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: 10291780
• 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/10291780
• 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; 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; intestinal barrier; 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系统性红斑狼疮（SLE）。以前的研究表明 环境因素如细菌产物或它们诱导的炎症介质（例如，IFN-α） 参与SLE发病机制。其他人和我们以前的研究表明，多个autoAb 与无关的健康对照相比，在狼疮患者的一级亲属（FDR）中常见 （UHC）。此外，FDR具有升高的炎症水平（例如，B淋巴细胞刺激因子（BLyS），和 与UHC相比，IFN-α与TLR刺激和B细胞活化相关。目前尚不清楚最初的触发因素 用于自身抗体的产生。对自身免疫发展的早期事件缺乏了解， 是预防疾病的重要屏障。FDR，而不是患者，提供了一个研究人群， 并且可能暴露于环境中，他们没有服用免疫调节药物，也没有受到疾病的影响， 从而使结论较少受到外部因素的干扰。 在初步研究中，我们发现：1）在狼疮的健康FDR中，autoAb的存在和多样性增加 与无关的健康对照（UHC）相比，患者; 2）增加微生物产物易位（血浆 LPS）与升高的血浆自身抗体水平（抗dsDNA、抗ssDNA和抗核小体）相关;和3） FDR中血浆微生物多样性降低，链球菌科和链球菌属富集 链球菌产物在UHC中的易位和假单胞菌产物在UHC中的相对富集 相对于UHC的FDR。最近，在两个调节肠道通透性的基因编码区的SNP被发现， 与狼疮疾病风险相关。我们假设增加的肠道微生物产物 FDR个体中的易位及其相关炎症，由于“泄漏”肠道， autoAb生产和后来SLE发展的启动子。在目前的研究中，我们将招募匹配的 UHC，FDR，和狼疮患者。“渗漏”肠道导致全身性细菌产物和autoAb诱导， 狼疮的发病机制代表了一种新的机制，可以解释易感遗传性高- 风险个人。 具体目标1：确定肠屏障完整性、全身性细菌产物移位及其 在B细胞活化中介导炎症。我们假设血浆自身抗体水平与 肠道屏障完整性、炎症和全身细菌产物。体内肠道渗透性试验， 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 亚群激活和一系列狼疮相关的自身抗体（例如，抗dsDNA和抗核小体IgG）将被 在患者、FDR和UHC中进行评估。 具体目标2：确定全身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。我们观察到相对富集的 相对于UHC，FDR血浆中的假单胞菌产物。全身和粘膜之间的比较 在狼疮患者、FDR或UHC中以前没有报道过微生物组。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 在人类和小鼠的研究中。 在目前的研究中，我们提出了一种新的机制，autoAb生产和SLE病因。我们 相信来自“渗漏”肠道的一系列广泛的TLR激动剂是autoAb起始的基本驱动因素。 这项工作将提供深入了解的潜在治疗策略针对粘膜或特定的细菌 以防止自身抗体和疾病发作。