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：
10291401
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 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291401
关键词：
Adolescent Adult Affect African American population 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 antagonist base 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.

项目概要/摘要系统性红斑狼疮 (SLE) 主要影响女性，发病率是男性的十倍，尽管是主要的，但非洲裔美国人的发病率是白人的五倍左右。 SLE 的病因尚未确定，遗传、激素和环境因素共同作用近年来的研究表明，已知有助于这种疾病的发展。遗传易感受试者的过程在临床疾病发生前几年就开始了，并且它可能会受到性激素和环境因素（包括肠道微生物群）的抑制或加速。表明增加对环境和遗传因素相互作用的了解触发/延续疾病过程的早期事件并识别自身免疫的早期预测因子流程将有助于制定新的安全有效的策略，以在 SLE 发作之前控制或预防在这方面，使用具有相同病因和自身抗原的狼疮临床前模型。我们首次证明了促炎症事件的贡献和自身抗体的产生在青少年时期就在肠道粘膜中开始产生，远早于全身性疾病的发生我们还发现了自身免疫和临床疾病在疾病发作过程中的结合。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根据我们的初步观察，我们进展到“系统性自身免疫过程狼疮是由 TLR7/8 肠道微生物群相互作用依赖性炎症引发和延续的肠粘膜中自身抗体的产生，在肾炎前期阶段抑制这种相互作用可以有效地预防高危人群的疾病，并抑制狼疮患者自身抗体的产生”。提出研究：1) 通过关联肠道来定义 TLR7/8 与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，以及这些细胞的微生物群相互作用依赖性促炎症反应，与自身免疫和狼疮易感性；2) 阐明 TLR7/8 肠道微生物群相互作用在引发肠道炎症和我们还将使用临床前模型确定自身抗体的产生和系统性自身免疫。口服拮抗剂治疗在预防/抑制肠道炎症、系统性自身免疫方面的潜力我们提出的研究不仅会识别引发的早期促炎症事件。狼疮的全身性自身免疫，但也将引入一种新颖且合理的口服疗法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受试者的耀斑系统性红斑狼疮。