than previously thought.

[See alsoAIDS; Antibody and Antigen; Immunization; Lymphatic System; Vaccine ]

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Immune System

Immune System

The human immune system is a series of defensive shields with which the body is equipped to repulse both outside attacks as well as any internal uprisings that occur within its organs, communications networks, or bloodstream. The immune system is a series of interdependent parts that begin at the surface of the skin. A number of the internal organs contribute to the function of these defenses. The lymph glands and the cardiovascular system are the means by which the active agents of the immune system are transported throughout the body. Immunology is the specialized scientific study of immune system function.

Immunity is a characteristic of the human body that is present through two general mechanisms. Innate immunity is the manner in which the response to certain types of threat is genetically determined. The components of the body that contribute to its innate immunity are those that work to prevent or repel the entry of foreign matter, including the skin, the lungs, and the mucus contained within them. Secretions such as tears, saliva, and vaginal discharges that remove potentially harmful organisms are a function of the innate immune system.

The second general aspect of human immunity is its acquired or adaptive nature. Lymphocytes are important cellular mechanisms that are created by the body for the purpose of adapting to the threats presented to the body. The immune system produces a number of specialty cells, known as antibodies, whose function is to target pathogens and build immunities.

The innate and the adaptive characteristics of the immune system do not operate in isolation from one another. The response to biological threat made against the body is often the subject of a two-tiered reaction, engaging both innate and adaptive responses.

The immune system has a number of weapons with which it will respond to a threat to the body's health. Antigens are any substances that are capable of eliciting an immune response from the body. Antigens may be such microscopic particles as a strain of dangerous bacteria or a virus; a nail or a sliver of wood that punctures the skin is also an antigen. Certain aspects of the immune system function as antigen specific, designed to combat a particular threat that is identified by the body.

Other immune system components are systemic, in that they operate by means of their recognition of certain types of potentially dangerous cells; when the cell is not recognized by the immune system, it is attacked and destroyed. Certain types of illnesses, such as multiple sclerosis, are conditions that affect the autoimmune system. These illnesses are progressive, as they direct the systemic parts of the immune system to attack themselves.

The third class of immune system response is built upon the memory of the immune system as it developed from the knowledge of a prior immune threat. When the immune system has been the subject of a previous attack by a foreign substance, it responds with a greater force to repel the invader on the next occurrence. Inoculation against disease, which involves the injection of a small amount of dangerous living bacteria into the body, is a preventative measure that permits the body to build a successful future defense mechanism against specific threats. Diseases such as poliomyelitis, or polio, are prevented in this fashion.

The blood circulating through the cardiovascular system has a number of immune system responsibilities. Blood is comprised of three major components with respect to immune function: plasma, which is approximately 90% water; erythrocytes (red blood cells) in an approximate volume of 5 million cells per mm3; and leukocytes (white blood cells), in a usual volume that ranges from 5,000 to 10,000 per mm3.

When blood volumes are low due to dehydration, the ability of the circulatory system to provide support to the immune system is reduced. Red blood cells are the transport mechanism for the cardiovascular system, particularly with respect to the delivery of oxygen and other nutrients essential to the production of energy. White blood cells are infection-fighting agents within the bloodstream and a backbone to the preservation of immunity; the generally fatal condition of leukemia is a cancer of the blood that occurs when the white cell production system self-destructs through the production of an abnormally high number of white blood cells.

The lymph system has two primary components: the first is the bone marrow, responsible for white blood cell production, and the second is the thymus gland, a small organ located above the heart. The secondary organs of the lymph system are located near the usual entrances into the body by foreign objects, which are known as pathogens. The first such organs are the adenoids and the tonsils, located in the throat, which are in close contact with all foods, liquids, and other substances passing into the body. The second secondary organ of the lymph system is the spleen, a structure that, among its responsibilities, is a center for the reprocessing of dead and damaged red blood cells that are extracted from the bloodstream. Another group of secondary organs are the lymph nodes, which are designed to act as filters to strain out particular organisms that may present a threat to the health of the body; these nodes are located in the neck, armpits, and groin.

In the lymph nodes and elsewhere in the immune system are bacteria specially created by the body to consume potentially dangerous foreign bacteria. These eating substances, known as macrophage, attack antigens.

There are a number of other external factors that may influence the efficiency of the immune system. Stress has been proven to decrease immune function, as has the abuse of alcohol, the use of corticosteroids, and the ingestion of stimulants such as cocaine. Poor nutrition, either alone or in combination with insufficient exercise, will have a negative impact upon the immune system.

see also Cardiovascular system; Mental stress; Sports medical conditions.

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