Commensal microbes and sexual dimorphism in autoimmunity

自身免疫中的共生微生物和性别二态性

• 批准号: 8643918
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643918
• 关键词: Accounting; Address; Adult; Affect; Animal Model; Antibiotic Therapy; Autoimmune Diseases; Autoimmunity; Chicago; Complex; Data; Dependence; Development; Diabetes Mellitus; Disease; Disease Progression; Environment; Female; Gender; Gene Expression; Gene Expression Profiling; Genetic; Genetic Variation; Germ-Free; Gnotobiotic; Gonadal Steroid Hormones; Hormonal; Hormones; Human; Immunity; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Knowledge; Lead; Metabolism; Microbe; Minor; Modeling; Multiple Sclerosis; Mus; Mutation; Procedures; Production; Publications; Publishing; Regulation; Reporting; Research; Resistance; Role; Scleroderma; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Sterility; Surveys; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Testosterone; The Jackson Laboratory; Thyroid Gland; Time; Uncertainty; Universities; Work; antimicrobial; cell type; commensal microbes; macrophage; male; microbial; mouse model; public health relevance; repository; sexual dimorphism

Many of major autoimmune diseases are sexually dimorphic. Sytemic Lupus Erythematosus (SLE), scleroderma, multiple sclerosis, Sjogren's syndrome, autoimmune diseases of thyroid gland and others are primarily occurring in females. In a mouse model of spontaneous type 1 diabetes (T1D in non obese diabetic, NOD, mice) the disease is stronger in females. A survey of NOD colonies around the world found that not only overall incidence of T1D varied greatly between different facilities, but that the female/male incidence ratio varied. The variability suggests that some factors that cannot be easily accounted for clearly affect the disease progression. In other facilities, including ours, the incidence in males is even lower (about 15-20% at 30 wks), whereas the incidence in females is around 65-80%. As a part of the studies of the role of microbial environment on T1D development, we have rederived NOD mice into germ-free (sterile) conditions. We realized that these mice no longer showed sexual dimorphism! That means that the hormones (clearly shown to be involved) and the microbiota are interacting in some way that affects the disease progression. Our main hypothesis suggests that the hormones and microbial products act together (dual-signal hypothesis) to induce tolerance to T1D in males. Preliminary analysis has revealed a role for Interferon-gamma in protection of males from T1D. It is proposed to test the hypothesis by a variety of approaches including colonization of germ-free mice with defined microbiota, genetic approach and gene expression analysis. We will also to test whether systemic immunity in a common genetically complex mouse model of SLE is also sexually dimorphic because of the presence of microbes. Accordingly, two specific aims are: Specific Aim 1. Investigate the effector mechanisms that make NOD males more resistant to T1D. We will test the role of specific microbial lineages in controlling sexual dimorphism; We will study the signaling pathway and cell types involved in tolerance induction using gene-expression and genetic approaches. We will study how manipulations of sex hormones affect microbial composition and functions; We will use gene expression analysis to delineate signaling pathways important for hormone-dependent control over microbiota. Specific Aim 3. Investigate whether sexual dimorphism in a mouse model of SLE is dependent on microbes. We will study the role of microbiota in induction and sexual dimorphism in NZBWF1 mice in germ-free environment.

许多主要的自身免疫性疾病是性二态性的。系统性红斑狼疮（SLE）， 硬皮病、多发性硬化症、干燥综合征、甲状腺自身免疫性疾病等， 主要发生在女性身上。在自发性1型糖尿病（非肥胖糖尿病中的T1 D， NOD，小鼠）这种疾病在女性中更强。一项对世界各地NOD殖民地的调查发现， T1 D的总体发病率在不同机构之间差异很大，但女性/男性发病率比 各种各样。这种变异性表明，一些不容易解释的因素显然会影响这种疾病 进展在其他机构，包括我们的机构，男性的发病率甚至更低（30周时约为15-20%）， 而女性的发病率约为65- 80%。作为微生物作用研究的一部分 环境对T1 D发育的影响，我们将NOD小鼠再衍生为无菌（无菌）条件。我们 发现这些老鼠不再表现出两性异形！这意味着荷尔蒙（清楚地显示 参与）和微生物群以某种方式相互作用，影响疾病的进展。我们的主要 双信号假说认为激素和微生物产物共同作用（双信号假说）， 男性对T1 D的耐受性。初步分析显示干扰素-γ在保护男性中的作用 从T1 D建议通过各种方法来检验这一假设，包括无菌的定殖 小鼠与确定的微生物群，遗传方法和基因表达分析。我们还将测试 常见遗传复杂的SLE小鼠模型中的全身免疫也是性二态的， 微生物的存在。因此，有两个具体目标： 具体目标1.研究使NOD男性对T1 D更具抵抗力的效应机制。 我们将测试特定微生物谱系在控制两性异形中的作用; 我们将研究信号通路和细胞类型参与耐受诱导使用基因表达和 基因方法。 我们将研究如何操纵性激素影响微生物的组成和功能; 我们将使用基因表达分析来描绘信号通路的重要性， 控制微生物群。 具体目标3。研究SLE小鼠模型中的两性异形是否依赖于 微生物 我们将在无菌环境中研究微生物群在NZBWF 1小鼠的诱导和性二型性中的作用。 环境