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)的研究积累了证据，表明在生命早期受到抗原和环境因素的刺激会使遗传易感的小鼠容易患上早发性和晚发性自身免疫性疾病，这可以从早期存在的CD4+CD25+调节性T细胞的相对缺乏来解释。我们现在进行了一项新的、引人注目的观察，进一步加强了这一范式。抗卵巢透明带3(ZP3)B细胞表位(335-342)的自身抗体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，虽然卵巢疾病是由ZP3自身抗体引发的，但疾病的表达依赖于新生儿中T细胞的存在，并与新生儿自身免疫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)的自身抗体是非致病的。更令人兴奋的是，只有当自身抗体第一次到达出生后5天的新生小鼠身上时，新生儿AOD才会发生。因此，母体自身抗体可以在新生儿中触发病理性自身免疫T细胞反应和新生儿AOD；疾病诱导是B细胞表位特异性的，并且只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和令人兴奋的观察结果。首先，我们将检验这一假设，即新生儿AOD是由表位特异性的自身抗体触发的，它与内源性抗原形成免疫复合物，诱导ZP3特异性致病T细胞反应和长期自身免疫记忆。其次，我们将检验一种假设，即免疫复合物激活抗原提呈细胞依赖于其Fc受体，而这一事件是诱导新生儿AOD所必需的。第三，我们将检验这样一种假设，即新生小鼠的CD4+CD25+调节性T细胞缺陷解释了新生小鼠发生自身免疫反应和疾病的倾向。因此，该提案将解决诱导和预防自身免疫的基本机制，特别是新生儿自身免疫性疾病，包括系统性红斑狼疮相关的先天性心脏传导阻滞。