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

描述（由申请人提供）：类风湿关节炎（RA）是最常见的衰弱性系统性炎症之一。苏博士的研究研究了识别自身抗原的T细胞如何促进自身免疫性疾病的发生和传播。迄今为止，对于哪些自身抗原参与类风湿性关节炎以及识别这些自身蛋白的T细胞如何成为疾病的致病性知之甚少。阻碍这一领域进展的一个主要限制是难以识别涉及的特定T细胞群和自身抗原。苏博士已经生成了初步数据，首次证明可以直接从RA患者体内鉴定出针对假定的RA自身抗原（人糖蛋白39 (Hcgp39)）的T细胞。有趣的是，hcgp39特异性T细胞也可以在一些健康个体中发现。这一数据使她提出了一种假设，即自身抗原特异性T细胞在健康人体内功能不活跃，但识别相同自身抗原的细胞在类风湿关节炎患者体内功能上容易发生炎症。在这个K08中，她建议研究自身抗原特异性T细胞库在健康和患病状态下如何随时间变化。然后，她将确定这些自我识别的T细胞之间的功能差异，并研究来自RA患者和健康人的T细胞是否具有识别相同抗原的T细胞受体，但其贪婪度和灵活性不同。她将使用肽- mhc四聚体和磁柱富集来进行这些实验，以鉴定自身抗原特异性CD4 T细胞。四聚体标记细胞的功能表征和T细胞受体分析将在单细胞水平上进行。本研究的主要目的是了解识别自身蛋白的T细胞如何参与类风湿关节炎的发病机制。苏博士的近期职业目标是获得优秀的培训，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。这份申请详细描述了一个经过深思熟虑的职业发展计划，包括与其他实验室的广泛合作，参加研讨会和科学会议，以及生物统计学课程。苏博士有强大的机构支持，这将使她能够专注于拟议的研究。K08指导临床科学家职业发展奖将促进苏博士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者。

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.