Antibody induced T cell-mediated neonatal autoimmunity.

这是一个竞争性的更新申请，以扩展我们在AI 51420 - 01 A支持下的工作。显著 已经取得了进展，大大阐明了独特的新生儿自身免疫性卵巢癌的机制， 疾病（nAOD）。抗卵巢ZP 3的自身抗体（Ab）导致卵巢免疫复合物的形成。 这引起了由FcgR+调节的器官特异性自身免疫性疾病，并且依赖于从头免疫。 病原性CD 4 T细胞（TD-nAOD）的活化。独特的是，nAOD仅影响新生小鼠和备用小鼠 小鼠超过5天的年龄;因此，了解新生儿自身免疫倾向是我们的主要任务。 目标.我们发现，在重组酶激活基因（RAG）敲除中也诱导了严重的nAOD (KO)小鼠，因此单独的先天免疫也足以诱导nAOD（TI-nAOD）。NK细胞发挥多种作用 在TI-nAOD中的关键作用。一项重要的观察结果是TI患者NK细胞功能的个体发生调节， nAOD。穿孔素缺陷的RAG KO小鼠没有发展TI-nAOD，并且通过免疫抑制剂治疗恢复了该疾病。 来自野生型供体的新生儿而非成人（或第9天）NK细胞。TI-nAOD中的NK功能也依赖于 NKG 2D-一种主要的NK细胞活化受体。在AIM 1中，我们将检验以下假设： Ly 49 NK细胞抑制性受体的表达允许新生儿NK细胞逃避调节 在新生儿1-5天之间，并诱导新生儿卵巢损伤。促炎细胞因子IFNg和 FcgR在TI-nAOD和TD-nAOD的发病机制中也起非冗余作用。在AIM 2中，我们将 研究RAG KO小鼠的TI-nAOD中IFNg和NK细胞依赖性功能的细胞基础。 在AIM 3中，我们将研究新生儿NK细胞和IFNg如何促进从头致病性T细胞， 在野生型小鼠的TD-nAOD中的应答;特别地，确定NK细胞的相对贡献， 树突状细胞在这个过程中。最后，NK细胞依赖的TI-nAOD很容易被成年人抑制。 CD 4 + CD 25 + Treg，需要IL 10。这一发现首次证明了Treg抑制任何 新生儿免疫反应的形式。在AIM 4中，我们将研究IL 10 - 1的细胞机制。 依赖性Treg抑制。并通过比较成虫和成虫的抑制机制， 新生儿宿主，我们希望获得新的洞察新生儿免疫系统的生理，并进一步 阐明新生儿自身免疫性疾病倾向的重要观察结果。

This is the competitive renewal application to extend our work supported by AI51420-01A. Significant progress has been made that greatly elucidate the mechanism of the unique neonatal autoimmune ovarian disease (nAOD). Autoantibody (Ab) to the ovarian ZP3 led to the formation of ovarian immune complex. This provokes an organ specific autoimmune disease that is regulated by FcgR+, and dependent on de novo activation of pathogenic CD4 T cells (TD-nAOD). Uniquely, nAOD affects only neonatal mice and spares mice beyond 5 days of age; therefore, the understanding neonatal propensity to autoimmunity is our major goal. We discovered that severe nAOD is also induced in the recombinase activating gene (RAG) knockout (KO) mice, thus innate immunity alone is also sufficient to induce nAOD (TI-nAOD). NK cells play multiple and pivotal roles in TI-nAOD. A seminal observation is the ontogenetic regulation of NK cell function in TI- nAOD. RAG KO mice deficient in perforin did not develop TI-nAOD, and the disease was restored by neonatal but not adult (or day 9) NK cells from wild type donors. NK function in TI-nAOD also depended on NKG2D - a major NK cell activating receptor. In AIM 1, we will test the hypothesis that the late ontogeny of expression of the Ly49 NK cell inhibitory receptors allows neonatal NK cells to escape from regulation between neonatal 1-5 days, and to induce neonatal ovarian injury. The pro-inflammatory cytokine IFNg and also FcgR played non-redundant roles in the pathogenesis of both TI-nAOD and TD-nAOD. In AIM 2, we will investigate the cellular basis for the IFNg- and NK cell- dependent functions in TI-nAOD of RAG KO mice. And in AIM 3, we will investigate how neonatal NK cells and IFNg promote de novo pathogenic T cell responses in TD-nAOD of wild type mice; in particular, determine the relative contribution of NK cells and dendritic cells in this process. Finally, the NK cell-dependent TI-nAOD was readily suppressed by adult CD4+CD25+ Treg, and it requires IL10. This finding documents, for the first time, Treg suppression of any form of neonatal immune response. In AIM 4, we will investigate the cellular mechanism of the IL10- dependent Treg suppression. Also, by comparing the mechanism of suppression between the adult and the neonatal hosts, we expect to obtain new insight into the physiology of neonatal immune system, and further elucidate the important observation of neonatal propensity to autoimmune disease.