Immunity 2012 Nov 6. pii: S1074-7613(12)00462-1. doi: 10.1016/j.immuni.2012.07.017.
Chan, TD; Wood, K; Hermes, JR; Butt, D; Jolly, CJ; Basten, A; Brink, R
Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
Secondary diversification of the B cell repertoire by immunoglobulin gene somatic hypermutation in the germinal center (GC) is essential for providing the high-affinity antibody specificities required for long-term humoral immunity. While the risk to self-tolerance posed by inadvertent generation of self-reactive GC B cells has long been recognized, it has not previously been possible to identify such cells and study their fate. In the current study, self-reactive B cells generated de novo in the GC failed to survive when their target self-antigen was either expressed ubiquitously or specifically in cells proximal to the GC microenvironment. By contrast, GC B cells that recognized rare or tissue-specific self-antigens were not eliminated, and could instead undergo positive selection by cross-reactive foreign antigen and produce plasma cells secreting high-affinity autoantibodies. These findings demonstrate the incomplete nature of GC self-tolerance and may explain the frequent association of cross-reactive, organ-specific autoantibodies with postinfectious autoimmune disease.