Uncovering the Missing Link that Determines Susceptibility to Autoimmunity

描述 摘要 自身免疫是一种自我破坏性的免疫疾病，通常针对特定的组织或器官。虽然疾病表现可以是组织特异性的，但它们不一定起源于该特定组织。此外，患有特定自身免疫性疾病的个体有风险发展针对其他靶组织的额外自身免疫性。所有自身免疫性疾病的共同点是，它们是由自身耐受性崩溃引起的，其中致病性自身反应性T细胞发挥了重要作用。T细胞对“自身”的耐受性最初是在胸腺选择过程中在胸腺中建立的。强的自身反应性T细胞被克隆删除或克隆偏离，成为调节性T细胞，其是自身攻击性免疫细胞的关键抑制因子。由于这种决定性的选择过程中发挥了重要作用，自我耐受性，我们假设，自身免疫的易感性可能源于一个主要的缺陷，在中央过程中，管理克隆缺失与克隆偏差。该提案将测试这一假设，并最终寻求确定原发性缺陷和导致自身免疫易感性的因素。了解缺陷是这种选择过程最终将允许早期检测处于高风险发展自身免疫性疾病的个体。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。虽然通过用自身抗原免疫诱导抑制性调节性T细胞的产生是可行的，但可能会产生致病性自身反应性细胞，从而使疾病恶化。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。肝星状细胞将作为天然的、调节性的、抗原提呈细胞，以保证肝细胞的有效分化。

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