Antibody-induced T cell-mediated neonatal autoimmunity

描述(申请人提供)：我们最近对自身免疫性卵巢的研究 疾病(AOD)已积累的证据表明，抗原和 生命早期的环境因素使遗传易感的小鼠容易患上 早发和晚发的自身免疫性疾病，这是可以解释的 相对缺乏的CD4+CD25+调节性T细胞出现在生命早期。我们 现在提出了一个新的惊人的观察结果，进一步加强了 范例。抗卵巢透明带3(ZP3)B细胞自身抗体 表位(335-342)优先损伤新生小鼠卵巢 同时保留成年小鼠的卵巢。有趣的是，虽然卵巢 疾病是由ZP3自身抗体触发的，疾病的表现取决于是否存在 并与新生儿自身免疫性T细胞有关 细胞对卵巢抗原的反应。此外，这种原生性AOD的诱导 是B细胞表位特异性的；因此针对第二个ZP3天然B细胞表位的自体抗体 (171-180)是非致病性的。更令人兴奋的是，前驱AOD只发展成 当自体抗体第一次到达新生小鼠的头5天时。 因此，母体自身抗体可在新生儿中触发病理性自身免疫T细胞 细胞反应和原性AOD；疾病的诱导是B细胞 表位特异性，并且只影响已知缺陷的新生小鼠 在调节性T细胞中。我们现在提出以下试验性方法来 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 原基因AOD是由抗原表位特异性自身抗体触发的假说 与内源性抗原形成免疫复合物诱导ZP3特异性致病T细胞 细胞反应和长期自身免疫记忆。第二，我们将测试 假设免疫复合体激活抗原提呈细胞是 依赖于它们的Fc受体，而这一事件是原发AOD所必需的 归纳法。第三，我们将检验这一假设，即CD4+CD25+调节性T细胞 新生小鼠的缺陷解释了新生小鼠的发育倾向 自身免疫反应和疾病。因此，这项提案将解决 诱导和预防自身免疫的基本机制，以及 具体地说，新生儿自身免疫性疾病包括与系统性狼疮相关的 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.