Elimination of Germinal-Center-Derived Self-Reactive B Cells Is Governed by the Location and Concentration of Self-Antigen

SummarySecondary 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (266 K)Download as PowerPoint slideHighlights► A new model that allows analysis of self-reactive B cells generated in the GC ► Self-reactive GC B cells are eliminated or inactivated by SHM ► Self-reactive GC B cells not eliminated if target self-antigen is in a distal tissue ► Explains postinfection production of cross-reactive tissue-specific autoantibodies