Antibody induced T cell mediated neonatal autoimmunity

抗体诱导 T 细胞介导的新生儿自身免疫

• 批准号: 6983362
• 负责人: KENNETH S.K. TUNG
• 金额: $ 32.52万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983362
• 关键词: Antibody; induced; cell; mediated; neonatal

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 zonapellucida 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 neonatal AOD is B cell epitope-specific; thus autoAb to a second ZP3 native B cell epitope (171-180) is non-pathogenic. Even more exciting, neonatal 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 neonatal 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 neonatal AOD is triggered by epitope-specific autoAb, which forms immune complexes with endogenous Ag, to induce ZP3 specific pathogenic T cell response and tong-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 neonatal 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.

描述（由申请人提供）：我们最近对自身免疫性卵巢疾病（AOD）的研究已经积累了证据，即在生命早期受到抗原和环境因素的刺激使遗传易感小鼠易患早发性和迟发性自身免疫性疾病，这可以通过生命早期存在的CD 4 + CD 25+调节性T细胞的相对缺乏来解释。我们现在提出了一个新的和引人注目的意见，进一步加强了这一范式。卵巢透明带3（ZP 3）B细胞表位（335-342）的自身抗体（autoAb）被发现优先损伤新生小鼠的卵巢，而不损伤成年小鼠的卵巢。有趣的是，尽管卵巢疾病是由ZP 3 autoAb触发的，但疾病表达取决于新生儿中T细胞的存在，并且与新生儿自身免疫T细胞对卵巢抗原的应答相关。此外，该新生儿AOD的诱导是B细胞表位特异性的;因此针对第二ZP 3天然B细胞表位（171-180）的autoAb是非致病性的。更令人兴奋的是，只有当autoAb在出生后的前5天首次到达新生小鼠时，新生小鼠才会发生AOD。因此，母体自身抗体可在新生儿中触发致病性自身免疫T细胞应答和新生儿AOD;疾病诱导是B细胞表位特异性的，并且仅影响已知缺乏调节性T细胞的新生小鼠。我们现在提出以下实验方法来进一步研究这些新的令人兴奋的观察结果。首先，我们将检验以下假设：新生儿AOD是由表位特异性自身抗体触发的，其与内源性Ag形成免疫复合物，以诱导ZP 3特异性致病性T细胞应答和长时自身免疫记忆。第二，我们将检验免疫复合物激活抗原呈递细胞依赖于其Fc受体的假设，并且该事件是新生儿AOD诱导所需的。第三，我们将检验新生小鼠中的CD 4 + CD 25+调节性T细胞缺陷解释新生小鼠发展自身免疫反应和疾病的倾向的假设。因此，本提案将解决自身免疫性诱导和预防的基本机制，特别是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。