Role of Gut Microbial Translocation in Initiating Autoimmunity

遗传和环境因素导致系统性红斑狼疮(SLE)。先前的研究表明 环境因素，如细菌产物或其诱导的炎症介质(如干扰素-α) 参与了SLE的发病机制。之前来自其他人的研究和我们发现，多个自动抗体 通常在狼疮患者的一级亲属(FDR)中检测到，与无关的健康对照相比 (UHCS)。此外，FDR具有更高的炎症水平(例如，B淋巴细胞刺激因子(BLyS)，以及 干扰素-α)与脐血巨噬细胞集落刺激因子刺激和B细胞活化有关。目前尚不清楚最初的触发因素 用于生产自身抗体。对自身免疫发展的早期事件缺乏了解是一种 疾病预防的关键障碍。富兰克林·罗斯福，而不是病人，提供了一个遗传易感的研究人群 而且可能暴露在环境中，他们没有服用免疫调节药物，也没有受到疾病的影响， 允许结论更少地受到外部因素的干扰。 在初步研究中，我们发现：1)在健康的狼疮FDR中，自身抗体的存在和多样性增加 患者与无血缘关系的健康对照组比较(UHCS)；2)微生物产物移位(血浆)增加 与血浆自身抗体水平升高(抗双链DNA、抗单链DNA和抗核小体)相关；以及3) 随着链球菌科和链球菌属的丰富，FDR中血浆微生物多样性减少 链球菌在脐带血中的产物转位及假单胞菌的相对富集性 相对于UHCS的FDR。最近，调节肠道通透性的两个基因编码区的SNPs是 被确定为与狼疮疾病风险相关。我们假设增加肠道微生物产物 富兰克林·罗斯福患者的易位及其相关炎症，是肠道泄漏的结果，可作为 自身抗体生产和后来的系统性红斑狼疮开发的引发剂。在目前的研究中，我们将招募匹配的 UHCS、FDRS和狼疮患者。肠道渗漏导致全身性细菌产物和自身抗体的诱导 狼疮的发病机制代表了一种新的机制，解释了易感基因高危人群的发病机制。 有风险的个人。 具体目标1：确定肠道屏障的完整性、全身性细菌产物易位及其 B细胞活化过程中的炎症反应。我们假设血浆自身抗体水平与 具有肠道屏障完整性、炎症性和全身性细菌产品。活体肠道通透性测试， 血浆内毒素和总细菌rDNA水平、血浆TLR相关炎症(如IL-6和干扰素-α)、B细胞 亚集激活和一系列与狼疮相关的自身抗体(例如，抗dsDNA和抗核小体IgS)将是 在患者、FDR和UHCS中进行评估。 具体目标2：确定系统和粘膜微生物成分以及某些 细菌产物易位对自身抗体产生的影响。我们观察到了相对丰富的 FDRS患者血浆中的假单胞菌产生量与UHCS相关。全身和粘膜的比较 此前，在狼疮患者、FDR或UHCS中尚未报道微生物群。因此，我们将评估 系统和粘膜微生物组，并确定微生物易位在自身抗体产生和狼疮中的作用 人类和小鼠研究中的疾病。 在目前的研究中，我们建议研究一种新的自身抗体产生机制和系统性红斑狼疮病因学。我们 相信广泛的TLR激动剂，从“泄漏”的肠道，是启动自身抗体的基本驱动因素。 这项工作将提供对针对粘膜或特定细菌的治疗策略的潜在洞察力 以防止自身抗体和疾病的发生。

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.