Host's and microbiota's contribution to sexual dimorphism of autoimmunity

许多主要的自身免疫性疾病都是性二型的。系统性红斑狼疮 硬皮病、多发性硬化症、干燥综合征和某些形式的1型糖尿病(T1D)主要是 发生在雌性体内。它被归因于多种因素，包括编码的基因的表达 性染色体，荷尔蒙对基因表达的调节，以及最近共生对意想不到的调节 微生物区系。因此，对疾病的性别二型性的理解需要通过 不同策略的组合。在这项提议中，我们利用我们的能力来执行 利用原创和不断发展的转基因和灵知生菌动物进行艺术实验 计算方法。我们的初步数据证明了这种综合方法的有效性 问题就在这里。我们提出了自身免疫的“双信号”模型，该模型涉及微生物和 性激素。因此，荷尔蒙和微生物的影响不必同时发生：它们可能是同时发生的。 在发育的不同阶段或疾病发展的不同阶段很重要。我们关注的是T细胞固有的和T- 雄激素受体(AR)的细胞外效应及微生物区系对T1D影响的机制 发展。考虑到问题的复杂性，我们计划追求几个精心挑选的目标，这些目标将 继续为今后这一重要领域的研究拓展奠定基础。 具体目标1.确定T细胞内在机制和T细胞外在机制在性行为中的输入 T1D的二形性。 1.1.确定是否所有参与AR介导的T1D保护作用的细胞都来自骨髓； 1.2.明确髓系细胞在男性T1D保护中的作用； 1.3.检测髓系细胞在T细胞转移实验中的作用； 1.4.检测转录因子AIRE在T1D性二型性中的作用。 具体目的2.研究AR信号对T细胞选择和功能的影响 2.1.确定AR对TCR曲目的影响； 2.2.确定TCR的属性如何影响AR对曲目选择的影响； 2.3.研究AR在自身免疫相关干扰素-γ(IFNG)调节中的作用； 2.4.研究AR在IFNG基因位点调控中的作用； 具体目标3.确定微生物群何时何地放大AR对T1D发育的影响。 3.1.检测有条件性AR缺陷的GF动物的T1D发育； 3.2.确定微生物在发育过程中是否对免疫细胞特性的变化起到促进作用； 3.3.建立通过微生物区系印记雄性变得对T1D产生抗性的时间表； 3.4.确定哪些免疫相关途径受到微生物区系的影响。

Many of major autoimmune diseases are sexually dimorphic. Systemic Lupus Erythematosus (SLE), scleroderma, multiple sclerosis, Sjogren’s syndrome, and some forms of Type 1 diabetes (T1D) are primarily occurring in females. It has been attributed to multiple factors including expression of the genes encoded by sex chromosomes, hormonal regulation of gene expression, and lately to unexpected regulation by commensal microbiota. Thus, understanding of sexual dimorphism of diseases requires that the problem be approached by a combination of different strategies. In this proposal, we take advantage of our abilities to perform state of the art experiments using genetically modified and gnotobiotic animals with original and constantly developing computational methods. Our preliminary data demonstrates the efficiency of such an integrative approach to the problem. We have suggested a ‘dual signal’ model of autoimmunity involving regulation by microbes and sex hormones. Accordingly, hormonal and microbial influences do not have to be simultaneous: they may be important at different stages of development or disease progression. We are focusing on T cell-intrinsic and T- cell-extrinsic effects of Androgen Receptor (AR) and the mechanisms of microbiota’s effect on T1D development. Given the complexity of the problem, we plan to pursue several carefully selected goals that will continue to lay foundation for the future expansion of research in this important area. Specific Aim 1. Determine the input of T cell-intrinsic and T cell-extrinsic mechanisms in the sexual dimorphism of T1D. 1.1. Determine whether all cells involved in AR-mediated protection from T1D are of bone marrow origin; 1.2. Define the role of myeloid cells in male protection from T1D; 1.3. Test the contribution of myeloid cells in T cell transfer experiments; 1.4. Test a role that transcription factor AIRE plays in sexual dimorphism of T1D. Specific Aim 2. Investigate the influence of AR signaling on T cell selection and function 2.1. Determine the influence of AR on the TCR repertoires; 2.2. Determine how the properties of the TCR affect the influence of AR on repertoire selection; 2.3. Study the role of AR in regulation of interferon gamma (IFNg) related to autoimmunity; 2.4. Study the role of AR in regulation of the IFNg locus; Specific Aim 3. Determine where and when the microbiota amplifies AR effects on T1D development. 3.1. Test T1D development in GF animals with conditional AR deficiencies; 3.2. Determine whether microbes contribute to changes in immune cells properties during their development; 3.3. Establish the timeline to imprinting males to become resistant to T1D by the microbiota; 3.4. Determine which immune-related pathways are affected by the microbiota.