Characterization of human cytokine-producing B cells in Sjogren's Syndrome

描述（由申请人提供）：这个指导临床科学家发展奖将提供博士詹姆斯M。罗杰必要的支持，他继续他的训练，从一个最近的牙科学校毕业生（DOS，2008年）在免疫学博士与追求学术生涯的长期目标。罗杰博士的培训将在共同导师伊格纳西奥桑兹博士和詹姆斯E。梅尔文在开始了他的研究生论文项目的教学和初步实验后，他将集中精力研究干燥综合征（SS）中B细胞产生的细胞因子。导致口干和干眼的腺体破坏的标志性症状与炎症和浸润淋巴细胞有关。最近在B细胞耗竭疗法中的研究已经表明B细胞在自身免疫中的中心致病作用，以及进一步观察到B细胞通过“抗体非依赖性”手段如细胞因子产生促进疾病进展。已经观察到人SS以及小鼠模型中的B细胞产生多种细胞因子，如IL-10、IL-6、TNF-α和IFN-γ.虽然观察到B细胞能够产生各种细胞因子，无论是在局部腺体和全身在血液中的SS是有趣的，一个系统的方法来剖析这些细胞因子产生B细胞的功能，提出进一步定义其效应功能。Roger博士将在三个具体目标中检验这一假设，即产生烟碱的B细胞通过全身炎症调节和靶组织影响而促成SS。目的1：在健康受试者的本地队列中表征细胞因子和产生嘌呤的B细胞群体。目的2：在本地SS患者队列中表征细胞因子和产生嘌呤的B细胞群。目的3：探讨唾液腺干燥综合征（SS）中浸润的B细胞在疾病过程中的作用。 公共卫生相关性：干燥综合征是最常见的自身免疫性疾病之一，估计折磨1-4%的美国人口，女性与男性的比例为9：1。通过表征B细胞在SS与健康患者中的作用，将来可能开发新的和特异性的SS筛查工具和治疗方法。最后，该奖项将为罗杰博士提供必要的工具，以准备更先进的资助申请，从而在学术研究的职业生涯。

DESCRIPTION (provided by applicant): This Mentored Clinical Scientist Development Award will provide Dr. James M. Roger the support necessary for him to continue his training from that of a recent dental school graduate (DOS, 2008) towards a PhD in Immunology with the long term goal of pursuing an academic career. Dr. Roger's training will be under the guidance of co-mentors, Dr. Ignacio Sanz and Dr. James E. Melvin. Having begun the didactic and preliminary experiments of his graduate thesis project, he will focus his efforts on studying cytokine production by B cells in Sjogren's Syndrome (SS). The hallmark symptoms of glandular destruction leading to dry mouth and dry eye are associated with inflammation and infiltrating lymphocytes. Recent studies in B cell depletion therapy have suggested a central pathogenic role for B cells in autoimmunity as well as further observations that B cells contribute to disease progression by "antibody independent" means such as cytokine production. B cells in human SS as well as mouse models have been observed to produce a diverse array of cytokines such as, IL-10, IL-6, TNF- Ipha, and IFN- amma. While the observation that B cells are capable of producing a variety of cytokines both locally in the gland and systemically in the blood in SS is intriguing, a systematic approach to dissect the function of these cytokine producing B cells is proposed to further define their effector function. Dr. Roger will test the hypothesis that cytokine-producing B cells contribute to SS through systemic inflammatory modulation and target-tissue influences in three specific aims. Aim 1: Characterization of the cytokines and cytokine-producing B cell populations in a local cohort of healthy subjects. Aim 2: Characterize the cytokines and cytokine-producing B cell populations in a local cohort of SS patients. Aim 3: Examine the involvement that infiltrating B cells play in the disease process in SS salivary glands. Public Health Relevance: Sjogren's Syndrome is one of the most common autoimmune diseases afflicting an estimated 1-4% of the US population and women to men in a ratio of 9:1. By characterizing the role of B cells in the SS versus the healthy patient, it may be possible to develop new and specific screening tools and treatments for SS in the future. Finally, this award will provide Dr. Roger the tools necessary to prepare more advanced grant submissions leading to a career in academic research.