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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, namely, autoimmune diseases develop.

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, eliminates T cells (“negative selection”) that react strongly to antigens encountered in the thymus.

Tolerance acquired outside the thymus is called peripheral tolerance. Peripheral tolerance is necessary because some self-antigens are not encountered in the thymus, and therefore, some potentially self-reactive T cells are not eliminated by negative selection. In addition, there are foreign antigens, such as those from commensal organisms on the barriers of our skin and gastrointestinal tract, which are harmless and should therefore elicit tolerance. A sensitization response to these antigens could be pathogenic (see Chapter 65).

There are several mechanisms involved in peripheral tolerance:


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