Publications

Abstract

Secondary diversification of the B cell repertoire by Ig gene somatic hypermutation in the germinal center (GC) is essential for providing the high-affinity antibody specificities required for long-term humoral immunity. Whilst the risk to self-tolerance posed by inadvertent generation of self-reactive B cells in the GC has long been recognized, it has not previously been possible to identify such cells and study their fate. Using a newly developed experimental model, we show that self-reactive B cells generated de novo in the GC do not survive when their target self-antigen is either expressed ubiquitously or in cells proximal to the GC microenvironment. By contrast, GC B cells recognizing rare or tissue-specific self-antigens are not eliminated, and can 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 post-infectious autoimmune disease.