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Immune tolerance is the lack of responsiveness to a specific antigen that could otherwise elicit an immune response. The best example of antigen tolerance is a host’s normal absence of response for “self” antigens, while those same antigens might be considered “foreign” if transplanted to a different host. Because it applies to responses to antigens, tolerance is a feature of adaptive immunity, although certain antigen-presenting cells can have a tolerogenic effect on T cells. In this chapter, we will discuss how immune tolerance to “self” develops and what happens when that tolerance is broken.

Whether an antigen will induce tolerance rather than sensitization is largely determined by:

  1. The immunologic maturity of the immune system. In general, antigens that are present during early development do not stimulate an immunologic response (i.e., we are tolerant to those antigens). On the other hand, antigens that are not present during the process of immune maturation (i.e., that are encountered first when the body is more immunologically mature) are considered “foreign” and usually elicit an immunologic response.

  2. The structure of the antigen. For example, simple molecules (small proteins) are more likely to induce tolerance than complex molecules (polysaccharides).

  3. The antigen’s potential to cross-react with other immunogenic antigens. T-cell and B-cell receptors are highly specific, but occasionally, they can confuse one antigen with another. When this happens, an appropriate response against a foreign antigen can inappropriately begin to target self-antigens, causing host tissue damage.

  4. The presence of proinflammatory signals, such as those induced by pathogen-associated molecular patterns (PAMPs) (see Chapter 58), or anti-inflammatory treatment, such as the immunosuppressive drugs described below and in Chapter 62.

  5. The duration of antigen exposure. Tolerance is maintained best if the antigen to which the immune system is tolerant continues to be present.

T-Cell Tolerance

Although both B cells and T cells participate in tolerance, it is T-cell tolerance that plays the primary role. The main process by which T lymphocytes acquire the ability to distinguish self from nonself occurs in the thymus (see Chapter 59). Tolerance to self-antigens acquired within the thymus is called central tolerance. This process, which includes positive and negative clonal selection, involves the killing of T cells (“negative selection”) that react strongly to antigens presented to them in the thymus. How do thymic cells display peptides from proteins that are usually found in the pancreas, lung, or salivary glands? A transcription factor called the autoimmune regulator (AIRE) causes enhanced synthesis of various self-proteins in the thymus. Mutations in the gene encoding the AIRE protein result in the development of an autoimmune disease called autoimmune polyendocrinopathy in which the immune system inappropriately attacks multiple organs.

Note that the thymus is usually a protected space where “truly foreign” proteins are rarely found. But experiments in mice have shown that if an exogenous protein is introduced into ...

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