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 enormous—in 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): 5–8.

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): 3342–3349.

Klinman, N. R. and Kline, G. H. "The B-Cell Biology of Aging." Immunology Review 160 (1997): 103–114.

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): 977–982.

Linton, P., and Thoman, M. L. "T Cell Senescence." Front Biosci. 6 (2001): D248–D261.

Miller, R. A. "Effect of Aging on T Lymphocyte Activation." Vaccine 18, no. 16 (2000): 1654–1660.

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. 1–2 (2001): 10–20.

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): 509–518.