Fas in host defense and autoimmune diseases

Fas(Apo-1，CD95)参与了正常和自身特异性免疫反应的调节。 Fas在自身免疫中的作用是双重的：它参与了对T细胞增殖的限制 免疫反应及其参与器官特异性自身免疫中T细胞靶向细胞的死亡 回应。研究了几种细胞类型的条件缺失Fas的小鼠，我们发现小鼠缺乏 来自抗原提呈细胞(ARC)的Fas可引起全身自身免疫。我们提出了一个假设 APC的Fas受体缺失会延长它们的存活时间，延长T细胞的抗原提呈时间 因此，在Fas缺陷的动物和人类中观察到的自身免疫是有贡献的。我们也是 追求一种假设，即靶细胞(产生胰岛素的细胞)的Fas表达对 器官特异性自身免疫性疾病(1型糖尿病)的自发发展。已经使用了几个 在发展动物模型的基础上，我们将追求以下具体目标： 特定目的1.确定抗原提呈T细胞对Fas表达的贡献 正常的和自身特异的免疫反应。 A.我们将研究APC对Fas敏感性的动态变化及其在免疫反应中的作用。我们会 也验证了一种假设，即Fas介导的APC消除可以影响慢性前列腺癌的发展 感染。 B.我们将确定Fas介导的抗原提呈细胞死亡如何调节 器官特异性自身免疫(T1D)。 特定目的2.确定Fas在B细胞破坏中的参与程度 自身免疫性糖尿病。 A.我们将确定FI细胞特异性的Fas缺失是否影响自发性高血压的发生 糖尿病T1D NOD模型； B.我们将确定其他细胞毒机制对Fas依赖和Fas非依赖的输入 细胞的凋亡。 我们的研究将通过控制人的寿命为免疫反应的调节开辟新的途径 APC和预防自身免疫性疾病的发展。

Fas (Apo-1, CD95), has been implicated in the regulation of normal and auto-specific immune responses. The role of Fas in autoimmunity is dual: it is involved in the limitation of T cell proliferation in the course of an immune response and it participates in the death of cells targeted by T cells in organ-specific autoimmune responses. Studying mice with conditional deletion of Fas from several cell types we found that mice lacking Fas from antigen presenting cells (ARC) developed systemic autoimmunity. We formulated a hypothesis that a loss of Fas receptor by APC leads to their prolonged survival, extendedpresentation of antigens to T cells, and, thus, contributes to autoimmunity observed in Fas-deficient animals and humans. We are also pursuing a hypothesis that Fas expression by target cells (insulin-producing (I cells) is critical for spontaneous development of an organ-specific autoimmune disease (type 1 diabetes). Using several already developed animal models, we will pursue the following Specific Aims: Specific Aim 1. Determine the contribution of Fas expression by antigen-presenting T cells to normal and auto-specific immune responses. a. We will study the dynamics of Fas-sensitivity of APC and its role in the immune responses. We will also test a hypothesis that Fas-mediated elimination of APC can influence the development of chronic infections. b. We will determine how Fas-mediated death of antigen-presenting cells regulates the development of organ-specific autoimmunity (T1D). Specific Aim 2. Determine the degree of Fas involvement in Bcell destruction during development of autoimmune diabetes. a. We will determine whether fi-cell-specific deletion of Fas affects the development of spontaneous diabetes in NOD model of T1D; b. We will determine the input of other cytotoxic mechanisms into Fas-dependent and Fas-independent apoptosis of & cells. Our studies will open new venues to regulation of immune responses through controlling the lifespan of APC and to prevention of development of autoimmune diseases.