Publications

Abstract

Preventing self-reactive lymphocytes from participating in effector responses is fundamental to maintaining immunological self-tolerance and circumventing autoimmunity. A range of complementary mechanisms are known to act upon the primary B- and T-cell repertoires to this effect, eliminating or silencing lymphocytes expressing self-reactive antigen receptors generated through V(D)J recombination in early lymphoid precursors. In the case of B cells, secondary diversification of antigen receptor repertoire by somatic hypermutation (SHM) provides an additional challenge, especially because this occurs in germinal center (GC) B cells that are actively responding to antigen and primed for differentiation into antibody-producing plasma cells. While it is clear that self-tolerance mechanisms do act to prevent antibody production by self-reactive GC B cells, it is also apparent that most pathogenic autoantibodies carry somatic mutations and so have derived from a GC response. Recent advances in the analysis of autoantibody-producing cells associated with human autoimmune diseases together with insights gained from animal models have increased our understanding of the relationships between GCs, SHM and autoantibody production. Here we discuss these developments and focus in particular on how they have illuminated the genesis and pathogenesis of one archetypal autoantibody, rheumatoid factor.