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Influence of NMO gut microbiota on CNS autoantigen-specific T cell responses

NMO 肠道微生物群对 CNS 自身抗原特异性 T 细胞反应的影响

基本信息

批准号：
9766417
负责人：
SCOTT S ZAMVIL
金额：
$ 20.52万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766417
关键词：
Adenosine Triphosphate Adjuvant Amino Acid Sequence Anaerobic Bacteria Antibodies Astrocytes Autoantigens Autoimmune Diseases Autoimmune Diseases of the Nervous System Autoimmune Process Bacteria Binding CNS autoimmunity Cells Characteristics Clinical Clostridium Clostridium perfringens Demyelinating Diseases Development Epitopes Equilibrium Exhibits Gastrointestinal tract structure Germ-Free Gram-Positive Bacteria Household Human IgG1 Inflammatory Link Multiple Sclerosis Mus Neuraxis Neuromyelitis Optica Pathogenesis Pathologic Patients Predisposition Process Proteins Regulatory T-Lymphocyte Research Role T cell differentiation T cell response T-Lymphocyte T-Lymphocyte Epitopes Taxon Testing antigen-specific T cells aquaporin 4 base cross reactivity gut microbiome gut microbiota multiple sclerosis patient peptide permease permease programs response water channel

项目摘要

PROJECT SUMMARY / ABSTRACT Neuromyelitis optica (NMO) is a rare, disabling and sometimes fatal, central nervous system (CNS) autoimmune inflammatory demyelinating disease. Aquaporin-4 (AQP4), a water channel that is expressed abundantly on astrocytes, is the primary target in NMO. A majority of NMOSD patients have AQP4-specific Abs, which are IgG1, a T cell-dependent subclass, indicating that AQP4-specific T cells have a key role in this humoral autoimmune disease. Certain clinical and pathologic findings suggest that Th17 cells participate in NMO pathogenesis. Our group first identified AQP4-specific T cells, an observation that was confirmed by other groups. We observed that T cells specific for dominant AQP4 epitopes exhibited Th17 polarization, providing further support that Th17 cells participate in NMO pathogenesis. Further, the dominant AQP4 T cell epitope identified in NMO contains a ten amino acid (aa) sequence that shares 90% homology to an aa sequence within an ABC-TP in Clostridium perfringens, a ubiquitous anaerobic gram-positive bacterium found in human commensal gut flora. This discovery, along with the demonstration that certain Clostridia species in the gut of humans can regulate the balance between regulatory T cells (Treg) and Th17 cells, suggest that gut microbiota, and possibly C. perfringens itself, could participate in NMO pathogenesis. Recently, we evaluated the gut microbiome in NMO, multiple sclerosis (MS) and healthy controls (HC). Remarkably, C. perfringens was the second most significantly enriched taxon in NMO, and among bacteria identified at the species level, C. perfringens was the one most highly associated with NMO. Thus, we have hypothesized that C. perfringens may have dual functions in NMO pathogenesis: it may (1) serve as its own proinflammatory adjuvant, promoting Th17 polarization, and (2) expose a determinant of a Clostridium ABC-TP that cross-reacts with AQP4, leading to expansion of AQP4-reactive T cells. Here, we propose to colonize germ-free mice with gut microbiota from NMO patients or by mono-colonization with C. perfringens, in order to directly examine the potential role of gut microbiota in NMO and C. perfringens, respectively, in proinflammatory T cell differentiation. In the process of examining our hypothesis regarding C. perfringens, our study should provide important information regarding the potential role of gut microbiota in NMO and CNS autoimmunity in general.

项目总结/摘要视神经肌萎缩症（NMO）是一种罕见的，致残的，有时是致命的，中枢神经系统（CNS）的自身免疫性疾病。炎性脱髓鞘疾病水通道蛋白-4（AQP 4）是一种在星形胶质细胞上大量表达的水通道， NMO的主要目标大多数NMOSD患者具有AQP 4特异性抗体，其为IgG 1，一种T细胞依赖性抗体。亚类，表明AQP 4特异性T细胞在这种体液自身免疫性疾病中具有关键作用。某些临床和病理结果提示Th 17细胞参与了NMO的发病过程。我们的小组首先确定了AQP 4特异性T细胞，细胞，这一观察得到了其他团体的证实。我们观察到对优势AQP 4表位特异的T细胞显示Th 17极化，进一步支持Th 17细胞参与NMO发病机制。此夕h 在NMO中鉴定的显性AQP 4 T细胞表位含有10个氨基酸（aa）序列，其与在NMO中鉴定的AQP 4 T细胞表位具有90%同源性。产气荚膜梭菌ABC-TP中的aa序列，产气荚膜梭菌是一种普遍存在于人体中的厌氧革兰氏阳性菌肠道植物群。这一发现，沿着的是人类肠道中的某些梭菌物种可以调节调节性T细胞（Treg）和Th 17细胞之间的平衡，表明肠道微生物群，可能还有C. 产气荚膜杆菌本身可能参与NMO的发病。最近，我们评估了NMO，多发性硬化症（MS）和健康对照（HC）的肠道微生物组。值得注意的是， C.产气荚膜杆菌是NMO中第二个最显著富集的分类群，并且在物种水平上鉴定的细菌中， C.产气荚膜杆菌是与NMO相关性最高的一种。因此，我们假设C。产气荚膜杆菌可能具有在NMO发病机制中的双重功能：它可以（1）作为其自身的促炎佐剂，促进Th 17极化，和（2）暴露与AQP 4交叉反应的梭菌ABC-TP的决定子，导致AQP 4反应性的扩增， T细胞。在这里，我们建议用来自NMO患者的肠道微生物群或通过以下单定植来定植无菌小鼠： C.产气荚膜梭菌，以直接检查肠道微生物群在NMO和C.产气荚膜杆菌，分别，在促炎性T细胞分化中的作用在检验我们关于C.产气荚膜杆菌，我们的研究应该提供关于肠道微生物群在NMO和CNS自身免疫中的潜在作用的重要信息，将军