Antibody induced T cell-mediated neonatal autoimmunity.

抗体诱导 T 细胞介导的新生儿自身免疫。

• 批准号: 8206614
• 负责人: KENNETH S.K. TUNG
• 金额: $ 37.12万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206614
• 关键词: Ablation; Address; Adoptive Transfer; Adult; Affect; Age; Aleurites; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD94 Antigen; Cell physiology; Complex; Cytolysis; Dendritic Cells; Disease; Disease model; Equilibrium; Event; Frequencies; Genes; Goals; Grant; Growth; IL2RA gene; Immune response; Immune system; Inflammatory; Infusion procedures; Injury; Interleukin-10; Investigation; Knockout Mice; Life; Ligands; Mediating; Modeling; Mus; Natural Immunity; Natural Killer Cells; Neonatal; Oocytes; Organ; Ovarian; Ovarian Diseases; Ovary; Pathogenesis; Physiology; Play; Predisposing Factor; Process; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research Personnel; Resistance; Rheumatoid Arthritis; Role; Seminal; Specificity; T cell response; T-Lymphocyte; Testing; Time; Wild Type Mouse; Work; base; cytokine; insight; knockout gene; neonate; novel; perforin; programs; receptor; recombinase; response; zona pellucida glycoprotein

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.

这是 AI51420-01A 支持的竞争性续订应用程序，用于扩展我们的工作。重要的 已取得的进展极大地阐明了独特的新生儿自身免疫性卵巢的机制 疾病（nAOD）。卵巢 ZP3 的自身抗体 (Ab) 导致卵巢免疫复合物的形成。 这会引发一种器官特异性自身免疫性疾病，该疾病受 FcgR+ 调节，并依赖于 de novo 致病性 CD4 T 细胞 (TD-nAOD) 的激活。独特的是，nAOD 仅影响新生小鼠和备件 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任务 目标。我们发现重组酶激活基因 (RAG) 敲除也会诱导严重的 nAOD (KO) 小鼠，因此仅先天免疫也足以诱导 nAOD (TI-nAOD)。 NK细胞发挥多种作用 并在 TI-nAOD 中发挥关键作用。一个开创性的观察是 TI-中 NK 细胞功能的个体发育调控 nAOD。缺乏穿孔素的 RAG KO 小鼠没有出现 TI-nAOD，并且通过以下方法使疾病恢复： 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 功能还取决于 NKG2D - 一种主要的 NK 细胞激活受体。在 AIM 1 中，我们将检验以下假设：个体发育晚期 Ly49 NK 细胞抑制性受体的表达使新生儿 NK 细胞逃避调控 新生儿1-5天之间，诱发新生儿卵巢损伤。促炎细胞因子 IFNg 和 FcgR 在 TI-nAOD 和 TD-nAOD 的发病机制中也发挥着非冗余的作用。在 AIM 2 中，我们将 研究 RAG KO 小鼠 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 如何促进新生致病性 T 细胞 野生型小鼠 TD-nAOD 的反应；特别是，确定 NK 细胞的相对贡献和 树突状细胞在此过程中。最后，NK 细胞依赖性 TI-nAOD 很容易被成人抑制 CD4+CD25+Treg，需要IL10。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 IL10-的细胞机制 依赖性 Treg 抑制。此外，通过比较成人和成人之间的抑制机制 新生儿宿主，我们期望获得对新生儿免疫系统生理学的新见解，并进一步 阐明新生儿自身免疫性疾病倾向的重要观察结果。