Molecular and Cellular Analysis of Autoreactive B Cell Elimination from Germinal

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Self-reactivity in antibodies isolated from patients with autoimmune disorders is often imparted by somatic mutations. Indeed, reversion of immunoglobulin genes to germ line sequences typically eliminates reactivity against self-antigens. These data suggest that many autoreactive B cells are derived from the germinal center reaction, in which somatic hypermutation of immunoglobulin variable genes occurs. The mechanisms by which self-reactive B cells are eliminated during early development are well-understood. In contrast, very little is known about how somatic mutation-induced self-reactivity is normally prevented in healthy individuals, and which of these pathways fail in patients with autoimmune disorders. In this proposal, we will identify the survival pathways downstream of B cell receptor (BCR) signals and CD4+ T cell help that allow autoreactive B cells to survive.