Uncovering the Missing Link that Determines Susceptibility to Autoimmunity

二、摘要： 自身免疫是一种自我破坏性的免疫紊乱，通常会导致 特定的组织或器官。尽管这种疾病的表现可能是组织特异性的，但它们确实是 不一定起源于那个特定的组织。此外，患有特定疾病的个人 自身免疫性疾病有可能发展成针对其他疾病的额外自身免疫 目标组织。所有自身免疫性疾病的共同点是，它们都是由一种 自我耐受性崩溃，主要原因是致病的自我反应性T细胞。T 细胞对自身的耐受最初是在胸腺过程中建立起来的 选择。强大的自我反应性T细胞要么被克隆删除，要么被克隆 偏离成为自身侵袭性免疫的关键抑制者的调节性T细胞 细胞。由于这一决定性的选择过程对自我容忍起着至关重要的作用，我们 假设对自身免疫的易感性可能起源于 控制克隆缺失与克隆偏离的中心过程。 该提案将检验这一假设，并最终寻求找出主要缺陷 以及导致自身免疫易感性的因素。了解 缺陷(S)是这个遴选过程最终将允许及早发现符合以下条件的个人 患上自身免疫性疾病的风险很高。 除了检测自身免疫易感性，这项研究还将具有重要意义。 用于预防和有效治疗自身免疫性疾病。尽管这是可行的 通过自身抗原免疫诱导抑制性调节性T细胞的产生， 可能会产生致病的自身反应细胞，从而加剧 这种疾病。 我们提出的研究将探索一种预防和/或治疗自身免疫的新策略。 肝星状细胞将被用作天然的、调节的、抗原提呈细胞，以确保 高效生成调节性T细胞，可能抑制致病的自身免疫细胞和 从而控制自身免疫力。

II. Abstract: Autoimmunity is a self-destructive immune disorder and often directed towards a particular tissue or organ. Although the disease manifestations can be tissue-specific, they do not necessarily originate in that particular tissue. Furthermore, individuals with a specific autoimmune disease are at risk to develop additional autoimmunity directed towards other target tissues. What all autoimmune diseases do have in common is that they result from a breakdown in self-tolerance, with a major contribution from pathogenic self-reactive T cells. T cell tolerance towards ¿self¿ is initially established in the thymus during the process of thymic selection. Strong self-reactive T cells are either clonally deleted or alternatively clonally deviated to become regulatory T cells that are key suppressors of auto-aggressive immune cells. Since this decisive selection process plays a fundamental role in self-tolerance, we postulate that susceptibility to autoimmunity might originate from a principal defect in the central process that governs clonal deletion versus clonal deviation. The proposal will test this hypothesis and ultimately seek to identify the primary deficiency and contributing factors that underlie susceptibility to autoimmunity. Understanding the defect(s) is this selection process will ultimately allow for early detection of individuals that are at a high risk to develop autoimmune diseases. Aside from detecting autoimmune susceptibility, this research will have vital implications for the prevention and effective treatment of autoimmune diseases. Although it is feasible to induce the production of suppressive regulatory T cells through immunization with selfantigens, it is possible that pathogenic self-reactive cells will be generated, thus exacerbating the disease. Our proposed study will explore a novel strategy to prevent and/or treat autoimmunity. Hepatic stellate cells will be used as natural, regulatory, antigen-presenting cells to assure the efficient generation of regulatory T cells that may suppress pathogenic autoimmune cells and thereby control autoimmunity.