Immunodeficiency and Autoimmunity

描述（由申请人提供）：本项目的目标是探索免疫缺陷和自身免疫之间公认的联系的机制。我们已经开发了一种转基因小鼠模型，其中特异于卵清蛋白（Ova）的CD 4辅助T细胞在遇到分泌形式的Ova（sOva）时变得耐受（功能上无反应），该分泌形式的Ova在淋巴细胞充足的宿主中作为自身抗原产生。与此形成鲜明对比的是，如果相同的T细胞看到循环中的 卵母细胞在淋巴细胞减少（RAG-/-）宿主中，耐受失败，导致严重的全身性自身免疫反应，通常是急性致死的。我们的假设是，多种类型的宿主（内源性）淋巴细胞有助于维持自身耐受性的几种机制，包括：竞争抗原和其他刺激，抗原呈递耐受性条件下，和生产的调节细胞因子。使用这个模型，我们将解决以下具体目标。 1.内源性淋巴细胞的调节功能：我们将通过两种方法确定哪种类型的宿主淋巴细胞具有维持耐受的功能。首先，表达sOva的小鼠将耗尽选定的淋巴细胞（CD 4或CD 8 T细胞、B细胞、γ-δ细胞、NK-T细胞）。卵特异性T细胞将被转移到这些宿主中，并随后进行耐受性或自身免疫反应。其次，表达sOva的淋巴细胞减少宿主将用不同的淋巴细胞群重建，并再次检查Ova特异性T细胞的应答。 2.内源性淋巴细胞维持耐受性的机制：确定内源性淋巴细胞如何帮助维持自身耐受性并防止自身反应性T细胞的活化。我们将首先定义与耐受性和病理性自身免疫相关的这些T细胞的反应类型。然后，我们将抑制或消除来自自身反应性T细胞或宿主的选定分子（如细胞因子），或来自宿主的选定非淋巴细胞类型，以确定内源性淋巴细胞如何控制耐受性和自身免疫性之间的平衡。 3.成像耐受性和自身免疫：我们将使用常规免疫组织化学和双光子共聚焦显微镜来定义在存在和不存在内源性淋巴细胞的情况下，自身抗原表达宿主中自身反应性T细胞的迁移。这些研究将告诉我们，抗原识别和与宿主淋巴细胞竞争的解剖结构是否影响耐受的维持或失败。该项目将提供关于为什么免疫缺陷与自身免疫相关的有价值的信息，并可能深入了解耐受失败和系统性自身免疫发展的一般机制。

DESCRIPTION (provided by applicant): The goal of this project is to explore the mechanisms underlying the well-recognized link between immune deficiencies and autoimmunity. We have developed a transgenic mouse model in which CD4 helper T-cells specific for ovalbumin (Ova) become tolerant (functionally unresponsive) when they encounter a secreted form of Ova (sOva) produced as a self antigen in lymphocyte-sufficient hosts. In striking contrast, if the same T-cells see the circulating Ova in a lymphopenic (RAG-/-) host, tolerance fails, resulting in a severe, systemic autoimmune reaction that is usually acutely lethal. Our hypothesis is that multiple classes of host (endogenous) lymphocytes help to maintain self-tolerance by several mechanisms, including: competition for antigen and other stimuli, antigen presentation under tolerogenic conditions, and production of regulatory cytokines. Using this model, we will address the following specific aims. 1. Regulatory functions of endogenous lymphocytes: We will determine which types of host lymphocytes function to maintain tolerance by two approaches. First, mice expressing the sOva will be depleted of selected lymphocytes (CD4 or CDS T cells, B cells, gamma-delta cells, NK-T cells). Ova-specific T-cells will be transferred into these hosts and followed for tolerance or autoimmune reactions. Second, lymphopenic hosts expressing the sOva will be reconstituted with different lymphocyte populations, and the responses of Ova-specific T cells will again be examined. 2. Mechanisms by which endogenous lymphocytes maintain tolerance: To determine how endogenous lymphocytes help to maintain self-tolerance and prevent the activation of self-reactive T-cells. We will first define the types of responses of these T-cells that correlate with tolerance vs pathologic autoimmunity. We will then inhibit or eliminate selected molecules (such as cytokines) from the self-reactive T-cells or the host, or selected non-lymphoid cell types from the host, to define how endogenous lymphocytes control the balance between tolerance and autoimmunity. 3. Imaging tolerance and autoimmunity: We will use conventional immunohistochemistry and 2-photon confocal microscopy to define the migration of self-reactive T-cells in a self antigen-expressing host, in the presence and absence of endogenous lymphocytes. These studies will tell us if the anatomy of antigen recognition and competition with host lymphocytes influence the maintenance or failure of tolerance. This project will provide valuable information about why immune deficiencies are associated with autoimmunity, and may give insights into the general mechanisms of failure of tolerance and development of systemic autoimmunity.