Selection and Regulation of B Lymphocytes in IDDM

描述（由申请人提供）：IA型或胰岛素依赖型糖尿病（T1 D）由破坏胰岛中产生胰岛素的β细胞的自身免疫过程引起。虽然已知T淋巴细胞介导该疾病，但我们发现大部分入侵细胞是B淋巴细胞。最近B细胞定向疗法在其他T细胞介导的疾病中的成功已经导致人们认识到B细胞在这些疾病中比以前认为的更重要。因此，本项目的目标是了解B淋巴细胞的功能，催化T细胞相互作用，促进自身免疫性β细胞破坏，导致1型糖尿病（T1 D）。为了了解B细胞在T1 D中的作用，我们将来自胰岛素自身抗体（mAb 125）的免疫球蛋白（IG）转基因（Tg）引入NOD小鼠，并产生偏向于这种关键胰岛抗原的B细胞库。重要的是，我们发现抗胰岛素B细胞在NOD小鼠中维持在耐受状态，但尽管存在这种耐受性，抗胰岛素B细胞保留了T1 D所必需的B-T细胞相互作用。此外，我们使用仅具有H链Tg（VH 125）的VH 125 Tg NOD小鼠来产生多克隆库，其中仅小部分B细胞结合胰岛素。出乎意料的是，这些多克隆VH 125 Tg NOD B细胞在胰腺中经历扩增，并且它们的自身免疫应答扩散到胰岛素以外的抗原。这些发现表明：1）抗胰岛素B细胞以一种新的耐受状态保留在库中，这种耐受状态保留了抗原呈递功能并诱导自身攻击性T细胞的扩增; 2）胰岛中的新自身抗原介导胰岛病变内的B细胞选择，通过促进自身抗原扩散放大疾病风险。我们将在三个目标中检验这些假设。首先，入侵的VH 125 Tg B细胞上的受体结构将用于鉴定驱动胰岛攻击的抗原。第二，将鉴定维持耐受性B细胞中抗原呈递功能的信号通路，我们将利用这些信息阻断关键的B-T细胞相互作用。第三个目标是在T1 D的抗原特异性模型中直接测试耐受性B细胞驱动T细胞介导的胰岛炎和糖尿病的潜力。 该项目与1型糖尿病的管理具有直接的临床相关性;它将1）通过识别新的靶抗原来改善诊断; 2）开发阻断T1 D中胰岛抗原向T细胞呈递的策略，以及3）促进靶向T1 D中B淋巴细胞的治疗。

DESCRIPTION (provided by applicant): Type IA or insulin dependent diabetes (T1D) results from of an autoimmune process that destroys insulin producing beta cells in the pancreatic islets. Although T lymphocytes are known to mediate the disease, we find that a large proportion of the invading cells are B lymphocytes. Recent success with B cell directed therapy in other T cell-mediated disorders has led to the recognition that B cells are more important in these diseases than previously thought. Accordingly, the goal of this project is to understand the functions of B lymphocytes that catalyze T cell interactions and promote autoimmune beta cell destruction leading to type 1 diabetes (T1D). To understand the actions of B cells in T1D, we introduced immunoglobulin (Ig) transgenes (Tg) from an insulin autoantibody (mAb125) into NOD mice and generated B cell repertoires that are skewed toward this critical islet antigen. Importantly, we discovered that anti-insulin B cells are maintained in a tolerant state in NOD mice, but despite this tolerance, anti-insulin B cells preserve B-T cell interactions that are essential for T1D. In addition, we used VH125Tg NOD mice that harbor only an H-chain Tg (VH125) to generate a polyclonal repertoire in which only a small fraction of B cells bind insulin. Unexpectedly, these polyclonal VH125Tg NOD B cells undergo expansion in the pancreas, and their autoimmune response spreads to antigens other than insulin. These findings suggest that 1) anti-insulin B cells are retained in the repertoire in a novel state of tolerance that preserves antigen presenting functions and induces the expansion of autoaggressive T cells; and 2) novel autoantigens in the pancreatic islets mediate B cell selection within the islet lesions, amplifying the risk of disease by promoting autoantigen spread. We will test these hypotheses in three aims. First, receptor structures on invading VH125Tg B cells will be used to identify the antigens that are driving the islet attack. Second, signaling pathways that maintain antigen presenting functions in tolerant B cells will be identified and we will use this information to block critical B-T cell interactions. A third aim will directly test the potential for tolerant B cells to drive T cell mediated insulitis and diabetes in an antigen specific model of T1D.Project Narrative This project has direct clinical relevance for the management of type 1 diabetes; it will 1) improve diagnosis by identifying new target antigens; 2) develop strategies to block presentation of islet antigens to T cells in T1D, and 3) facilitate therapy targeted at B lymphocytes in T1D.