Commensal microbes and sexual dimorphism in autoimmunity

描述（由申请人提供）：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中。在自发性1型糖尿病小鼠模型（非肥胖糖尿病NOD小鼠的T1 D）中，雌性小鼠的疾病更严重。对世界各地NOD群体的调查发现，不仅T1 D的总体发病率在不同设施之间差异很大，而且女性/男性发病率也各不相同。这种变异性表明，一些不能轻易解释的因素明显影响疾病进展。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%。作为研究微生物环境对T1 D发展的作用的一部分，我们将NOD小鼠重新衍生为无菌（无菌）条件。我们意识到这些老鼠不再表现出两性异形！这意味着激素（清楚地表明参与其中）和微生物群以某种方式相互作用，影响疾病的进展。我们的主要假设表明，激素和微生物产物共同作用（双信号假说），以诱导耐受T1 D的男性。初步分析揭示了干扰素-γ在保护男性免受T1 D中的作用。建议通过多种方法来检验这一假设，包括用确定的微生物群定殖无菌小鼠、遗传方法和基因表达分析。我们还将测试在一个常见的遗传复杂的SLE小鼠模型中的系统免疫是否也由于微生物的存在而具有性二态性。因此，两个具体目标是：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性二型性中的作用;我们将使用基因表达和遗传方法研究参与耐受诱导的信号传导途径和细胞类型。我们将研究性激素的操纵如何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对微生物群的依赖性控制重要的信号通路。具体目标3。研究SLE小鼠模型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小鼠诱导和性二型性中的作用。

DESCRIPTION (provided by applicant): Many of major autoimmune diseases are sexually dimorphic. Systemic 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 te 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.