Project 2: Microbiome pathobionts and Lupus pathogenesis

项目2：微生物组病原体和狼疮发病机制

• 批准号: 10249215
• 负责人: Gregg Joshua Silverman
• 金额: $ 28.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249215
• 关键词: Abnormal Cell; Adult; Affect; Alleles; Antibacterial Response; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Cell Antigen Receptor; B-Lymphocytes; Bacteria; Bacterial Antigens; Biological Assay; Blood; Blood Circulation; Cell Compartmentation; Chromatin; Chronic; Clinical; Clonal Expansion; Clone Cells; Collaborations; Collection; Data; Databases; Disease; Environmental Risk Factor; Flare; Genes; Genetic; Goals; Gut associated lymphoid tissue; Immune; Immune response; Immunoglobulin A; Immunoglobulin G; Individual; Inflammatory; Intestines; Ku70 protein; Libraries; Link; Lupus; Machine Learning; Mass Spectrum Analysis; Mediating; Memory; Metadata; Modeling; Molecular Profiling; Pathogenesis; Pathogenicity; Pathologic; Patients; Pattern; Plasma Cells; Plasmablast; Predisposition; Proteomics; RNA-Binding Proteins; Recording of previous events; Ribosomes; Role; Sampling; Stable Disease; Surveys; Systemic Lupus Erythematosus; Testing; Time; Transcript; Woman; bacterial community; base; biobank; body system; chemokine; cohort; cross reactivity; cytokine; ds-DNA; dysbiosis; fecal microbiome; genome wide association study; gut microbiome; gut microbiota; human monoclonal antibodies; in vivo; microbial community; microbiome; mouse model; pathobiont; pre-clinical; recruit; response; symbiont; tissue injury; tool

ABSTRACT Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting many organ systems, with hallmarks of B-cell abnormalities and clonal expansions in the blood, specific types of circulating autoantibodies and immune-complex mediated tissue injury. While the cause is unknown, in-depth genome- wide association studies have identified genetic intervals and alleles that are associated with disease predisposition. Environmental factors appear to have a large, although still poorly understood, influence. There have been accelerating advances in understanding how the bacterial communities that live in us and on us contribute to inflammatory and autoimmune disorders. Bacterial species, that in most hosts are normal components of our microbial communities, have been implicated in pathogenesis and therefore termed pathogenic symbionts or pathobionts. Yet in the great majority of adults these same commensal species are completely innocuous or even beneficial. We have found that SLE patients with active disease have imbalances (termed dysbiosis) in the distribution/diversity of bacterial taxa in their intestinal microbiomes. Our overarching goal is to test the hypothesis that specific pathobiont commensal intestinal bacterial species contribute to lupus flares. In these studies we seek to understand how specific candidate pathobiont bacterial isolates contribute to Lupus pathogenesis and the expansion of disease-associated blood B-cell clones. In addition, we will study the effect of transferred gut microbiomes in murine models. The relationships between clones in the gut-associated B-cell compartment and in the systemic compartment in SLE patients will also be investigated.

摘要 系统性红斑狼疮(SLE)是一种累及多器官的慢性炎症性自身免疫性疾病 系统，在血液中有B细胞异常和克隆性扩张的特征，特定类型的循环 自身抗体和免疫复合体介导的组织损伤。虽然原因尚不清楚，但深入的基因组- 广泛的关联研究已经确定了与疾病相关的遗传区间和等位基因 性情。环境因素似乎有很大的影响，尽管人们对此仍知之甚少。 在理解生活在我们体内的细菌群落是如何 对我们造成炎症和自身免疫性疾病。细菌种类，在大多数宿主中是正常的 我们微生物群落的组成部分，被认为与发病有关，因此被称为 致病共生菌或致病细菌。然而，在绝大多数成年人中，这些相同的共生物种 完全无害，甚至是有益的。我们发现有活动期疾病的SLE患者 肠道微生物群中细菌分类群分布/多样性的不平衡(称为生物失调)。 我们的首要目标是检验这样一种假设，即特定的病原体与肠道细菌共生 导致狼疮发作。在这些研究中，我们试图了解特定的候选致病细菌 分离株有助于狼疮的发病和疾病相关血液B细胞克隆的扩大。此外, 我们将研究转移的肠道微生物群在小鼠模型中的作用。无性系之间的关系 此外，还将调查SLE患者的肠道相关B细胞亚群和全身亚群。