Role of microbiota-TLR7/8 Interaction in systemic lupus erythematosus

微生物群-TLR7/8 相互作用在系统性红斑狼疮中的作用

• 批准号: 10051383
• 负责人: CHENTHAMARAKSHAN VASU
• 金额: $ 69.97万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-06 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10051383
• 关键词: Adolescent; Adult; Affect; African American; Age; Age of Onset; Antibiotics; Antibody Formation; Antigens; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Caucasians; Cells; Clinical; Cohort Studies; Data; Defect; Development; Disease; Disease Progression; Dose; Early identification; Environmental Risk Factor; Epithelial Cells; Epitopes; Estrogens; Etiology; Event; Exposure to; Female; First Degree Relative; Flare; Genes; Genetic; Germ-Free; Gonadal Steroid Hormones; Gut Mucosa; Haptoglobins; Hormonal; Human; IL17 gene; IL4 gene; IL6 gene; IL9 gene; Immune; Immune response; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferons; Intervention; Intestinal Mucosa; Intestinal permeability; Label; Leaky Gut; Ligands; Link; Lupus; Molecular; Mus; Nephritis; Onset of illness; Oral; Patients; Permeability; Pre-Clinical Model; Predisposition; Process; Production; Proteomics; Reporting; Risk; Rodent; Role; Sampling; Shotguns; Signal Transduction; Specificity; Systemic Lupus Erythematosus; Systemic disease; TLR7 gene; TLR8 gene; Testing; Time; Woman; X Chromosome; X Inactivation; base; clinical development; clinically relevant; cytokine; effective intervention; effective therapy; gastrointestinal epithelium; gut microbes; gut microbiota; inflammatory disease of the intestine; interleukin-21; intestinal epithelium; lupus prone mice; men; microbial; microbiota; novel; overexpression; preclinical study; prevent; receptor; systemic autoimmunity; targeted treatment

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) predominantly affects women, up to ten times more frequently than men, and it occurs about five times more commonly in African Americans than in Caucasians. Although the primary cause of SLE has not yet been identified, a combination of genetic, hormonal, and environmental factors is known to contribute to the development of this disease. Studies during recent years suggest that the disease process initiates in genetically susceptible subjects several years before the development of clinical disease and it could be suppressed or accelerated by sex hormones and environmental factors including gut microbiota. This suggests that increased understanding of the environmental and genetic factor interactions that trigger/perpetuate the early events of disease processes and identification of early predictors of autoimmune processes will help develop novel safe and effective strategies to control or prevent SLE, prior to the onset of clinical disease. In this regard, using a pre-clinical model of lupus which shares the etiology and auto-antigen epitopes with that of human SLE, we for the first time, demonstrate the contribution of pro-inflammatory events and autoantibody production initiated in the gut mucosa at juvenile age, long before the onset of systemic autoimmunity and clinical disease, in the onset of disease process. We have also identified a combination of previously unknown molecular events that initiates gut-inflammation and autoantibody production in a TLR7/8- gut microbiota interaction-dependent manner, and contributes to systemic autoimmunity and lupus disease progression. Based on our preliminary observations, we hypothesize that “the systemic autoimmune process in lupus is initiated and perpetuated by TLR7/8-gut microbiota interaction dependent inflammation and autoantibody production in the gut mucosa, and inhibition of this interaction at pre-nephritis stages can effectively prevent the disease in at-risk subjects, and suppress autoantibody production in lupus patients”. Here, we propose studies: 1) to define the role of TLR7/8 -microbiota interaction dose in human SLE by associating gut inflammation and permeability features with the expression levels of these receptors on immune cells, and microbiota interaction-dependent pro-inflammatory responses of these cells, with autoimmunity and lupus susceptibility; and 2) to elucidate the role of TLR7/8-gut microbiota interaction in initiating gut inflammation and autoantibody production, and systemic autoimmunity using pre-clinical models. We will also determine the potential of oral treatment with antagonists in preventing/suppressing gut inflammation, systemic autoimmunity and disease incidence. Our proposed study will not only identify early pro-inflammatory events that initiate systemic autoimmunity in lupus, but will also introduce the possibility of a novel and rational, oral therapy for suppressing intestinal inflammation to prevent SLE in at-risk subjects and flares in subjects with established SLE.

项目摘要/摘要 系统性红斑狼疮(SLE)主要影响女性，发病率高达男性的10倍， 它在非裔美国人中的发生率是白人的五倍左右。虽然主要的 SLE的原因尚未确定，遗传、激素和环境因素的组合是 已知对这种疾病的发展有促进作用。近年来的研究表明，这种疾病 这一过程在临床疾病发生前几年在遗传易感对象中启动，并 它可以被性激素和包括肠道微生物区系在内的环境因素抑制或加速。这 这表明，对环境和遗传因素相互作用的理解增加 触发/维持疾病进程的早期事件和识别自身免疫的早期预测因素 进程将有助于开发新的安全有效的战略，以控制或预防系统性红斑狼疮，在发病之前 临床疾病。在这方面，使用具有相同病因学和自身抗原的狼疮临床前模型 与人类系统性红斑狼疮的表位相比，我们第一次展示了促炎事件的贡献 自身抗体的产生始于幼年时期的肠道粘膜，远在系统性红斑狼疮发病之前。 自身免疫与临床疾病，在发病过程中。我们还发现了一种组合 在TLR7/8中引发肠道炎症和自身抗体产生的先前未知的分子事件- 肠道微生物区系相互作用依赖的方式，并有助于全身自身免疫和狼疮疾病 进步。根据我们的初步观察，我们假设“体内的系统性自身免疫过程 狼疮由TLR7/8-肠道微生物区系相互作用依赖的炎症和 在肾炎前期，肠粘膜产生自身抗体，并抑制这种相互作用可以有效地 在高危人群中预防疾病，并在狼疮患者中抑制自身抗体的产生。在这里，我们 建议研究：1)通过联合肠道确定TLR7/8-微生物区系相互作用剂量在人类系统性红斑狼疮中的作用 炎症和通透性特征与免疫细胞上这些受体的表达水平有关，以及 依赖微生物区系相互作用的这些细胞的促炎反应，与自身免疫和狼疮 以及2)阐明TLR7/8-肠道微生物区系相互作用在启动肠道炎症和 利用临床前模型产生自身抗体和系统自身免疫。我们还将确定 口服拮抗剂在预防/抑制肠道炎症、全身自身免疫方面的潜力 和疾病发病率。我们提议的研究不仅将识别引发炎症的早期促炎事件 系统性自身免疫狼疮，但也将引入一种新的和合理的，口服治疗的可能性 抑制肠道炎症以预防高危受试者的系统性红斑狼疮和已确诊的受试者的红斑 SLE。