Role of Gut Microbial Translocation in Initiating Autoimmunity

肠道微生物易位在启动自身免疫中的作用

• 批准号: 9564333
• 负责人: Gary S Gilkeson
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9564333
• 关键词: Agonist; Antibodies; Autoantibodies; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Biological; Cells; Code; Dependence; Development; Disease; Disease Progression; Disease model; Dose; Environmental Exposure; Environmental Risk Factor; Etiology; Event; Exposure to; Family; First Degree Relative; Funding; Genes; Genetic; Gut Mucosa; High Prevalence; Human; Immune system; Immunoglobulin G; Immunomodulators; Individual; Inflammation; Inflammation Mediators; Inflammatory; Integration Host Factors; Interferon-alpha; Interleukin-6; Intestinal permeability; Intestines; Leaky Gut; Ligands; Lupus; Mediating; Mucous Membrane; Mus; Nucleosomes; Onset of illness; Pathogenesis; Patients; Plasma; Play; Production; Pseudomonas; Receptor Signaling; Recombinant DNA; Reporting; Risk; Role; Saliva; Series; Source; Streptococcaceae; Streptococcus; Systemic Lupus Erythematosus; TALL-1 protein; TLR4 gene; TLR7 gene; Testing; Therapeutic; Toll-like receptors; Woman; Work; base; cytokine; disorder prevention; disorder risk; ds-DNA; genetic risk factor; high risk; high risk population; in vivo; insight; lupus prone mice; men; microbial; microbiome; mouse model; novel; prevent; recruit; response; stool sample; study population

Genetic and environmental factors contribute to systemic lupus erythematosus (SLE). Previous studies showed environmental factors such as bacterial products or their-induced inflammatory mediators (e.g., IFN-α) are involved in SLE pathogenesis. Previous studies from others and we revealed that multiple autoAbs are more commonly detected in first-degree relatives of lupus patients (FDRs), compared to unrelated healthy controls (UHCs). In addition, FDRs have heightened levels of inflammation (e.g., B lymphocyte stimulator (BLyS), and IFN-α) associated with TLR stimulation and B cell activation compared with UHCs. It is unclear the initial trigger for autoantibody production. This lack of understanding of early events in development of autoimmunity is a critical barrier for disease prevention. FDRs, rather than patients, provide a study population, genetically prone and possibly environmentally exposed, who are not on immune modulatory drugs nor impacted by disease, allowing conclusions less confounded by external factors. In preliminary studies, we found: 1) increased presence and diversity of autoAbs in healthy FDRs of lupus patients compared to unrelated healthy controls (UHCs); 2) increased microbial product translocation (plasma LPS) associated with elevated plasma autoAb levels (anti-dsDNA, anti-ssDNA, and anti-nucleosome); and 3) decreased plasma microbial diversity in FDRs with enrichment of the family Streptococcaceae and genus of Streptococcus product translocation in UHCs and relative enrichment of Pseudomonas product translocation in FDRs relative to UHCs. Recently SNPs in the coding region of two genes that mediate gut permeability were identified as associated with lupus disease risk. We hypothesize that increased gut microbial product translocation and its-associated inflammation in FDR individuals, a result of a “leaky” gut, serve as initiators for autoAb production and later SLE development. In the current study, we will recruit matched UHCs, FDRs, and lupus patients. A “leaky” gut leading to systemic bacterial products and autoAb induction in the pathogenesis of lupus represents a novel mechanism to explain disease initiation in susceptible genetic high- risk individuals. Specific Aim 1: Determine intestinal barrier integrity, systemic bacterial product translocation, and its mediated inflammation in the activation of B cells. We hypothesize that plasma autoAb levels are associated with intestinal barrier integrity, inflammation and systemic bacterial products. In vivo gut permeability tests, plasma LPS and total bacterial rDNA levels, plasma TLR-related inflammation (e.g., IL-6 and IFN-α), B cell subset activation and a series of lupus-related autoAbs (e.g., anti-dsDNA and anti-nucleosome IgGs) will be assessed in patients, FDRs and UHCs. Specific Aim 2: Determine systemic and mucosal microbial components and the effect of certain bacterial product translocation on autoantibody production. We have observed relative enrichment of Pseudomonas products in plasma of FDRs relative to UHCs. Comparisons between systemic and mucosal microbiomes has not been reported previously in lupus patients, FDRs or UHCs. We therefore will assess the systemic and mucosal microbiome and identify the role of microbial translocation in autoAb production and lupus disease in both human and mouse studies. In the current study, we propose to investigate a novel mechanism for autoAb production and SLE etiology. We believe that a broad array of TLR agonists, from a “leaky” gut, are the fundamental drivers of autoAb initiation. This work will provide insight into the potential of a therapeutic strategy targeting mucosa or particular bacteria to prevent autoAbs and disease onset.

