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

基本信息

批准号：
10520068
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-06 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520068
关键词：
Acceleration Adolescent Adult Affect African American population Age Age of Onset Antibiotics Antibody Formation Antigens Autoantibodies Autoantigens Autoimmune Process Autoimmunity B-Lymphocytes Caucasians Cells Chromosomes Clinical Cohort Studies Data Defect Development Disease Disease Outcome 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 Proteins Proteomics Reporting Risk Rodent Role Sampling Shotguns Signal Induction Specificity Systemic Lupus Erythematosus Systemic disease TLR7 gene TLR8 gene Testing Time Woman X Inactivation antagonist clinical development clinically relevant cytokine effective intervention effective therapy gastrointestinal epithelium gut inflammation gut microbes gut microbiota interleukin-21 intestinal epithelium lupus prone mice men microbial microbiota novel overexpression preclinical study prevent receptor systemic autoimmunity targeted treatment

项目摘要

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/摘要全身性红斑狼疮（SLE）主要影响女性，比男性高出十倍它发生在非洲裔美国人中的五倍，是高加索人的五倍。虽然是主要的尚未确定SLE的原因，遗传，荷尔蒙和环境因素的结合是已知会为这种疾病的发展做出贡献。近年来的研究表明该疾病在临床疾病发展之前的几年和性激素和包括肠道菌群在内的环境因素可以抑制或加速它。这表明对环境和遗传因素相互作用的了解增加了触发/永久疾病过程的早期事件和自身免疫的早期预测因子的鉴定过程将有助于制定新颖的安全有效策略来控制或防止SLE，然后在开始之前临床疾病。在这方面，使用具有病因和自动抗原的狼疮的临床前模型我们第一次与人类SLE的表演表达了促炎事件的贡献和自身抗体的产生在少年时代开始于肠道粘膜，很久以前自身免疫性和临床疾病，在疾病过程中。我们还确定了以前未知的分子事件会启动肠炎和自身抗体的产生TLR7/8-- 肠道菌群相互作用依赖性方式，并有助于系统性自身免疫性和狼疮性疾病进展。根据我们的初步观察，我们假设“系统性自身免疫过程狼疮是由TLR7/8-GUT微生物群相互作用依赖于炎症和肠粘膜中的自身抗体产生，并在肾炎前阶段抑制这种相互作用可以有效预防高危受试者的疾病，并抑制狼疮患者的自身抗体产生”。在这里，我们提案研究：1）通过关联肠道来定义人类SLE中TLR7/8-微生物群的作用这些受体在免疫细胞上具有表达水平的炎症和渗透性特征，并且这些细胞的微生物群相互作用依赖性促炎反应，自身免疫性和狼疮敏感性； 2）阐明TLR7/8-GUT微生物群相互作用在肠道注射和使用临床前模型的自身抗体产生和全身自身免疫。我们还将确定用拮抗剂进行口服治疗的潜力，以防止/抑制肠道注射，全身自身免疫性和疾病事件。我们提出的研究不仅会确定提起的早期促炎事件狼疮中的系统性自身免疫，但也将引入一种新颖，理性的口服治疗的可能性抑制肠道炎症，以防止患有已建立的受试者的处于危险的受试者和耀斑 sle。