Uncovering the Missing Link that Determines Susceptibility to Autoimmunity

描述 摘要 自身免疫是一种自杀性免疫疾病，通常针对特定的组织或器官。虽然疾病的表现可能是特定于组织的，但它们不一定起源于特定的组织。此外，患有特定自身免疫性疾病的人有可能产生针对其他靶组织的额外自身免疫。所有自身免疫性疾病的共同点是，它们都是自我耐受性崩溃的结果，主要原因是致病的自我反应性T细胞。T细胞对“自我”的耐受最初是在胸腺选择的过程中在胸腺建立起来的。强大的自我反应性T细胞要么被克隆性删除，要么被克隆性偏离，成为调节性T细胞，后者是自我侵略性免疫细胞的关键抑制者。由于这种决定性的选择过程在自我耐受中起着基础性的作用，我们推测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央过程中的一个主要缺陷。该提案将检验这一假说，并最终寻求确定自身免疫易感性的主要缺陷和促成因素。对缺陷的理解(S)是，这一选择过程最终将允许及早发现患有自身免疫性疾病的高危个体。除了检测自身免疫易感性，这项研究将对预防和有效治疗自身免疫性疾病具有重要意义。虽然通过自身抗原免疫诱导抑制性调节性T细胞的产生是可行的，但也有可能产生致病的自我反应细胞，从而加重疾病。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，以确保有效的GE

DESCRIPTION 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 self antigens, 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 ge