Immunopathogenesis of Sjogren syndrome

描述（由申请人提供）：该提案描述了一个为期5年的儿科风湿病学学术生涯发展培训计划。PI已经在费城儿童医院完成了儿科和儿科风湿病学的正式住院医师和奖学金培训，目前正在扩大他在免疫耐受和自身免疫模型方面的科学技能。国际淋巴细胞生物学权威Gary Koretzky博士将指导PI的科学发展。Koretzky博士是宾夕法尼亚大学研究副主席、首席科学官和Francis C. Wood医学教授。他在成功指导学生、博士后研究员和初级教师方面拥有丰富的经验。为了进一步促进研究者的科学发展，一个由备受尊敬的医学科学家组成的咨询委员会，包括dr。史蒂文·莱纳，特里·芬克尔和爱德华·贝伦斯已经成立。格林综合征专家博士。车承熙（Seunghee Cha）和罗查（Eduardo M. Rocha）也将担任顾问。Drs。芬克尔和贝伦斯也是儿科风湿病学的领导者，并将指导PI的临床发展。拟议的研究重点是免疫失调在Sj¿green综合征发展中的机制，这是一种常见但知之甚少的自身免疫性疾病。格林综合征是由泪腺和唾液腺的破坏和功能障碍引起的，随后出现严重的眼和口腔干燥，并可能发展为威胁视力或严重的牙齿症状。非肥胖糖尿病（NOD）小鼠自发地产生类似Sj¿green综合征的自身免疫，为研究疾病起源提供了工具。泪腺和唾液腺的炎症细胞浸润是由T细胞主导的，但不同的T细胞亚群在疾病发生中的作用尚不清楚。调节性T细胞是CD4+ T细胞的一个亚群，在正常宿主中阻止自身免疫，在非自身免疫易感性小鼠中解剖组织；然而，这是否在自身免疫易感性小鼠中被破坏是未知的。雌性NOD小鼠出现唾液腺炎症，而雄性出现泪腺疾病。这是由于免疫细胞的内在或外在机制尚不清楚。本提案的具体目标是：1)明确CD8+和CD4+ T细胞在疾病起始中的作用；2)明确Sj¿green综合征NOD模型中调节性T细胞缺陷的程度和机制。了解Sj¿green综合征自身免疫发展的早期事件将为更好地诊断和治疗这种疾病和其他自身免疫性疾病提供目标。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in Pediatric Rheumatology. The PI has completed formal residency and fellowship training in Pediatrics and Pediatric Rheumatology at The Children's Hospital of Philadelphia and is currently expanding his scientific skills in immune tolerance and autoimmunity models. Dr. Gary Koretzky, an international authority in lymphocyte biology, will mentor the PI's scientific development. Dr. Koretzky is Vice Chair for Research, Chief Scientific Officer, and Francis C. Wood Professor of Medicine at the University of Pennsylvania. He has extensive experience in successfully mentoring students, post-doctoral fellows, and junior faculty members. To further promote the investigator's scientific development, an Advisory Committee comprising highly regarded medical scientists including Drs. Steven Reiner, Terri Finkel, and Edward Behrens has been established. Sj¿gren syndrome experts Drs. Seunghee Cha and Eduardo M. Rocha will participate in advisory roles as well. Drs. Finkel and Behrens are also leaders in Pediatric Rheumatology and will mentor the PI's clinical development. The proposed research focuses on mechanisms of immune dysregulation in the development of Sj¿gren syndrome, a common but poorly understood autoimmune disease. Sj¿gren syndrome is caused by destruction and dysfunction of lacrimal and salivary glands with subsequent profound ocular and oral dryness which may progress to sight-threatening or severe dental manifestations. The nonobese diabetic (NOD) mouse spontaneously develops autoimmunity resembling Sj¿gren syndrome, providing a tool for studying disease initiation. Inflammatory cell infiltrates of lacrimal and salivary glands are dominated by T cells, but the contributions of different T cell subsets in disease initiation are unknown. Regulatory T cells, a subset of CD4+ T cells which prevent autoimmunity in normal hosts, are organized anatomically in non-autoimmune-prone mice; however, whether this is disrupted in autoimmune-prone mice is unknown. Female NOD mice develop salivary gland inflammation, whereas males develop lacrimal gland disease. Whether this is due to immune- cell intrinsic or extrinsic mechanisms is unknown. This proposal specifically aims to: 1) define the roles of CD8+ and CD4+ T cells in disease initiation; 2) define the extent and mechanisms of regulatory T cell defects in the NOD model of Sj¿gren syndrome. Understanding the earliest events in the development of Sj¿gren syndrome autoimmunity will provide targets for better diagnostic and therapeutic modalities for use in this and other autoimmune diseases.