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检查风湿病学中的系统性疾病，通过检查 眼部炎症并确定哪种机制特定于眼睛，哪些机制与其他机制共享 器官，特别是关节。这项为指导的临床科学家研究职业的五年建议 发展奖将帮助我成为一名富有成效的独立学术研究员 眼风湿病。该领域的进步应该补充现场的工作体系，以便更多 对系统性自身免疫性疾病的全面了解。 轴向脊椎关节炎与HLA-B27密切相关，并且经常出现关节外表现 例如前葡萄膜炎，可能导致白内障，青光眼和永久性的炎性眼疾病 视力丧失。虽然风湿病疾病中的病原体和旁观者免疫细胞的歧视已有 充满挑战的是，眼睛的内在免疫特权增加了致病细胞类型的富集。 因此，研究眼部免疫细胞和外周血中的相应种群提供了 了解疾病发病机理的器官特异性和系统机制的新机会。 在三个个体中使用单细胞RNA测序（SCRNASEQ），我们先鉴定了两个 在HLA-B27+期间，CD8 T细胞的子集占眼睛内所有CD8 T细胞的50％ 前葡萄膜炎。两种类型的CD8 T细胞共享转录程序，例如表达 表面受体CD161，抗原特异性对于每个人群都不同。第一个人口是 常规的多克隆CD8 T细胞群识别病毒抗原等，但能够表达 IL-17，因此被称为TC17细胞。相比之下，第二个人群是一个非常规的T细胞 主要使用单个T细胞受体基因段的种群，该基因段专门识别代谢产物 核黄素合成，称为粘膜相关不变t（MAIT）细胞。考虑到差异 抗原特异性，我们假设这两种CD8 T细胞类型在抗原中起冗余的作用 炎症的独立机制。 我们建议通过使用MAIT或TC17细胞在HLA-B27+前葡萄膜炎中起核心作用 SCRNASEQ和多维流式细胞术，以评估（1）一个或两种CD161+ CD8 T细胞亚型 在HLA-B27+前葡萄膜炎中保守，（2）哪种机制激活了眼睛内的这些细胞，（3） 在进入眼睛之前，这两个子集中的一个或两个子集是否在循环中失调。通过 成功完成了这项研究，接受教学培训，并从 多学科专家小组，我计划启动我的职业生涯 研究风湿病的眼部表现。