Antibody induced T cell-mediated neonatal autoimmunity.

描述（由申请人提供）：这是竞争性续期申请，以扩展我们在AI 51420 -01 A支持下的工作。近年来，对新生儿自身免疫性卵巢疾病（nAOD）发病机制的研究取得了重要进展。抗卵巢ZP 3的自身抗体（Ab）导致卵巢免疫复合物的形成。这引起由FcgR+调节的器官特异性自身免疫性疾病，并且依赖于致病性CD 4 T细胞（TD-nAOD）的从头活化。独特的是，nAOD只影响新生小鼠和备用小鼠超过5天的年龄，因此，了解新生儿的自身免疫倾向是我们的主要目标。我们发现在重组酶激活基因（RAG）敲除（KO）小鼠中也诱导严重的nAOD，因此单独的先天免疫也足以诱导nAOD（TI-nAOD）。NK细胞在TI-nAOD中起着多重和关键的作用。一个重要的观察结果是TI-nAOD中NK细胞功能的个体发生调节。穿孔素缺陷的RAG KO小鼠没有发展TI-nAOD，并且该疾病通过来自野生型供体的新生儿而不是成年（或第9天）NK细胞恢复。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Ly 49 NK细胞抑制性受体表达的晚期个体发育允许新生儿NK细胞在新生儿1-5天之间逃避调节并诱导新生儿卵巢损伤的假设。促炎细胞因子IFNg和FcgR在TI-nAOD和TD-nAOD的发病机制中发挥非冗余作用。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NK细胞和IFNg如何促进野生型小鼠TD-nAOD中的从头致病性T细胞应答;特别是，确定NK细胞和树突状细胞在此过程中的相对贡献。最后，NK细胞依赖性TI-nAOD容易被成人CD 4 + CD 25 + Treg抑制，并且它需要IL 10。这一发现首次证明了Treg对任何形式的新生儿免疫应答的抑制。在AIM 4中，我们将研究IL 10依赖性Treg抑制的细胞机制。同时，通过比较成人和新生儿免疫系统的抑制机制，我们期望对新生儿免疫系统的生理学有新的认识，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。

DESCRIPTION (provided by applicant): This is the competitive renewal application to extend our work supported by AI51420-01 A. 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.