The mechanisms that normally prevent autoimmunity may be thought of as a succession of checkpoints. Each checkpoint is partially effective in preventing antiself responses, and together the checkpoints act synergistically to provide efficient protection against autoimmunity without inhibiting the ability of the immune system to mount effective responses to pathogens. Central tolerance mechanisms eliminate newly formed, strongly autoreactive lymphocytes. On the other hand, mature self-reactive lymphocytes that do not sense self strongly in the central lymphoid organs—because their cognate self antigens are not expressed there, for example—may be killed or inactivated in the periphery. The principal mechanisms of peripheral tolerance are anergy (functional unresponsiveness), suppression by T cells, induction of T cell development instead of effector T-cell development (functional deviation), and deletion of lymphocytes from the repertoire due to activation-induced cell death. In addition, some antigens are sequestered in organs that are not normally accessible to the immune system (Fig. 15.2).
Each checkpoint strikes a balance between preventing autoimmunity and not impairing immunity too greatly, and in combination, all the checkpoints provide an effective overall defense against autoimmune disease. It is relatively
The different ways in which the immune system prevents activation of and damage caused by autoreactive lymphocytes are listed, along with the specific mechanism and where such tolerance predominantly occurs.
Autoimmunity Immune dysregulation Genetic factors Infection and environmental exposure Fig. 15.3 Requirements for the development of autoimmune disease. In genetically predisposed individuals, autoimmunity may be triggered as a result of the failure of intrinsic tolerance mechanisms and/or environmental triggers such as infection.
easy to find isolated breakdowns of one or even more layers of protection, even in healthy individuals. Thus, activation of autoreactive lymphocytes does not necessarily equal autoimmune disease. In fact, a low level of autoreactivity is physiologic and crucial to normal immune function. Autoantigens help to form the repertoire of mature lymphocytes, and the survival of naive T cells and B cells in the periphery requires continuous exposure to autoantigens (see Chapter 8). Autoimmune disease develops only if enough safeguards are overcome to lead to a sustained reaction to self that includes the generation of effector cells and molecules that destroy tissues. Although the mechanisms by which this occurs are incompletely understood, autoimmunity is thought to result from a combination of genetic susceptibility, breakdown in natural tolerance mechanisms, and environmental triggers such as infections (Fig. 15.3).
15-3 Central deletion or inactivation of newly formed lymphocytes is the first checkpoint of self-tolerance.
Central tolerance mechanisms, which remove strongly autoreactive lymphocytes, are the first and most important checkpoints in self-tolerance (see Chapter 8). Without them, the immune system would be strongly self-reactive, and lethal autoimmunity would occur early in life. It is unlikely that peripheral tolerance mechanisms would be sufficient to compensate for the failure to remove self-reactive lymphocytes during primary development. Indeed, no known autoimmune diseases are attributable to complete failure of these mechanisms, although some are associated with a partial failure of central tolerance.