Fig. 15.6 Elimination of autoreactive B cells in germinal centers. During somatic hypermutation in germinal centers (top panel), B cells with autoreactive B‑cell receptors can arise. Ligation of these receptors by soluble autoantigen (center panel) induces apoptosis of the autoreactive B cell by signaling through the B‑cell antigen receptor in the absence of helper T cells (bottom panel).
Fig. 15.8 Damage to an immunologically privileged site can induce an autoimmune response. In the disease sympathetic ophthalmia, trauma to one eye releases the sequestered eye antigens into the surrounding tissues, making them accessible to T cells. The effector cells that are elicited attack the traumatized eye, and also infiltrate and attack the healthy eye. Thus, although the sequestered antigens do not induce a response by themselves, if a response is induced elsewhere they can serve as targets for attack.
In murine models of diabetes, when cytokines were infused to influence T-cell differentiation or when knockout mice predisposed to TH2 differentiation were studied, the development of diabetes was inhibited. In some cases, potentially pathogenic T cells specific for pancreatic islet-cell components, and expressing TH2 instead of TH1 cytokines, actually suppressed disease caused by TH1 cells of the same specificity. So far, attempts to control human autoimmune disease by switching cytokine profiles from one effector cell type to another (for example, TH1 to TH2), a procedure termed immune modulation, have not proved successful. Another subset of CD4 T cells, Treg cells, might prove to be more important in the prevention of autoimmune disease, and efforts to deviate effector to regulatory T-cell responses are being studied as a novel therapy for autoimmunity.
15-7 Autoimmune responses can be controlled at various stages by regulatory T cells.
Autoreactive cells that escape the tolerance-inducing mechanisms described above can still be regulated so that they do not cause disease. This regulation takes two forms: the first is extrinsic, and is mediated by regulatory T cells that act on activated T cells and antigen-presenting cells; the second is intrinsic, and has its basis in limits on the size and duration of immune responses that are programmed into lymphocytes themselves. We shall first discuss the role of regulatory T cells (introduced in Chapter 9).