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

描述（由申请人提供）：该指导临床科学家发展奖将为James M. Roger博士提供必要的支持，使他能够从牙科学校的应届毕业生（DOS, 2008）继续接受免疫学博士学位的培训，并实现追求学术生涯的长期目标。Roger博士的培训将在共同导师Ignacio Sanz博士和James E. Melvin博士的指导下进行。他已经开始了他的研究生论文项目的教学和初步实验，他将集中精力研究干燥综合征（SS）中B细胞产生细胞因子的研究。导致口干和眼干的腺破坏的标志性症状与炎症和淋巴细胞浸润有关。最近对B细胞耗竭疗法的研究表明，B细胞在自身免疫中起核心致病作用，并进一步观察到B细胞通过“抗体独立”的方式（如细胞因子的产生）促进疾病进展。人类SS和小鼠模型中的B细胞已被观察到产生多种细胞因子，如IL-10、IL-6、TNF- Ipha和IFN- amma。虽然观察到B细胞能够在SS的腺体局部和全身血液中产生各种细胞因子是有趣的，但提出了一种系统的方法来解剖这些产生细胞因子的B细胞的功能，以进一步确定它们的效应功能。Roger博士将在三个特定目标中测试产生细胞因子的B细胞通过系统性炎症调节和靶组织影响来促进SS的假设。目的1：在当地健康人群中细胞因子和细胞因子产生B细胞群的特征。目的2：描述局部SS患者队列中细胞因子和产生细胞因子的B细胞群。目的3：探讨浸润性B细胞在SS唾液腺疾病过程中的作用。

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.