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.