Antibody induced T cell mediated neonatal autoimmunity

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， 生命早期的环境因素使遗传易感小鼠易患早发型和晚发型自身免疫性疾病， 这可以通过在生命早期存在的CD 4 +CD2.5+调节性T细胞的相对缺乏来解释。我们现在已经 提出了一个新的和惊人的观察，进一步加强了范式。抗卵巢癌自身抗体 发现pellncida 3（ZP 3）B细胞表位（335-342）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自身抗体触发的，但疾病表达 依赖于新生儿中T细胞的存在，并与新生儿自身免疫T细胞应答相关 卵巢抗原此外，这种新生儿AOD的诱导是B细胞表位特异性的;因此autoAb针对第二个ZP 3 天然B细胞表位（171-180）是非致病性的。更令人兴奋的是，新生儿AOD只有在自身抗体 在出生后的前5天内首先到达新生小鼠。理论，母体自身抗体可引发新生儿致病性 自体T细胞反应和新生儿AOD;诱导B细胞表型特异性， 已知新生儿mi_t是一种特定的巨噬细胞。我们现在提出以下实验 进一步研究这些新的和令人兴奋的观察的方法。我们将检验新生儿 AOD由表位特异性自身抗体触发，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细胞反应和长期自身免疫记忆。第二，我们将检验假设， 免疫复合物对抗原呈递细胞的激活依赖于它们的Fc受体，并且这一事件是必需的。 用于新生儿AOD诱导。第三，我们将检验以下假设： 新生小鼠解释了新生小鼠发展自身免疫反应和疾病的倾向。这项建议 因此，将解决负责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。 Si_（S）（组织状态） 弗吉尼亚大学 伊尔吉尼亚？恰里奥特斯维尔泰 关键人员，请参阅说明，根据需要使用页码/nuat/onpage，以下列格式提供所需信息。 从主要研究者开始，按字母顺序列出所有其他关键人员，首先列出姓名， 名称组织项目角色 Kenneth S，K.董博士弗吉尼亚大学首席研究员 Yulius Sctiady博士弗吉尼亚大学联合首席研究员 Eilccn Samy，弗吉尼亚大学MS，共同研究者 __$t_t_/Nmt. _icabtetoS_R/STTR狂欢。见_。[：]Villi [_否 - PHS 398（Roy. 05/01）Page _ Form Page2 o o P_paJ Jnves_gator/ProgrDamJr_k_（rLast，firstm，_e）：Tung，Kenneth S.K. 主要研究者/项目负责人的姓名必须在打印页和续页的顶部提供。 研究资助 目录 页面Nurnbet_ 首页...... 1 说明，

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, See tnstruotions, Use cont/nuat/onpages as neededto provide the requited information in the format shown below. Start with Principal Investigator, List all other key personnel inalphabette,al order, tast name first, Name Organization Role on Projeot Kenneth S,K. Tung, M.D. Universityof Virginia PrincipalInvestigator Yulius Sctiady, Ph.D. University of Virginia Co- Principal Investigator Eilccn Samy, MS Universityof Virginia Co- investigator __$t_t_/Nmt. _icabtetoS_R/STTR Orgy. See_. [:]Villi [_No - PHS 398 (Roy. 05/01) Page _ Form Page2 o o P_paJ Jnves_gator/ProgrDamJr_k_(rLast,firstm, _e): Tung, Kenneth S.K. The name of the principalinvestigator/progrsm directormust be provided at the top of each printed page and each continuationpage. RESEARCH GRANT TABLE OF CONTENTS Page Nurnbet_ Face Page .................................................................................................................................................. 1 Description,