Impact of Pathogenic and Protective Environmental Exposures on Autoimmune Disease

 描述(由申请人提供)：系统性红斑狼疮(SLE)是一种慢性和潜在严重的自身免疫性疾病，对女性和非裔美国人(AA)有不成比例的影响。尽管环境因素在调节自身免疫发病机制中发挥了作用，但其作用的具体机制仍不清楚。越来越多的证据表明肠道微生物区系与自身免疫性疾病的发展有关。在这项研究中，我们将表征来自再生障碍性贫血患者、他们表现出自身免疫迹象的未受影响的一级亲属以及健康的、无关的、自身抗体阴性的再生障碍性贫血对照的粪便DNA的微生物组成(微生物组)和基因含量(元基因组)。这一建议的总体假设是，个体之间在结构和功能水平上都存在肠道微生物差异，影响自身免疫和自身免疫性疾病的发展。我们将通过实现3个具体目标来检验这一假说：1)检验肠道群落结构(微生物组)与自身免疫和SLE疾病标志物相关的假说。2)检验微生物组的基因、变异体和功能能力(元基因组)与自身免疫和SLE疾病有关的假设。3)在多变量模型中检验肠道微生物组成与自身免疫和SLE疾病标志物相关的假设，考虑宿主基因数据、表型特征、饮食和其他暴露。在完成这些目标后，我们将系统地识别与SLE相关的细菌生物标记物(例如SNPs、基因、菌株)，可以在其他自身免疫性疾病中进行研究，并作为疾病治疗的潜在靶点。

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease which disproportionately affects women and African Americans (AA). Despite the role of environmental factors in modulating autoimmunity pathogenesis, the specific mechanisms by which it acts remain poorly understood. A growing body of evidence implicates the gut microbiota in the development of autoimmune disorders. In this study we will characterize the microbial composition (microbiome) and gene content (metagenome) of fecal DNA from samples obtained from AA patients with SLE, their unaffected first-degree relatives who show signs of autoimmunity, and healthy, unrelated, autoantibody-negative AA controls. The overall hypothesis of this proposal is that there is gut microbial variation at both the structural and functional level between individuals that influences development of autoimmunity and autoimmune disease. We will test this hypothesis by accomplishing 3 Specific Aims: 1) Testing the hypothesis that gut community structure (microbiome) correlates with markers of autoimmunity and SLE disease. 2) Testing the hypothesis that the microbiome's genes, variants and functional capabilities (metagenome) are associated with autoimmunity and SLE disease. 3) Testing the hypothesis that the gut microbial composition correlates with markers of autoimmunity and SLE disease in a multivariate model, taking into account host genotype data, phenotypic traits, diet and other exposures. Upon completion of these Aims we will have systematically identified bacterial biomarkers (e.g. SNPs, genes, strains) that correlate with SLE, can be investigated in other autoimmune diseases, and serve as potential targets for disease treatment.