Identification of Pathogenic T cells in Axial Spondyloarthritis

中轴型脊柱关节炎致病性 T 细胞的鉴定

• 批准号: 10449769
• 负责人: Michael Alexander Paley
• 金额: $ 15.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449769
• 关键词: Address; Anatomy; Anterior uveitis; Antigens; Area; Bioinformatics; Blindness; Blood; Blood Circulation; Blood donor; Blood specimen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cataract; Cells; Clinical; Committee Members; Complement; Complex; Cytometry; Data; Development; Discrimination; Disease; Disease remission; Distant; Exhibits; Eye; Flare; Flow Cytometry; Frequencies; Future; Gene Expression Profile; Genetic Transcription; Glaucoma; Goals; HLA Antigens; Homing; Human; Immune; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-17; Joints; K-Series Research Career Programs; KLRB1 gene; Lead; Learning; Mentors; Methods; Mucous Membrane; Onset of illness; Organ; Paracentesis; Pathogenesis; Pathogenicity; Pathology; Patients; Phenotype; Play; Population; Process; Property; Psoriasis; Receptor Signaling; Research; Research Personnel; Rheumatism; Rheumatology; Riboflavin; Role; Sampling; Scientist; Skin; Specificity; Spondylarthritis; Stimulus; Surface; Systemic disease; T cell receptor repertoire sequencing; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Tissues; Training; Uveitis; Viral Antigens; anterior chamber; biobank; career; cell type; cohort; cytokine; experience; eye chamber; high risk; insight; joint inflammation; lifetime risk; multidisciplinary; new therapeutic target; novel; peripheral blood; programmed cell death protein 1; programs; protein expression; receptor; receptor expression; single-cell RNA sequencing; skills; systemic autoimmune disease; trafficking; translational scientist

PROJECT SUMMARY My career goal is to better understand systemic diseases in rheumatology by examining the mechanisms of ocular inflammation and determining which mechanisms are specific to the eye and which are shared with other organs, particularly the joint. This five-year proposal for a Mentored Clinical Scientist Research Career Development Award will help me mature into a productive, independent academic investigator in the field of ocular rheumatology. Advances in this area should complement the body of work in the field to allow for a more comprehensive understanding of systemic autoimmune disorders. Axial spondyloarthritis is strongly associated with HLA-B27 and has frequent extra-articular manifestations such as anterior uveitis, an inflammatory ocular disease that can lead to cataract, glaucoma, and permanent vision loss. While discrimination between pathogenic and bystander immune cells in rheumatologic diseases has been challenging, the intrinsic immune privilege of the eye increases the enrichment for pathogenic cell types. Therefore, studying ocular immune cells and the corresponding populations in the peripheral blood provides a novel opportunity to understand both organ-specific and systemic mechanisms of disease pathogenesis. Using single-cell RNA sequencing (scRNAseq) in three individuals, we have preliminarily identified two subsets of CD8 T cells that collectively accounts for ~50% of all CD8 T cells within the eye during HLA-B27+ anterior uveitis. While both types of CD8 T cells share a transcriptional program, such as expression of the surface receptor CD161, the antigen-specificity is distinct for each population. The first population is a conventional polyclonal CD8 T cell population that recognizes viral antigens, among others, but is able to express IL-17 and therefore have been termed Tc17 cells. In contrast, the second population is an unconventional T cell population that predominantly uses a single T cell receptor gene segment that specifically recognizes metabolites of riboflavin synthesis and are called mucosal-associated invariant T (MAIT) cells. Given the difference in antigen-specificity, we hypothesize that these two CD8 T cell types serve redundant roles in an antigen- independent mechanism of inflammation. We propose to establish whether MAIT or Tc17 cells play a central role in HLA-B27+ anterior uveitis by using scRNAseq and multidimensional flow cytometry to assess (1) whether one or both CD161+ CD8 T cell subtypes are conserved in HLA-B27+ anterior uveitis, (2) what mechanisms of activate these cells within the eye, and (3) whether one or both of these subsets are dysregulated in the circulation prior to entry into the eye. Through successful completion of this research, undergoing the didactic training, and receiving guidance from a multidisciplinary group of experts, I plan to launch my career as an independent translational researcher investigating the ocular manifestations of rheumatologic diseases.

项目摘要 我的职业目标是通过研究血液流变学中的机制， 眼部炎症和确定哪些机制是眼睛特有的，哪些机制是与其他眼睛共享的。 器官，尤其是关节。这份为期五年的指导临床科学家研究生涯提案 发展奖将帮助我成长为一个富有成效的，独立的学术研究者在该领域 眼流变学这一领域的进展应补充这一领域的大量工作， 全面了解系统性自身免疫性疾病。 轴性脊柱关节炎与HLA-B27密切相关，并有频繁的关节外表现 例如前葡萄膜炎，一种可导致白内障、青光眼和永久性 视力丧失虽然在风湿性疾病中区分致病性和旁观者免疫细胞， 眼睛的内在免疫特权增加了致病细胞类型的富集。 因此，研究眼免疫细胞和外周血中相应的群体提供了一种新的方法。 了解疾病发病机制的器官特异性和全身机制的新机会。 在三个个体中使用单细胞RNA测序（scRNAseq），我们初步鉴定了两个 在HLA-B27+期间，CD 8 T细胞的亚群共同占眼内所有CD 8 T细胞的约50%。 前葡萄膜炎虽然这两种类型的CD 8 T细胞共享转录程序，例如表达CD 8 T细胞的转录因子。 表面受体CD 161，抗原特异性对于每个群体是不同的。第一个种群是 常规的多克隆CD 8 T细胞群，其识别病毒抗原，但能够表达 IL-17，因此被称为Tc 17细胞。相比之下，第二个群体是非常规T细胞， 主要使用特异性识别代谢物的单个T细胞受体基因片段的群体 它们是核黄素合成的关键细胞，被称为粘膜相关不变T细胞（MAIT）。考虑到 抗原特异性，我们假设这两种CD 8 T细胞类型在抗原中起着冗余的作用， 独立的炎症机制。 我们建议通过使用MAIT或Tc 17细胞来确定MAIT或Tc 17细胞在HLA-B27+前葡萄膜炎中是否发挥核心作用。 scRNAseq和多维流式细胞术来评估（1）一种或两种CD 161 + CD 8 T细胞亚型 在HLA-B27+前葡萄膜炎中是保守的，（2）在眼睛内激活这些细胞的机制，以及（3） 这些亚群中的一个或两个是否在进入眼睛之前在循环中失调。通过 成功完成这项研究，接受教学培训，并接受指导， 作为一个多学科的专家小组，我计划作为一个独立的翻译研究者开始我的职业生涯 研究风湿性疾病的眼部表现。