Antibody-induced T cell-mediated neonatal autoimmunity

描述（由申请人提供）：我们最近对自身免疫性卵巢癌的研究 疾病（AOD）已经积累的证据表明，刺激抗原和 生命早期的环境因素使遗传易感小鼠易于 早发型和晚发型自身免疫性疾病，这是可以解释的 在生命早期存在的CD4 + CD25+调节性T细胞相对缺乏。我们 现在，我提出了一个新的和惊人的观察，进一步加强了 范例抗卵巢透明质酸3（ZP3）B细胞自身抗体 发现表位（335 - 342）优先损伤新生小鼠的卵巢 同时保留成年小鼠的卵巢。有趣的是，虽然卵巢 疾病由ZP3自身抗体触发，疾病表达取决于 新生儿的T细胞，并与新生儿自身免疫性T 细胞对卵巢抗原的反应。此外，诱导这种前代AOD， 是B细胞表位特异性的;因此是针对第二ZP3天然B细胞表位的autoAb （171 - 180）是非致病性的。更令人兴奋的是， 当autoAb在生命的前5天首次到达新生小鼠时。 因此，母体自身抗体可触发新生儿致病性自身免疫性T细胞 细胞反应和前基因AOD;疾病诱导是B细胞 表位特异性，仅影响已知缺乏的新生小鼠 在调节性T细胞中。我们现在提出以下实验方法， 进一步研究这些新的令人兴奋的观察结果。首先，我们将测试 假设前代AOD是由表位特异性自身抗体触发的， 与内源性Ag形成免疫复合物，诱导ZP3特异性致病性T细胞 细胞反应和长期自身免疫记忆。第二，我们将测试 假设免疫复合物对抗原呈递细胞的激活是 依赖于它们的Fc受体，并且该事件是前基因AOD所必需的。 诱导第三，我们将检验CD4 + CD25+调节性T细胞是否能在细胞内表达。 新生小鼠的缺乏解释了新生小鼠发展的倾向， 自身免疫反应和疾病。因此，该提案将解决 负责自身免疫诱导和预防的基本机制， 具体地，新生儿自身免疫性疾病包括系统性狼疮相关的 先天性心脏传导阻滞

DESCRIPTION (provided by applicant): Our recent studies on autoimmune ovarian disease (AOD) have accrued evidence that stimulation by antigen and environmental factor early in life predisposes genetically-susceptible mice to early- and late-onset autoimmune disease, and this is explicable by the relative paucity of the CD4+CD25+ regulatory T cells present early in life. We have now made a new and striking observation that further strengthens the paradigm. Autoantibody (autoAb) to the ovarian zona pellucida 3 (ZP3) B cell epitope (335-342) was found to preferentially injure ovaries in neonatal mice while sparing ovaries of adult mice. Interestingly, although the ovarian disease is triggered by ZP3 autoAb, disease expression depends on the presence of T cells in the neonate, and is associated with de novo neonatal autoimmune T cell response to ovarian antigen. In addition, induction of this progenic AOD is B cell epitope-specific; thus autoAb to a second ZP3 native B cell epitope (171-180) is non-pathogenic. Even more exciting, progenic AOD develops only when the autoAb first reaches the neonatal mice in the first 5 days of life. Therefore, maternal autoAb can trigger in neonates pathogenic autoimmune T cell response and progenic AOD; the disease induction is B cell epitope-specific, and only impacts neonatal mice that are known to be deficient in regulatory T cells. We now propose the following experimental approaches to further investigate these new and exciting observations. First, we will test the hypothesis that progenic AOD is triggered by epitope-specific autoAb, which forms immune complexes with endogenous Ag, to induce ZP3 specific pathogenic T cell response and long-term autoimmune memory. Second, we will test the hypothesis that activation of antigen presenting cells by immune complex is dependent on their Fc receptor, and this event is required for progenic AOD induction. Third, we will test the hypothesis that CD4+ CD25+ regulatory T cell deficiency in neonatal mice explains the propensity of neonatal mice to develop autoimmune response and disease. This proposal will therefore address fundamental mechanisms responsible for autoimmune induction and prevention, and specifically, neonatal autoimmune diseases including systemic lupus-related congenital heart block.