B lymphocyte Tolerance in Health and Autoimmunity

描述（由申请人提供）：这是一份用于研究外周B细胞耐受性的RO 1资助的更新申请。几条证据线，包括先前的工作，这项赠款，已表明，外周B细胞的耐受性发生，往往是通过删除。这种耐受性是自身免疫性疾病发展的障碍。然而，外周中的B细胞也必须能够对外来抗原作出反应。B淋巴细胞受许多信号通路调节，以确保适当的发育、活化和免疫耐受。在这个建议中，我们集中在三个途径，调节外周免疫系统中的B细胞亚群的发展，外周B细胞耐受组织特异性自身抗原，和T-非依赖性抗体反应。影响toll样受体、细胞表面抑制性受体和TNF家族细胞因子BAFF的受体的信号传导途径的突变将用于探测它们在B细胞自主生物应答中的作用。第一个目标评估了所有Tlr信号传导缺陷的小鼠中的B细胞发育、B细胞耐受性和TI-2应答。在目的2中，将评估抑制或消除B细胞中的SHP-1对外周B细胞耐受性和TI-2应答的影响。目标3中的实验测试了TACI缺陷型B细胞由于BAFF信号传导失调而具有特异性外周耐受缺陷的预测，并试图定义TACI在TI-2应答中的B细胞自主作用。这些研究的长期目标是了解自我/非自我的区分是如何进行的，在自身免疫的发展中出现了什么问题，并确定可以操纵这些机制来改善或预防疾病的方法。

DESCRIPTION (provided by applicant): This is a renewal application of an RO1 grant to study tolerance in peripheral B cells. Several lines of evidence, including prior work on this grant, have shown that peripheral B cell tolerance occurs, often by deletion. This tolerance is a barrier to the development of autoimmune disease. However, B cells in the periphery must also be capable of responding to foreign antigens. B lymphocytes are regulated by many signaling pathways that ensure appropriate development, activation and immune tolerance. In this proposal we focus on three pathways that regulate the development of B cell subsets in the peripheral immune system, peripheral B cell tolerance to tissue specific self-antigens, and the T-independent antibody response. Mutations affecting signaling pathways for toll-like receptors, cell surface inhibitory receptors and receptors for the TNF family cytokine BAFF will be used to probe their roles in B cell autonomous biological responses. The first Aim assesses B cell development, B cell tolerance and TI-2 responses in mice deficient in all Tlr signaling. In Aim 2, the effects on peripheral B cell tolerance and the TI-2 response of suppressing or eliminating SHP-1 in B cells will be assessed. Experiments in Aim 3 test the prediction that TACI-deficient B cells have a specific peripheral tolerance defect owing to dysregulated BAFF signaling and attempt to define the B cell autonomous role of TACI in the TI-2 response. The long term goals of these studies are to understand how the self/non-self discrimination is made, what goes wrong in the development of autoimmunity, and to identify ways that these mechanisms may be manipulated to ameliorate or prevent disease.