Antibody induced T cell-mediated neonatal autoimmunity.

描述(由申请人提供)：这是竞争续签申请，以延长我们的工作支持AI51420-01A已取得重大进展，极大地阐明了独特的新生儿自身免疫性卵巢疾病(NAOD)的机制。卵巢ZP3自身抗体可导致卵巢免疫复合体的形成。这会引发一种器官特异性自身免疫性疾病，这种疾病由FcgR+调节，依赖于致病CD4T细胞的从头激活(TD-Naod)。独特的是，NAOD只影响新生小鼠，而不影响5日龄以上的小鼠；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)基因敲除(KO)的小鼠中也能诱导出严重的NAOD，因此仅靠先天免疫也足以诱发NAOD(TI-NAOD)。NK细胞在TI-NAOD中发挥着多种关键作用。一个开创性的观察是对TI-NAOD中NK细胞功能的个体发育调节。穿孔素缺乏的RAG KO小鼠没有发生TI-Naod，这种疾病可以通过新生而不是成年(或第9天)的野生型捐赠者的NK细胞恢复。TI-Naod的NK功能还依赖于主要的NK细胞激活受体NKG2D。在AIM 1中，我们将验证一种假设，即Ly49 NK细胞抑制受体表达的个体发育晚期允许新生儿NK细胞在新生儿1-5天之间逃避调节，并导致新生儿卵巢损伤。促炎细胞因子IFNG和FcgR在TI-NAOD和TD-NAOD的发病机制中起着非多余的作用。在AIM 2中，我们将研究RAG KO小鼠TI-NAOD依赖IFNG和NK细胞功能的细胞学基础。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的从头致病T细胞反应，特别是确定NK细胞和树突状细胞在这一过程中的相对贡献。最后，依赖于NK细胞的TI-Naod很容易被成人的CD4+CD25+Treg抑制，这需要IL10。这一发现首次证明Treg抑制了任何形式的新生儿免疫反应。在AIM 4中，我们将研究IL10依赖的Treg抑制的细胞机制。此外，通过比较成人和新生儿宿主的抑制机制，我们希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。

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.