Читать книгу Immunology - Richard Coico - Страница 20

A turning point in immunology came in the 1950s with the introduction of a Darwinian view of the cellular basis of specificity in the immune response. This was the now universally accepted clonal selection theory proposed and developed by Jerne and Burnet (both Nobel Prize winners) and by Talmage. The clonal selection theory had a truly revolutionary effect on the field of immunology. It dramatically changed our approach to studying the immune system and stimulated research carried out during the last half of the twentieth century. This work ultimately provided us with knowledge regarding the molecular machinery associated with activation and regulation of cellular elements of the immune system. The essential postulates of this theory are summarized below.

As we have discussed earlier, the specificity of the immune response is based on the ability of B and T lymphocytes to recognize particular foreign molecules (antigens) and respond to them in order to eliminate them. The process of clonal expansion of these cells is highly efficient, but there is always the rare chance that errors or mutations will occur, resulting in the generation of cells bearing receptors that bind poorly or not at all to the antigen, or, in a worse‐case scenario, cells that have autoreactivity. Under normal conditions, nonfunctional cells may survive or be aborted with no deleterious consequences to the individual. In contrast, the rare self‐reactive cells are clonally deleted or suppressed by other regulatory cells of the immune system charged with this role, among others. If such a mechanism were absent, autoimmune responses might occur routinely. It is noteworthy that during the early stages of development, lymphocytes with receptors that bind to self‐antigens are also produced, but fortunately they are also eliminated or functionally inactivated. This process gives rise to the initial repertoire of mature lymphocytes that are programmed to generate antigen‐specific responses with a relatively minute population functionally benign, albeit potentially autoreactive cells (Figure 1.2). The circumstances and predisposing genetic conditions that may lead to the latter phenomenon are discussed in Chapter 12.

Figure 1.2. Clonal selection theory of B cells leading to antibody formation.

As we have already stated, the immune system is capable of recognizing innumerable foreign substance serving as antigens. How is a response to any one antigen accomplished? In addition to the now proven postulate that self‐reactive clones of lymphocytes are functionally inactivated or aborted, the clonal selection theory proposed the following.

 T and B lymphocytes of myriad specificities exist before there is any contact with the foreign antigen.

 Lymphocytes participating in an immune response express antigen‐specific receptors on their surface membranes. As a consequence of antigen binding to the lymphocyte, the cell is activated and releases various products. In the case of B lymphocytes, these receptors, so‐called B‐cell receptors (BCRs), are the very molecules that subsequently get secreted as antibodies following B‐cell activation.

 T cells have receptors denoted as T‐cell receptors (TCRs). Unlike the B‐cell products, the T‐cell products are not the same as their surface receptors but are other protein molecules, called cytokines, that participate in elimination of the antigen by regulating the many cells needed to mount an effective immune response.

 Each lymphocyte carries on its surface receptor molecules of only a single specificity, as demonstrated in Figure 1.2 for B cells, and which also holds true for T cells.

These postulates describe the existence of a large repertoire of possible specificities formed by cellular multiplication and differentiation before there is any contact with the foreign substance to which the response is to be made. The introduction of the foreign antigen then selects from among all the available specificities those with specificity for the antigen, enabling binding to occur. The scheme shown in Figure 1.2 for B cells also applies to T cells; however, T cells have receptors that are not antibodies and secrete molecules other than antibodies.

The remaining postulates of the clonal selection theory account for this process of selection by the antigen from among all the available cells in the repertoire.

 Immunocompetent lymphocytes combine with the foreign antigen, or a portion of it termed the epitope or antigenic determinant, by virtue of their surface receptors. They are stimulated under appropriate conditions to proliferate and differentiate into clones of cells with the corresponding epitope‐specific receptors.

 With B‐cell clones, this will lead to the synthesis of antibodies having the same specificity. In most cases, the antigen stimulating the response is complex and contains many different epitopes, each capable of activating a clone of epitope‐specific B cells. Hence, collectively, the clonally secreted antibodies constitute what is often referred to as polyclonal antiserum, which is capable of interacting with the multiple epitopes expressed by the antigen.

 T cells are similarly selected by appropriate epitopes or portions thereof. Each selected T cell will be activated to divide and produce clones of the same specificity. Thus the clonal response to the antigen will be amplified, the cells will release various cytokines, and subsequent exposure to the same antigen will now result in the activation of many cells or clones of that specificity. Instead of synthesizing and releasing antibodies like the B cells, the T cells synthesize and release cytokines. These cytokines, which are soluble mediators, exert their effect on other cells to grow or become activated, facilitating elimination of the antigen. Several distinct regions of an antigen (epitopes) can be recognized: several different clones of B cells will be stimulated to produce antibody, whose sum total is an antigen‐specific antiserum that is made up of antibodies of differing specificity (see Figure 1.1); all the T‐cell clones that recognize various epitopes on the same antigen will be activated to perform their function.

A final postulate was added to account for the ability to recognize self‐antigens without making a response.

 Circulating self‐antigens that reach the developing lymphoid system before some undesignated maturational step will serve to shut off those cells that recognize it specifically, and no subsequent immune response will be induced.