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.

项目概要 我的职业目标是通过检查风湿病的机制来更好地了解风湿病的系统性疾病 眼部炎症并确定哪些机制是眼睛特有的，哪些是与其他眼睛共有的 器官，特别是关节。指导临床科学家研究职业的五年提案 发展奖将帮助我成长为该领域一位富有成效的、独立的学术研究者 眼风湿病学。这一领域的进展应补充该领域的工作，以便更多地开展工作。 对系统性自身免疫性疾病的全面了解。 中轴型脊柱关节炎与 HLA-B27 密切相关，并且频繁出现关节外表现 例如前葡萄膜炎，一种可能导致白内障、青光眼和永久性眼部炎症的疾病 视力丧失。虽然风湿病中致病性免疫细胞和旁观者免疫细胞之间的区别已经 尽管具有挑战性，但眼睛的固有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群体提供了一种方法。 了解疾病发病机制的器官特异性和系统机制的新机会。 通过对三个个体进行单细胞 RNA 测序 (scRNAseq)，我们初步鉴定出两个 在 HLA-B27+ 期间，CD8 T 细胞亚群总共占眼内所有 CD8 T 细胞的约 50% 前葡萄膜炎。虽然两种类型的 CD8 T 细胞共享转录程序，例如表达 表面受体 CD161，每个群体的抗原特异性都不同。第一个人口是 传统的多克隆 CD8 T 细胞群，可识别病毒抗原等，但能够表达 IL-17 因此被称为 Tc17 细胞。相比之下，第二个群体是非常规 T 细胞 主要使用特异性识别代谢物的单一 T 细胞受体基因片段的人群 核黄素合成的细胞，被称为粘膜相关不变 T (MAIT) 细胞。鉴于差异 抗原特异性，我们假设这两种 CD8 T 细胞类型在抗原特异性中发挥冗余作用 炎症的独立机制。 我们建议通过使用 MAIT 或 Tc17 细胞在 HLA-B27+ 前葡萄膜炎中发挥核心作用 scRNAseq 和多维流式细胞术评估 (1) 是否是一种或两种 CD161+ CD8 T 细胞亚型 在 HLA-B27+ 前葡萄膜炎中是保守的，(2) 激活眼内这些细胞的机制是什么，以及 (3) 这些子集之一或两者在进入眼睛之前是否在循环中失调。通过 成功完成这项研究，接受教学培训，并接受专家的指导 多学科专家组，我计划以独立转化研究员的身份开始我的职业生涯 研究风湿病的眼部表现。