Immunopathogenesis of Sjogren syndrome

描述(由申请人提供)：本建议书描述了一项为期5年的培训计划，旨在发展儿科风湿病的学术生涯。这位PI已经在费城儿童医院完成了儿科和儿科风湿病的正式住院医师和研究员培训，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。科雷茨基博士是宾夕法尼亚大学研究副主席、首席科学官和弗朗西斯·C·伍德医学教授。他在成功指导学生、博士后研究员和初级教员方面拥有丰富的经验。为了进一步促进研究人员的科学发展，已经成立了一个咨询委员会，成员包括史蒂文·莱纳博士、特里·芬克尔博士和爱德华·贝伦斯博士等备受尊敬的医学科学家。SJégren综合征专家Seunghee Cha博士和Eduardo M.Rocha博士也将参与顾问角色。Finkel博士和Behrens博士也是儿科风湿病学的领导者，并将指导PI的临床发展。这项拟议的研究集中在Sjégren综合征发展过程中免疫失调的机制，Sj？gren综合征是一种常见但知之甚少的自身免疫性疾病。干燥综合征是由泪腺和唾液腺的破坏和功能障碍引起的，随后出现严重的眼部和口腔干燥，可能发展为威胁视力或严重的牙科症状。非肥胖糖尿病(NOD)小鼠自发地产生类似于Sj？gren综合征的自身免疫，为研究疾病的发生提供了工具。泪腺和唾液腺的炎性细胞浸润以T细胞为主，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细胞是在正常宿主中阻止自身免疫的CD4T细胞的一个亚群，在非自身免疫倾向的小鼠中在解剖学上是有组织的；然而，这种结构在自身免疫倾向的小鼠中是否被破坏尚不清楚。雌性NOD小鼠患上唾液腺炎症，而雄性患上泪腺疾病。这是由于免疫细胞的内在机制还是外在机制尚不清楚。这项建议的具体目的是：1)明确CD8和CD4T细胞在疾病发生中的作用；2)确定干燥综合征NOD模型中调节性T细胞缺陷的程度和机制。了解干燥综合征自身免疫发展的最早事件将为更好地诊断和治疗该疾病和其他自身免疫疾病提供靶点。

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.