Immune Tolerance

  • The primary dilemma of immunity is properly distinguishing non-self microbes from self-proteins with both high specificity and high selectivity. Failure to attack non-self microbes will lead to infections while inappropriate attack of self-proteins can result in serious Autoimmune Disease. In this section we discuss the multiple immunoregulatory mechanisms, termed Immune Tolerance, which exist to prevent inappropriate mounting of an immune response to host tissues. The basic function of these tolerance mechanisms is to eliminate or functionally inactivate B-cells or T-cells whose antigen receptors recognize self-antigens. Mechanisms of tolerance can be thought of as occurring at two points in the lifespan of lymphocytes. Central Tolerance refers to mechanisms which occur during lymphocyte development where antigen receptors are being rearranged. Peripheral Tolerance refers to mechanism which operate once mature lymphocytes are released into the periphery.
Central Tolerance
  • Overview
    • As discussed in B-cell Development and T-cell Development, lymphocytes whose antigen-receptor can bind self-antigen are "eliminated". Elimination of auto-reactive lymphocytes can occur by one of four mechanisms discussed below.
  • Deletion
    • Deletion is the most straight-forward mechanism of tolerance and involves induction of cell death in auto-reactive lymphocytes. This usually occurs by inducing auto-reactive cells to undergo apoptosis.
  • Anergy
    • Some auto-reactive lymphocytes are given signals such that they achieve an irreversible anergy. Anergic cells continue their development and are released into the periphery; however, no amount of antigen stimulation can cause their proliferation and differentiation into effector cells. Consequently, although these cells are not deleted they are essentially "functionally" eliminated.
  • Ignorance
    • Some auto-reactive lymphocytes either bind self-antigens so weakly or are simply not exposed to their self-antigen during their development such that they are "Ignorant" of their own auto-reactivity. These "Ignorant" lymphocytes are thought to be a major source of auto-reactive lymphocytes in contexts of autoimmune disease. For those that bind self-antigen weakly, it is thought that certain inflammatory scenarios may provide such strong co-stimulatory signals that the ignorant lymphocyte will differentiate into an effector cell regardless of its weak antigen binding. Other lymphocytes may be strongly auto-reactive but may never encounter their antigen in the context of their organ of development. However, the self-antigen may be encountered in the periphery or be exposed during an inflammatory reaction.
Peripheral Tolerance
  • The mechanisms of peripheral tolerance are not well-understood. It is thought that T-cells which recognize MHC-bound antigen, but do not receive co-stimulatory signals from Antigen Presenting Cells may undergo a peripheral anergy. It is also clear that a class of specialized regulatory T-cells, termed T-regs, exist within the periphery which serve to suppress the immune response to self-antigens. Consequently, defects in T-reg function may be a source of autoimmune disease. Finally, certain cytokines, such as IL-10, appear to be important for maintaining peripheral tolerance as mice deficient in this cytokine develop a variety of autoimmune diseases.