Organ-specific autoimmunity resulting from two genetic defects in tolerance

项目摘要 多种耐受机制共同作用预防大多数个体的自身免疫性疾病 通过限制自身反应性淋巴细胞的活性。基因如何决定缺陷在特定的耐受性中 导致自身免疫性疾病的途径可能相互作用，但目前尚不清楚。这个项目的目标是 通过在小鼠中使用两种基因对多基因自身免疫易感性进行建模，提供对多基因自身免疫易感性的基础的见解 免疫机制特别清楚的缺陷，即LYN和LYN完全缺陷 艾尔部分缺乏症。AIRE控制着大量组织限制性自身抗原的表达。 胸腺，从而促进T细胞的中枢耐受。LYN是一种蛋白酪氨酸激酶，可以抑制 树突状细胞、巨噬细胞和B细胞的活性 这些细胞表面的抑制性受体。值得注意的是，含有两种亚型等位基因的小鼠 AIRE本身导致对自身免疫耐药的C57BL/6背景几乎没有自身免疫，以及一种 LYN缺陷会自发地对他们的视网膜产生高度破坏性的自身免疫攻击。这种病 发生在50%的Lyn-/-AireGW/+小鼠身上，所有这些小鼠在8周大时都有严重的疾病，而另一只 50%受到保护。在双突变小鼠中的疾病患病率与相同的结果惊人地相似 对患有自身免疫性疾病的人类进行的双胞胎研究。此外，这种新的自发器官动物模型-- 特定的自身免疫性疾病有几个特征，特别有利于机械性解剖和 可能会为自身免疫性疾病易感性的本质提供新的概念性见解 和入会。拟议的研究将确定CD4T细胞的表位特异性和亲和力 打破耐受性，发起自身免疫攻击。胸腺中减少的自身抗原表达如何使 这些T细胞的致病潜力将被确定。此外，对于没有患葡萄膜炎的小鼠， 在眼部引流的淋巴结中，视网膜自身抗原特异性的CD4T细胞有少量的扩张。这个 在50%的动物中，阻止这些T细胞发起自身免疫攻击的免疫机制将 要下定决心。我们将确定受保护动物的耐受性是否主要是由于对 效应T细胞，视网膜特异性Treg的优势抑制，或组织特异性检查点。在这些 受保护的小鼠，我们将确定免疫紊乱是否会在其他情况下引发疾病 受保护的动物，这种情况可能与某些癌症中出现的器官特异性自身免疫有关 接受检查站封锁治疗的患者。这些研究将为我们提供对 两种不同免疫耐受途径中的遗传缺陷如何相互作用导致遗传 对自身免疫性疾病的易感性以及了解自身免疫性疾病是如何在某些 并不是所有的个体都有相同程度的遗传易感性。

Project Summary A diversity of tolerance mechanisms work together to prevent autoimmune disease in most individuals by limiting the activity of self-reactive lymphocytes. How genetically determined defects in particular tolerance pathways may interact to lead to autoimmune disease is not well understood. The goal of this project is to provide insights into the basis of multigenic autoimmune susceptibility by modeling it in mice using two genetic defects with especially well understood immunologic mechanisms, namely a complete deficiency in Lyn and partial deficiency in Aire. Aire controls the expression of a large number of tissue-restricted self antigens in the thymus and therefore promotes central tolerance of T cells. Lyn is a protein tyrosine kinase that restrains the activities of dendritic cells, macrophages, and B cells due to its importance in mediating the signaling of inhibitory receptors on the surface of these cells. Remarkably, mice containing both a hypomorphic allele of Aire, which by itself leads to little autoimmunity on the autoimmune resistant C57BL/6 background, and a deficiency in Lyn spontaneously develop a highly destructive autoimmune attack on their retinas. This disease occurs in 50% of Lyn-/- AireGW/+ mice, all of which have severe disease by 8 weeks of age, whereas the other 50% are protected. The disease prevalence in the double mutant mice is strikingly similar to results of identical twin studies in humans with autoimmune diseases. Moreover, this new animal model of spontaneous organ- specific autoimmune disease has several features that are especially favorable for mechanistic dissection and may make it possible to provide new conceptual insights into the nature of autoimmune disease susceptibility and initiation. The proposed studies will determine the epitope specificity and avidity of the CD4 T cells that break tolerance and initiate autoimmune attack. How reduced self-antigen expression in the thymus enables the pathogenic potential of these T cells will be determined. In addition, for mice that do not develop uveitis, there is a small expansion of retinal autoantigen-specific CD4 T cells in the eye-draining lymph nodes. The immunological mechanisms that prevent these T cells from initiating autoimmune attack in 50% of animals will be determined. We shall determine whether tolerance in the protected animals is primarily due to anergy of effector T cells, to dominant suppression by retina-specific Treg, or to a tissue-specific checkpoint. In these protected mice, we shall determine whether immunological perturbations can unleash disease in otherwise protected animals, a situation that may be relevant to the organ-specific autoimmunity seen in some cancer patients treated with checkpoint blockade. These studies will provide novel and valuable insights into the question of how genetic defects in two different immune tolerance pathways can interact to result in genetic susceptibility to autoimmune disease and in understanding how autoimmune disease in initiated in some but not all individuals with the same degree of genetic susceptibility.