The Characteristics of Self-recognizing CD4 T Cells in Rheumatoid Arthritis

描述(由申请人提供)：类风湿性关节炎(RA)是最常见的使人衰弱的全身炎症条件之一。苏博士的研究调查了识别自身抗原的T细胞如何有助于自身免疫性疾病的启动和传播。到目前为止，对于哪些自身抗原与RA有关，以及识别这些自身蛋白的T细胞如何在疾病中致病，人们知之甚少。阻碍这一领域进展的一个主要限制是难以识别所涉及的特定T细胞群体和自身抗原。苏博士制作的初步数据首次证明，可以在体外直接从RA患者中鉴定出针对一种可能的RA自身抗原--人糖蛋白39(Hcgp39)的T细胞。有趣的是，在一些健康个体中也可以发现Hcgp39特异的T细胞。这些数据导致她提出了一种假设，即在健康人中，自身抗原特异性T细胞在功能上是不活跃的，但在RA患者中，识别相同自身抗原的细胞在功能上容易发生炎症。在这篇K08中，她建议研究自身抗原特异性T细胞在健康和疾病状态下如何随着时间的推移而变化。然后，她将确定这些自我识别的T细胞之间的功能差异，并调查RA患者和健康人的T细胞是否具有识别同一抗原的不同亲和力和灵活性的T细胞受体。她将使用多肽-MHC四聚体和磁柱浓缩来进行这些实验，以识别自身抗原特异性的CD4T细胞。四聚体标记细胞的功能鉴定和T细胞受体分析将在单细胞水平上进行。这项拟议研究的主要目的是了解识别自身蛋白质的T细胞如何在类风湿性关节炎的发病机制中做出贡献。苏博士目前的职业目标是接受优秀的培训，成为一名独立的调查员。她的长期职业目标是在免疫学领域做出重大贡献，并为自身免疫性疾病开发新的诊断和治疗策略。这份申请详细说明了一项经过仔细考虑的职业发展计划，其中包括与其他实验室的广泛合作互动，参加研讨会和科学会议，以及生物统计学课程。苏博士拥有强大的机构支持，这将使她能够专注于拟议中的研究。本次K08临床科学家导师职业发展奖将促进苏医生作为一名内科科学家的发展，最终成为一名完全独立的研究员。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is one of the most common debilitating systemic inflammatory conditions. Dr. Su's research investigates how T cells recognizing self-antigens contribute to the initiation and propagation of autoimmune diseases. To date, little is known about which autoantigens are involved in RA and how T cells recognizing these self-proteins may become pathogenic in disease. One major limitation that has hindered progress in this field is the difficulty in identifying the specific T cell populations and self-antigens that are involved. Dr. Su has generated preliminary data that demonstrate for the first time that T cells specific for a putative RA autoantigen, the human glycoprotein 39 (Hcgp39), can be identified directly ex vivo from RA patients. Interestingly, Hcgp39-specific T cells can also be found in some healthy individuals. This data lead her to propose the hypothesis that autoantigen-specific T cells are functionally inactive in a healthy person, but cells recognizing the same self-antigen are functionally prone to inflammation in RA patients. In this K08, she proposes to study how the autoantigen-specific T cell repertoire changes in healthy and diseased states over time. She will then determine the functional differences between these self-recognizing T cells and investigate whether T cells from RA patients and healthy people have T cell receptors that recognize the same antigen with different avidity and flexibility. She will carry out these experiments using peptide-MHC tetramers and magnetic column enrichment to identify self-antigen specific CD4 T cells. Functional characterization and T cell receptor analysis of tetramer tagged cells will be performed on the single cell level. The main objective of this proposed research is to understand how T cells that recognize self-proteins contribute to the pathogenesis of rheumatoid arthritis. Dr. Su's immediate career goal is to obtain excellent training to become an independent investigator. Her long-term career goal is to make significant contribution to the field of Immunology and develop new diagnostic and treatment strategies for autoimmune diseases. This application details a carefully thought out career development plan that includes extensive collaborative interaction with other laboratories, attendance at seminars and scientific meetings, and classes in biostatistics. Dr. Su has strong institutional support that will allow her to focus on the proposed research. This K08 Mentored Clinical Scientist Career Development Award will facilitate Dr. Su's development as a physician scientist to ultimately become a fully independent investigator.