IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 13. Regulation of the Immune Response

IDIOTYPIC MODULATION OF THE IMMUNE RESPONSE

Tolerance to self-Antigens develops during ontogeny (see Ch. 12). However, in the neonatal period, the unique binding sites of antigen-specific receptors on B AND T Cells are too sparse to induce tolerance. The same applies to Antibodies: although present in Blood serum, tolerance develops only to their Fc fragments, since these alone are present in sufficient concentration; tolerance does not occur to the determinants of light and heavy chains responsible for binding specific antigens. Thus, individual T-Cell receptors and IMMUNOGLOBULINS are immunogenic due to these unique sequences, termed idiotypes. Antibodies directed against the antigen-binding sites (termed anti-idiotypic antibodies) are capable of influencing the outcome of the Immune Response.

Idiotypic determinants may be encoded by germline V-region genes or arise through the recombination and mutation events that generate functionally active immunoglobulin V-region genes (see Ch. 8). Immunogenic epitopes located within or immediately surrounding the binding site are called idiotopes (Fig. 13.12). The renowned immunologist Jerne hypothesized the existence of an immune network within the body, in which interactions are mediated through the recognition of idiotypes. According to this concept, antibodies produced against an antigen in turn elicit a directed anti-idiotypic response. While this hypothesis is conceptually appealing, The Physiological Role of such an idiotypic network in regulating normal immune responses remains a subject of intense debate.

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Fig. 13.12. Anti-idiotypic serum may contain antibodies directed against various Regions of the immunoglobulin molecule. The binding of antibodies directed to the immunoglobulin binding site (idiotope) can be inhibited by a hapten. Conversely, the binding of antibodies to idiotopes localized outside the binding site is not inhibited by the hapten.

Idiotypic interactions can enhance or suppress the HUMORAL IMMUNE RESPONSE

Compelling evidence has demonstrated that anti-idiotypic antibodies can influence the expression of recognized idiotypes during an immune response. For instance, when C57BL/6 mice are administered the hapten nitrophenyl (NP), they predominantly produce antibodies of a few restricted idiotypes, such as the I46 idiotype. Anti-idiotypic antibodies directed against these antibodies (idiotype I46) can either enhance or suppress The production of the I46 idiotype in response to subsequent challenge with NP coupled to a carrier protein. The observed effect depends on the dose of administered anti-idiotypic antibodies (Fig. 13.13) and is idiotype-specific, since the overall level of anti-NP antibodies changes very little. Most importantly, the concentrations of anti-idiotypes used fall within the normal physiological range for antibodies bearing this idiotype, suggesting that idiotypic regulation may operate in vivo. Similar observations have been made in other idiotypic systems.

Fig. 13.13. Mice were injected with 10 or 0.1 µg of anti-idiotypic antibodies (anti-Id) directed against nitrophenyl (NP)-binding antibodies (idiotype I46). Six weeks later, the animals were challenged with NP conjugated to a carrier (chicken globulin, CG). Two weeks post-immunization, the serum levels of idiotype I46 antibodies (horizontal bars) and total anti-NP antibodies (not shown) were determined. Mice pretreated with 10 µg of anti-Id showed suppression of the I46 idiotype, whereas mice receiving 0.1 µg of anti-Id exhibited enhanced I46 production, although total anti-NP antibody levels were comparable in both groups.

Administering anti-idiotypic antibodies to newborn animals has dramatic consequences, as the resulting effects can persist throughout life. For example, the ability of mice to respond to phosphorylcholine is sharply reduced if they receive anti-idiotypic antibodies to T15 (the major idiotype in the phosphorylcholine response) during the neonatal period. This state of hyporesponsiveness lasts for many months. Upon subsequent administration of the specific antigen, such mice predominantly produce immunoglobulins lacking the T15 idiotype (Fig. 13.14).

Fig. 13.14. Newborn and adult mice were injected with anti-idiotypic antibodies (anti-Id) specific for T15. The animals were then immunized with the hapten phosphorylcholine (PC) coupled to a carrier, and the total amount of anti-PC antibodies—including the T15 component (darker portion of the horizontal bars)—was determined. Control adult mice mounted an effective response to PC, with the majority of antibodies consisting of T15 (1). Adult mice pretreated with anti-Id showed a temporary suppression of antibody synthesis accompanied by the loss of T15 and a consequent reduction in the overall PC response (2). In contrast, newborn mice administered anti-Id exhibited long-term suppression of T15⁺ B-cell production, accompanied by a compensatory increase in PC-specific T15^- B cells (3).