General Features Of Immunologic Tolerance

There are several characteristics of tolerance in T and B lymphocyte populations. It is important to appreciate the general principles before we discuss the specific mechanisms of tolerance in these lymphocytes.

• Normal individuals are tolerant of their own (self) antigens because the lymphocytes that recognize self antigens are killed or inactivated or the specificity of these lymphocytes is changed. All individuals inherit essentially the same antigen receptor gene segments, and these recombine and are expressed in lymphocytes as they arise from stem cells. The specificities of the receptors encoded by the recombined genes are random, and are not influenced by what is foreign or self for each individual (see Chapter 8). It is not surprising that during this process of generating a large and diverse repertoire, some developing T and B cells in every individual may express receptors capable of recognizing normal molecules in that individual (i.e., self antigens). Therefore, there is a risk for lymphocytes to react against that individual's cells and tissues, causing disease. The mechanisms of immunologic tolerance are designed to prevent such reactions.

The importance of self-tolerance for the health of individuals was appreciated from the early days of immunology. In Chapter 1, we introduced the concept of self-nonself discrimination, which is the ability of the immune system to recognize and respond to foreign antigens but not to self antigens. Macfarlane Burnet added to his clonal selection hypothesis the corollary that lymphocytes specific for self antigens are eliminated to prevent immune reactions against one's own tissues. As we shall see later in this chapter, self-tolerance is maintained by several different mechanisms that prevent the maturation and activation of potentially harmful self-reactive lymphocytes.

• Tolerance results from the recognition of antigens by specific lymphocytes. In other words, tolerance, in its strict definition, is antigen specific. This contrasts with therapeutic immunosuppression and inherited or acquired immunodeficiencies, which affect lymphocytes of many specificities. The key advances that allowed immunologists to study tolerance were induction of this phenomenon in animals by exposure to defined antigens under various conditions and analysis of the functions of the lymphocytes that had encountered tolerogenic antigens. The results that definitively established tolerance as an immunologically specific phenomenon that could be induced experimentally came from studies of graft rejection in inbred mice done by Peter Medawar and colleagues in the 1950s. An adult mouse of strain A will reject a skin graft from an allogeneic mouse of strain B that differs from strain A at the major histocompatibility complex (MHC). If the strain A mouse is injected with white blood cells of strain B during neonatal life (the cells serving as a source of strain B antigens), the injected cells will not be rejected (because the neonate is immunodeficient), and small numbers will survive indefinitely in the recipient. The persistence of allogeneic lymphoid cells in a host is called hematopoietic microchimerism. This strain A recipient will accept a graft from strain B even after it becomes an adult. However, the strain A recipient will reject skin grafts from all mouse strains whose MHC is different from that of strain B. Thus, tolerance to the graft is immunologically specific. Such experiments led to the concept that exposure of developing lymphocytes to foreign antigens induces tolerance to these antigens. Microchimerism is now being studied as a possible approach for preventing graft rejection in humans (see Chapter 16).

• Self-tolerance may be induced in immature self-reactive lymphocytes in the generative lymphoid organs (central tolerance) or in mature lymphocytes in peripheral sites (peripheral tolerance) (Fig. 14-1). Central tolerance ensures that the repertoire of mature lymphocytes becomes incapable of responding to self antigens that are expressed in the generative lymphoid organs (the thymus for T cells and the bone marrow for B lymphocytes, also called central lymphoid organs). However, central tolerance is not perfect, and it cannot account for unresponsiveness to antigens that are expressed only in peripheral tissues. Tolerance to such tissue-specific self antigens is maintained by peripheral mechanisms. Additional mechanisms of peripheral tolerance work in peripheral tissues to prevent activation of self-reactive lymphocytes that may have escaped central tolerance.

• Central tolerance occurs during the maturation of lymphocytes in the central (generative) lymphoid organs, where all developing lymphocytes pass through a stage at which encounter with antigen may lead to cell death or replacement of a self-reactive antigen receptor with a new one. The generative lymphoid organs contain mostly self antigens and not foreign antigens because foreign (e.g., microbial) antigens that enter from the external environment are typically captured and taken to peripheral lymphoid organs, such as the lymph nodes, spleen, and mucosal lymphoid tissues, and are not transported to the thymus or bone marrow. The antigens normally present in the thymus and bone marrow include ubiquitous, or widely disseminated, self antigens including those bought in by the blood. In addition, some peripheral tissue-specific antigens are expressed in specialized cells in the thymus. Therefore, in the generative lymphoid organs, the immature lymphocytes that specifically recognize antigens are typically cells specific for self, and not foreign, antigens. Strong recognition of self antigens by immature lymphocytes has several possible outcomes: the cells may die by apoptosis (called clonal deletion or negative selection because this process selects clones of antigen-specific cells for elimination); many immature B cells do not die but change their receptors (called receptor editing) and thus no longer recognize the self antigen that triggered this process; and some CD4+ T cells differentiate into regulatory T cells, which migrate to the periphery and prevent responses to the self antigens (see Fig. 14-1).

• Peripheral tolerance occurs when, as a consequence of recognizing self antigens, mature lymphocytes become incapable of responding to that antigen, or are induced to die by apoptosis, or mature T cells are actively suppressed by regulatory T cells. Peripheral tolerance is most important for maintaining unresponsiveness to self antigens that are expressed in peripheral tissues and not in the generative lymphoid organs and for tolerance to self antigens that are expressed only in adult life, after mature lymphocytes have been generated. Peripheral mechanisms may also serve as a back-up for the central mechanisms, which may not eliminate all self-reactive lymphocytes.

• Whether lymphocytes that recognize antigens become activated or tolerant is determined by the properties of the antigens, the state of maturation of the antigen-specific lymphocytes, and the types of stimuli received when these lymphocytes encounter self antigens. As we shall see in this chapter, these factors affect in different ways the fates of lymphocytes that encounter their cognate antigens.

• Some self antigens may be ignored by the immune system. The importance of this phenomenon of "ignorance" for the maintenance of self-tolerance is not established. Some antigens may be anatomically sequestered from the immune system and thus cannot d) c

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