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Clonal anergy is a major mechanism in the generation and maintenance of peripheral tolerance to self‐antigens (Figure 2.2) [10]. Autoreactive T‐cell clones not deleted in the thymus or the peripheral lymphoid tissues may become anergic to autoantigens if TCR activation occurs in the absence of obligatory costimulation. Lack of costimulation results in inadequate secretion of IL‐2 and growth factors required for T‐cell clonal proliferation and maturation of effector functions. Without costimulation, autoantigen‐specific T cells cease to differentiate and fail to respond if reexposed to autoantigen. Anergic B cells have reduced surface IgM, impaired signal transduction and short lifespans, and exhibit anergy to autoantigen reexposure.