Discrimination between self and nonself is imperfect, partly because a proper balance must be struck between preventing autoimmune disease and preserving immune competence. Self-reactive lymphocytes always exist in the natural immune repertoire but are not often activated. In autoimmune diseases, however, these cells become activated by autoantigens. If activation persists, autoreactive effector lymphocytes are generated and cause disease. The immune system has a remarkable set of mechanisms that work together to prevent autoimmune disease (see Fig. 15.2). This collective action means that each mechanism need not work perfectly nor apply to every possible self-reactive cell. Self-tolerance begins during lymphocyte development, when autoreactive T cells in the thymus and B cells in the bone marrow are deleted or, in the case of CD4 T cells, give rise to a subpopulation of self antigen-reactive FoxP3+ ‘natural’ or ‘thymic’ Treg cells that suppress autoimmune responses after exiting the thymus. Mechanisms of peripheral tolerance, such as anergy and deletion, or the extrathymic production of ‘induced’ or ‘peripheral’ Treg cells, complement these central tolerance mechanisms for antigens that are not expressed in the thymus or bone marrow. Weakly self-reactive lymphocytes are not removed in the primary lymphoid tissues (thymus and bone marrow), as deletion of weakly autoreactive cells would impose too great a limitation on the immune repertoire, resulting in impaired immune responses to pathogens. Instead, weakly self-reactive cells are suppressed only if they are activated in the periphery, and the mechanisms that suppress them include inhibition by T cells, which are themselves autoreactive, although not pathogenic. T cells can inhibit self-reactive lymphocytes if the regulatory cells are targeting autoantigens located in the same vicinity as the autoantigens to which the self-reactive lymphocytes respond. This allows regulatory cells to home to and suppress sites of autoimmune inflammation. A final mechanism that controls autoimmunity is the natural tendency of immune responses to be self-limited; intrinsic programs in activated lymphocytes make them prone to apoptosis. Activated lymphocytes also acquire sensitivity to external apoptosis-inducing signals, such as those mediated by Fas.
Autoimmune diseases and pathogenic mechanisms.
Here we describe some common clinical autoimmune syndromes, and ways in which loss of self-tolerance can generate self-reactive lymphocytes that cause tissue damage. The mechanisms of pathogenesis resemble in many ways those that target invading pathogens. Damage by autoantibodies, mediated through the complement and Fc receptor systems, has an important role in some diseases, such as SLE. Similarly, cytotoxic T cells directed at self tissues destroy them much as they would virus-infected cells; this is one way by which pancreatic β cells are destroyed in diabetes. However, unlike most pathogens, self proteins are not typically eliminated, so that, with rare exceptions—such as the islet cells in the pancreas—the response persists chronically. Some pathogenic mechanisms are unique to autoimmunity, such as antibodies against cell-surface receptors that affect their function, as in myasthenia gravis. In this part of the chapter we describe the pathogenic mechanisms of some major autoimmune diseases.
15-8 Specific adaptive immune responses to self antigens can cause autoimmune disease.