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: 6825714
• 负责人: KENNETH S.K. TUNG
• 金额: $ 33.3万
• 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/6825714
• 关键词: Antibody; induced; cell; mediated; neonatal

EXCEED THE SPACE PROVIDED, Our recent studies on autoJmmune 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+CD2.5+ 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 pellncida 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 nero neonatal autoimmane 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. Theorem, maternal autoAb can trigger in neonates pathogenic autoi_une T ¿¿11_sponse and neonatal AOD; the di_ _duction i_ B cell epito_snecific, and only imvacts neonatal mi_ _t are known to be defi¿i_ in _gulato_ T cells. We now propose the following experimental approaches to further investigate these new and exciting observations. H_ 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 celt 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 autoimmane diseases including systemic lupus-related congenital heart block. PERFORCE Si_(S) (organizatiocnit,y,state) Universityof Virginia CiaariottesvilteV, irginia KEY PERSONNEL ========================================Section End===========================================

超出篇幅，我们最近关于自身免疫性卵巢疾病（AOD）的研究已经积累了证据，表明生命早期抗原和环境因素的刺激使遗传易感小鼠易患早发和迟发性自身免疫性疾病，这可以通过相对的生命早期存在的 CD4+CD2.5+ 调节性 T 细胞的缺乏，我们现在做出了一项新的、引人注目的观察，进一步强化了自身抗体的范式。研究发现，卵巢透明带 3 (ZP3) B 细胞表位 (335-342) 的 autoAb 会优先损伤新生小鼠的卵巢，而不会影响成年小鼠的卵巢，尽管卵巢疾病是由 ZP3 autoAb（疾病表达）引发的。取决于新生儿中 T 细胞的存在，并且与新生新生儿自身免疫 T 细胞对卵巢抗原的反应有关。此外，这种新生儿 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 (171-180) 的 autoAb 是非致病性的，更令人兴奋的是，只有当 autoAb 首先到达新生小鼠时，新生儿 AOD 才会发生。在生命的前 5 天，母体自身抗体可引发新生儿致病性自身抗体 T ¿ ¿ 11_反应和新生儿AOD；B细胞表位的分化，并且只有imvacts新生儿mi_ _t已知是defi¿ i_ 在 _gulato_ T 细胞中。我们现在提出以下实验方法来进一步研究这些令人兴奋的新观察结果，我们将测试新生儿 AOD 是由表位特异性 autoAb 触发的假设，该 autoAb 与内源性 Ag 形成免疫复合物，以诱导 ZP3。其次，我们将检验免疫复合物对抗原呈递细胞的激活依赖于其 Fc 受体的假设，并且该事件是新生儿所必需的。第三，我们将检验新生小鼠 CD4+ CD25+ 调节性 T 细胞缺乏解释新生小鼠发生自身免疫反应和疾病的倾向的假设，因此该提案将解决负责自身免疫诱导和预防的基本机制。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。 PERFORCE Si_(S)（组织，y，州）弗吉尼亚大学 CiaariottesvilteV，伊吉尼亚州关键人员==========================================章节结束===== =======================================