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: 6575358
• 负责人: KENNETH S.K. TUNG
• 金额: $ 22.2万
• 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/6575358
• 关键词: B lymphocyte; T lymphocyte; antibody receptor; antigen presenting cell; autoantibody; autoantigens; autoimmune disorder; developmental immunology; disease /disorder proneness /risk; genetically modified animals; immune complex; immunoglobulin G; immunologic memory; laboratory mouse; ovary disorder; passive immunization; pathologic process

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，表明抗原和环境因素在生命早期的刺激使遗传易感的小鼠易患早发性和晚发性自身免疫性疾病，这可以解释为CD4+CD25+调节性T细胞在生命早期相对缺乏。我们现在有了一个新的、引人注目的观察结果，进一步加强了这一范式。发现卵巢无斑点带3 (ZP3) B细胞表位（335-342）的自身抗体（autoAb）优先损伤新生小鼠卵巢，而保留成年小鼠卵巢。有趣的是，尽管卵巢疾病是由ZP3自身抗体引发的，但疾病的表达取决于新生儿中T细胞的存在，并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，对第二个ZP3原生B细胞表位（171-180）的自身抗体是非致病性的。更令人兴奋的是，只有当autoAb在出生后5天内首次到达新生小鼠体内时，新生儿AOD才会发生。因此，母体自身抗体可引发新生儿致病性自身免疫T细胞反应和新生儿AOD；这种疾病的诱导是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。首先，我们将验证新生儿AOD是由表位特异性自身抗体触发的假设，其与内源性Ag形成免疫复合物，诱导ZP3特异性致病性T细胞反应和长期自身免疫记忆。其次，我们将验证免疫复合物激活抗原呈递细胞依赖于其Fc受体的假设，这一事件是新生儿AOD诱导所必需的。第三，我们将验证新生小鼠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，该提案将解决自身免疫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。