Immunodefiency and Autoimmunity

描述(由申请人提供)：这个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潜在机制。我们开发了一种转基因小鼠模型，在该模型中，针对卵蛋白(OVA)的CD4辅助T细胞在遇到分泌形式的OVA(SOVA)时变得耐受(功能无反应)，在淋巴细胞充足的宿主中，SOVA作为自身抗原产生。与之形成鲜明对比的是，如果同样的T细胞看到循环中的 卵子在淋巴细胞减少(RAG-/-)宿主中，耐受性失败，导致严重的系统性自身免疫反应，通常是急性致命的。我们的假设是，多种宿主(内源性)淋巴细胞通过几种机制帮助维持自身耐受，包括：竞争抗原和其他刺激，耐受条件下的抗原提呈，以及调节性细胞因子的产生。使用这一模式，我们将实现以下具体目标。 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些类型的宿主淋巴细胞具有维持耐受的功能。首先，表达SOVA的小鼠将失去选定的淋巴细胞(CD4或CDS T细胞、B细胞、伽马-德尔塔细胞、NK-T细胞)。卵子特异性T细胞将被转移到这些宿主体内，随后进行耐受或自身免疫反应。其次，表达SOVA的淋巴细胞减少宿主将与不同的淋巴细胞群重组，并再次检测OVA特异性T细胞的反应。 2.内源性淋巴细胞维持耐受的机制：确定内源性淋巴细胞如何帮助维持自身耐受性和阻止自身反应性T细胞的激活。我们将首先定义这些T细胞与耐受性和病理性自身免疫相关的反应类型。然后，我们将抑制或消除从自身反应性T细胞或宿主中选择的分子(如细胞因子)，或从宿主中选择非淋巴样细胞类型，以确定内源性淋巴细胞如何控制耐受和自身免疫之间的平衡。 3.影像耐受和自身免疫：我们将使用常规免疫组织化学和双光子共聚焦显微镜来确定在有和没有内源性淋巴细胞存在的情况下，自反应性T细胞在自我抗原表达的宿主中的迁移。这些研究将告诉我们，抗原识别的解剖结构以及与宿主淋巴细胞的竞争是否会影响耐受性的维持或失败。这个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，并可能对耐受失败和系统性自身免疫的发展的一般机制有深入的了解。

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.