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(T1D)是由于自身免疫过程破坏胰岛中产生胰岛素的β细胞所致。虽然T淋巴细胞被认为是疾病的媒介，但我们发现很大比例的侵袭细胞是B淋巴细胞。最近在其他T细胞介导的疾病中B细胞定向治疗的成功使人们认识到B细胞在这些疾病中比之前认为的更重要。因此，该项目的目标是了解B淋巴细胞催化T细胞相互作用的功能，并促进导致1型糖尿病(T1D)的自身免疫β细胞破坏。为了了解B细胞在T1D中的作用，我们将来自胰岛素自身抗体(MAb125)的免疫球蛋白(Ig)转基因(Tg)引入NOD小鼠，并产生了偏向这种关键胰岛抗原的B细胞谱系。重要的是，我们发现，在NOD小鼠中，抗胰岛素B细胞保持耐受状态，但尽管存在这种耐受，抗胰岛素B细胞保留了对T1D至关重要的B-T细胞相互作用。此外，我们使用只含有H链TG的VH125Tg NOD小鼠(VH125)来生成只有一小部分B细胞与胰岛素结合的多克隆谱系。出乎意料的是，这些多克隆的VH125Tg nod B细胞在胰腺中经历了扩张，它们的自身免疫反应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谱系中，这种状态保留了抗原递呈功能并诱导了自体侵袭性T细胞的扩张；2)胰岛中的新自身抗原介导了胰岛病变中的B细胞选择，通过促进自身抗原的扩散放大了疾病的风险。我们将在三个目标上检验这些假设。首先，入侵的VH125Tg B细胞上的受体结构将被用来识别驱动胰岛攻击的抗原。其次，将确定在耐受性B细胞中维持抗原提呈功能的信号通路，我们将利用这些信息来阻止关键的B-T细胞相互作用。第三个目标将直接测试耐受B细胞在T1D抗原特异性模型中驱动T细胞介导的胰岛素炎和糖尿病的潜力。 该项目对1型糖尿病的治疗具有直接的临床意义；它将1)通过识别新的靶抗原来改善诊断；2)开发策略阻止胰岛抗原呈递给T1D的T细胞；以及3)促进T1D的B淋巴细胞靶向治疗。

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.