Antibody induced T cell-mediated neonatal autoimmunity.

这是竞争续订申请，以延长我们的工作支持AI51420-01A。意义重大 目前对新生儿独特的自身免疫性卵巢的发病机制已有了很大的阐明 疾病(Naod)。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，这种疾病受FcgR+调节，依赖于从头开始 致病性CD4T细胞的激活(TD-NAOD)。独一无二的是，NAOD只影响新生小鼠和备用动物 5天以上的小鼠；因此，了解新生儿的自身免疫倾向是我们的主要任务 进球。我们发现，在重组酶激活基因(Rag)敲除中也会诱导严重的NaOD (KO)小鼠，因此仅有先天免疫也足以诱发NAOD(TI-NAOD)。NK细胞发挥多重作用 以及在TI-NAOD中的关键作用。一项开创性的观察是对TI患者NK细胞功能的个体发育调节。 纳奥德。穿孔素缺乏的RAG KO小鼠没有出现TI-Naod，这种疾病通过 来自野生型供者的新生儿而不是成人(或第9天)的NK细胞。TINaod中的NK功能也依赖于 NKG2D-一种主要的NK细胞激活受体。在目标1中，我们将检验这样一种假设，即 Ly49 NK细胞抑制受体的表达使新生儿NK细胞逃避调节 新生儿出生后1-5天，并可诱发新生儿卵巢损伤。促炎症细胞因子IFNG和 FcgR在TI-NAOD和TD-NAOD的发病机制中发挥了非多余的作用。在AIM 2中，我们将 探讨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，我们将研究新生儿NK细胞和IFNG如何促进从头致病T细胞 野生型小鼠对TD-NaOD的反应；特别是测定NK细胞和 树突状细胞参与了这一过程。最后，依赖于NK细胞的TI-Naod很容易被成人抑制 CD4+CD25+Treg，需要IL10。这一发现第一次证明了Treg对任何 新生儿免疫反应的形式。在目标4中，我们将研究IL-10的细胞机制- 从属Treg抑制。此外，通过比较成虫和幼虫的抑制机制 新生儿宿主，我们希望对新生儿免疫系统的生理学有新的见解，并进一步 阐明新生儿自身免疫性疾病倾向的重要观察。

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.