As discussed earlier, induced cellular and antibody responses follow challenge with anti-gens that are normally foreign; however, immunization may not only induce the enhanced reactivities described but may also lead to a diminished reactivity known as tolerance. When specifically diminished reactivity is induced by treatment with large doses of antigen, the phenomenon is referred to as immune paralysis. Because the immune system is based on a random generation of combining sites directed against molecular configurations, there is in principle no reason why the immune response cannot react with self components. When it does, autoimmune diseases such as rheumatoid arthritis, sys-temic lupus erythematosus, and others may result. However, it is now known that normal healthy individuals express detectable levels of autoantibodies against a variety of self components. A regulatory function for these autoantibodies in the maintenance of home-ostasis is suggested by the fact that aged red cells are removed from human circulation by a natural mechanism in which normally occurring IgG autoantibodies specific for a modi-fied membrane component (senescent cell antigen) bind to the cells, leading to their removal by phagocytic cells. Nevertheless, the generation of tolerance or the inability to react against self is a fundamental part of the process of development in vertebrates, which results essentially from the removal or inactivation of T cells in the thymus that can react to self antigens.
Parallel tolerization procedures for B cells occur, but currently a number of mecha-nisms now must be proposed for maintenance of nonreactivity to self. Antigen-specific T cells may be either deleted by contact with antigen (clonal abortion) or inactivated without being destroyed. In addition, suppressor T cells that downregulate the specific immune response may be generated that either shut off the antigen-specific helper T cells or are directed toward combining sites of B-cell antibodies. Antigen-specific B cells may be deleted or inactivated or rendered insensitive to secondary stimulation by cytokines. These central effects operate at the level of antigen-specific T or B cells.
Both experimentally induced tolerance and innate tolerance can be broken down in two general ways. First, if a large amount of antigen is needed to maintain tolerance, immunity can be generated if the level of antigen falls below the required tolerogenic level. A second way of breaking of tolerance is immunization with a cross-reactive antigen. Two clinically well-known examples of the capacity of cross-reactive antigens to break normal self toler-ance are (1) the induction of experimental allergic encephalomyelitis in an animal by the injection of heterologous brain tissue homogenates in emulsified adjuvant and (2) the capacity of infections with group A streptococci to cause rheumatic fever because of a cross-reaction between bacterial antigens and myocardial tissue. The concept of tolerance is critical to much of modem medicine because of increasing interest in autoimmune diseases, which can be considered to result from a failure or breakdown of tolerance.
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