遗传和环境因素有助于全身性红斑狼疮（SLE）。先前的研究显示 环境因素，例如细菌产物或它们诱导的炎症介质（例如IFN-α）是 参与SLE发病机理。以前来自其他人的研究，我们透露多个自动ab更多 与无关的健康对照组相比，在狼疮患者（FDR）的一级亲属中通常检测到 （UHCS）。此外，FDR的炎症水平升高（例如，B淋巴细胞刺激剂（BLYS）和 与UHC相比，与TLR刺激和B细胞激活相关的IFN-α）。目前尚不清楚初始触发器 用于自身抗体的生产。缺乏对自身免疫发展中早期事件的理解是 预防疾病的关键障碍。 FDR而不是患者提供研究人群，易于基因 并可能在环境中暴露，他们不接受免疫调节药物，也不受疾病影响， 允许的结论较少被外部因素混淆。 在初步研究中，我们发现：1）狼疮健康的FDR中自动ab的存在和多样性增加 患者与无关的健康对照（UHC）相比； 2）微生物产物易位增加（血浆 LPS）与等离子体自动启动水平升高（抗DSDNA，抗SSDNA和抗核体）相关； 3） 随着家族链球菌的富集和属的血浆微生物多样性的降低 UHC中的链球菌产品转运和假单胞菌产物易位的相对富集 FDR相对于UHC。最近在介导肠道渗透率的两个基因的编码区域的SNP是 被确定为与狼疮疾病风险有关的。我们假设增加肠道微生物产物 FDR个体中的易位及其相关感染是“渗漏”肠道的结果 自动生产和后来SLE开发的发起人。在当前的研究中，我们将招募匹配 UHC，FDR和狼疮患者。 “漏水”的肠道，导致全身细菌产物和自动诱导 狼疮的发病机理代表了一种解释易感遗传高位疾病的新机制 冒险个人。 特定目的1：确定肠壁完整性，全身细菌产品易位及其 B细胞激活中介导的炎症。我们假设等离子体自动启动水平与 具有肠道屏障完整性，感染和全身细菌产物。体内肠道渗透率测试， 血浆LPS和总细菌RDNA水平，血浆TLR相关炎症（例如IL-6和IFN-α），B细胞 子集激活和一系列与狼疮相关的自动动体动物（例如，抗DSDNA和抗核体IgGS）是 在患者，FDR和UHC中进行评估。 特定目标2：确定全身和粘膜微生物成分以及某些效果 自身抗体产生的细菌产品易位。我们已经观察到相对丰富的 FDR相对于UHC的血浆中的假单胞菌产物。系统性和粘膜之间的比较 先前尚未在狼疮患者，FDR或UHC中报道微生物组。因此，我们将评估 系统性和粘膜微生物组，并识别微生物易位在自动产生和狼疮中的作用 人类和小鼠研究中的疾病。 在当前的研究中，我们建议研究一种新型自动产生和SLE病因的机制。我们 相信从“泄漏”的肠道中，各种各样的TLR激动剂是自动启动的基本驱动因素。 这项工作将洞悉针对粘膜或特定细菌的治疗策略的潜力 为了防止自动动作和疾病发作。