B lymphocyte Tolerance in Health and Autoimmunity

描述(由申请人提供)：这是RO1资助的续期申请，用于研究外周B细胞的耐受性。一些证据，包括之前对这项授权的工作，已经表明外周B细胞耐受发生，通常是通过缺失。这种耐受性是自身免疫性疾病发展的障碍。然而，外周的B细胞也必须能够对外来抗原做出反应。B淋巴细胞受许多信号通路的调节，以确保适当的发育、激活和免疫耐受。在这项建议中，我们集中在三个途径，调节外周免疫系统中B细胞亚群的发展，外周B细胞对组织特异性自身抗原的耐受性，以及T非依赖性抗体反应。影响Toll样受体、细胞表面抑制受体和肿瘤坏死因子家族细胞因子BAFF受体信号通路的突变将被用来探讨它们在B细胞自主生物反应中的作用。第一个目标是评估所有TLR信号缺陷小鼠的B细胞发育、B细胞耐受性和TI-2反应。在目标2中，将评估抑制或消除B细胞中SHP-1对外周B细胞耐受性和TI-2反应的影响。Aim 3的实验验证了TACI缺陷的B细胞由于BAFF信号的失调而具有特定的外周耐受缺陷的预测，并试图确定TACI在TI-2反应中的B细胞自主作用。这些研究的长期目标是了解自我/非自我歧视是如何产生的，自身免疫的发展过程中出了什么问题，并找出了可以通过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.