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: 10462246
• 负责人: CHENTHAMARAKSHAN VASU
• 金额: $ 8.64万
• 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/10462246
• 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.

项目总结/摘要 系统性红斑狼疮（SLE）主要影响女性，发病率是男性的10倍， 非裔美国人的发病率是白种人的五倍。虽然主要 SLE的病因尚未确定，遗传，激素和环境因素的组合， 已知会导致这种疾病的发展近年来的研究表明， 该过程在遗传易感受试者中在临床疾病发展前几年开始， 性激素和包括肠道微生物群在内的环境因素可能会抑制或加速它。这 这表明，增加对环境和遗传因素相互作用的理解， 触发/延续疾病过程的早期事件和识别自身免疫性疾病的早期预测因子 这一过程将有助于开发新的安全有效的策略，以控制或预防系统性红斑狼疮， 临床疾病在这方面，使用共享病因和自身抗原的狼疮临床前模型， 表位与人类SLE的表位，我们首次证明了促炎事件的贡献 和自身抗体的生产开始在肠道粘膜在青少年的年龄，早在发病前的全身性 自身免疫与临床疾病密切相关，在疾病的发病过程中。我们还确定了一种组合， 以前未知的分子事件，启动肠道炎症和自身抗体的产生，在TLR 7/8- 肠道微生物群相互作用依赖的方式，并有助于系统性自身免疫和狼疮疾病 进展根据我们的初步观察，我们假设“全身性自身免疫过程中， 狼疮由TLR 7/8-肠道微生物群相互作用依赖性炎症引发并持续， 自身抗体的产生，并在肾炎前期抑制这种相互作用， 预防高危受试者的疾病，并抑制狼疮患者的自身抗体产生”。这里我们 建议研究：1）通过将肠道与TLR 7/8 -微生物群相互作用剂量相关联来确定TLR 7/8 -微生物群相互作用剂量在人类SLE中的作用 炎症和渗透性特征与免疫细胞上这些受体的表达水平有关， 这些细胞的微生物群相互作用依赖的促炎反应，与自身免疫和狼疮 易感性;以及2）阐明TLR 7/8-肠道微生物群相互作用在引发肠道炎症中的作用， 自身抗体产生和使用临床前模型的全身性自身免疫。我们还将确定 拮抗剂口服治疗预防/抑制肠道炎症、全身性自身免疫的潜力 和发病率。我们提出的研究不仅将确定早期促炎事件， 系统性自身免疫性狼疮，但也将介绍一种新的和合理的，口服治疗的可能性， 抑制肠道炎症以预防高危受试者中的SLE和已确定的SLE患者中的发作 SLE。