Molecular and Cellular Analysis of Autoreactive B Cell Elimination from Germinal

从自身免疫性疾病患者中分离出的抗体的自我反应性通常是由体细胞突变所致。事实上，免疫球蛋白基因回复到生殖系序列通常会消除对自身抗原的反应性。这些数据表明，许多自身反应性B细胞来源于生发中心反应，在生发中心反应中，免疫球蛋白可变基因发生体细胞超突变。自我反应性B细胞在早期发育过程中被消除的机制是众所周知的。相比之下，对于健康个体中体细胞突变诱导的自我反应性通常是如何防止的，以及这些途径中哪些在自身免疫性疾病患者中失败，人们知之甚少。在这项建议中，我们将确定B细胞受体(BCR)信号下游的生存途径，以及允许自身反应性B细胞存活的CD4+T细胞帮助。

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.