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: 7201821
• 负责人: KENNETH S.K. TUNG
• 金额: $ 37.88万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201821
• 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; Goals; Grant; Growth; Immune response; Immune system; Inflammatory; Infusion procedures; Injury; Interleukin-10; Investigation; KLRA1 gene; 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; Relative (related person); Research Personnel; Resistance; Rheumatoid Arthritis; Role; Seminal; Specificity; T-Lymphocyte; Testing; Time; Week; Wild Type Mouse; Work; base; cytokine; day; insight; knockout gene; neonate; novel; perforin; programs; receptor; recombinase; response; zona pellucida glycoprotein

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.

描述（由申请人提供）：这是 AI51420-01 A 支持的竞争性续展申请，旨在扩展我们的工作。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 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，并依赖于致病性 CD4 T 细胞 (TD-nAOD) 的从头激活。独特的是，nAOD 仅影响新生小鼠，并且不会影响 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目标。我们发现重组酶激活基因（RAG）敲除（KO）小鼠也会诱导严重的nAOD，因此仅先天免疫也足以诱导nAOD（TI-nAOD）。 NK 细胞在 TI-nAOD 中发挥多种关键作用。一个开创性的观察结果是 TI-nAOD 中 NK 细胞功能的个体发育调控。缺乏穿孔素的 RAG KO 小鼠不会出现 TI-nAOD，并且来自野生型供体的新生而非成年（或第 9 天）NK 细胞可以恢复该疾病。 TI-nAOD 中的 NK 功能还依赖于 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：Ly49 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 天之间逃脱调节，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细胞反应；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 很容易被成人 CD4+CD25+ Treg 抑制，并且需要 IL10。这一发现首次证明了 Treg 对任何形式的新生儿免疫反应的抑制。在 AIM 4 中，我们将研究 IL10 依赖性 Treg 抑制的细胞机制。此外，通过比较成人和新生儿宿主之间的抑制机制，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。