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疾病，通常针对 特定组织或器官。虽然疾病的表现可以是组织特异性的， 不一定起源于那个特定的组织。此外，具有特定 自身免疫性疾病有发展针对其他自身免疫性疾病风险， 靶组织。所有自身免疫性疾病的共同点是， 自身耐受性的破坏，主要来自致病性自身反应性T细胞。不 在胸腺发育过程中，细胞对自身的耐受性最初是在胸腺中建立的。 选择.强的自身反应性T细胞要么是克隆性缺失的，要么是克隆性缺失的。 偏离成为调节性T细胞，是自身攻击性免疫的关键抑制因子， 细胞由于这种决定性的选择过程在自我宽容中起着重要作用，我们 假设对自身免疫的易感性可能起源于免疫系统的主要缺陷， 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，并最终设法查明主要缺陷 以及自身免疫易感性的促成因素。了解 缺陷是这种选择过程最终将允许早期检测出 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，这项研究将有重要的意义， 用于预防和有效治疗自身免疫性疾病。虽然可行， 通过用自身抗原免疫诱导抑制性调节性T细胞的产生， 可能会产生致病性自身反应细胞，从而加剧 这种疾病 我们提出的研究将探索一种新的策略来预防和/或治疗自身免疫。 肝星状细胞将被用作天然的、调节性的、抗原呈递细胞，以确保 有效产生可抑制致病性自身免疫细胞的调节性T细胞， 从而控制自身免疫。

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.