Autoantibodies and B Cell Chemotaxis in Sjogren's Syndrome

描述(申请人提供)：作为一名口腔病理学住院医师，拥有免疫学博士学位，克莱默博士对具有口腔症状的自身免疫性疾病感兴趣，并选择研究干燥综合征(SS)。虽然她的长期目标是指导自己的实验室，在学术机构内教授和参与病人护理，但她的近期目标是获得独立开展自身免疫研究所需的知识和技能。她将在范斯坦医学研究所(FIMR)的罗斯坦博士的指导下实现这些目标。罗斯坦博士是一位有成就的临床科学家。因此，FIMR非常重视翻译研究，并将提供一个丰富的协作环境来实施她提议的项目。此外，她还将参加课程和研讨会，并根据自己的职业发展计划参加会议。她已经做好了实现目标的准备，因为她已经成功完成了一个具有挑战性的DDS/博士项目，现在正在与一位在B细胞生物学方面拥有相当专业知识的经验丰富的导师合作。克莱默博士的建议集中在SS上，这是一种罕见的自身免疫性疾病，主要影响产生泪水和唾液的腺体。原发类型的SS(PSS)主要影响唾液腺和泪腺，而继发形式(SSS)合并其他自身免疫性结缔组织疾病。SS患者表现为龋齿增加，说话和咀嚼困难，并有许多全身并发症。许多类型的免疫细胞在自身免疫的发展和进展中是必不可少的，这项建议将特别关注B细胞。虽然B细胞在SS中显然很重要，但它们在疾病的发生和发展中的作用尚不清楚。这项建议的第一个目的是寻求对SS病因学的基本了解。在这一目标中，我们将研究SS的解剖位置和负责产生自身抗体的特定B细胞亚群，以及免疫球蛋白基因的使用和精细抗体特异性。在具体目标2和3中，我们将寻求确定SS的创新治疗靶点。具体地说，我们将确定抑制一种驱动B细胞募集的特定介质，称为CXCL13，是否会改善SS的病理。我们将在SS小鼠模型中中和CXCL13，并评估疾病严重程度。此外，我们将把这些研究扩展到PSS患者，以确定血清和/或唾液CXCL13水平是否与疾病严重程度相关。最后，我们将检测SS中的CXCL13受体。我们将确定高水平表达该受体的亚群是否优先产生自身抗体，以及该受体的表达是否受SS中存在的炎症介质的影响。这些研究的结果可能会导致确定迄今为止在SS中尚未明确的基本疾病机制，以及治疗这种疾病的创新治疗目标，这可能会显著改善患有SS的患者的口腔和系统健康。

DESCRIPTION (provided by applicant): As an oral pathology resident with a PhD in immunology, Dr. Kramer is interested in autoimmune diseases with oral manifestations, and has chosen to study Sjogren's syndrome (SS). While her long-range goals are to direct her own laboratory, teach, and participate in patient care within an academic institution, her immediate goals are to acquire the knowledge and skills necessary to conduct autoimmune research independently. She will achieve these goals under the mentorship of Dr. Rothstein, an accomplished clinician scientist, at the Feinstein Institute for Medical Research (FIMR). Accordingly, the FIMR places a strong emphasis on translational research, and will provide a rich collaborative environment in which to conduct her proposed project. Moreover, she will participate in courses and seminars, and will also attend conferences in accordance with her career development plan. She is well poised to accomplish her goals, as she has successfully completed a challenging DDS/PhD program, and is now working with an experienced mentor who has considerable expertise in B cell biology. Dr. Kramer's proposal focuses on SS, a rare autoimmune disease that primarily affects the glands that produce tears and saliva. The primary form of SS (pSS) affects the salivary and lacrimal glands predominantly, while the secondary form (sSS) occurs in conjunction with other autoimmune connective tissue disorders. SS patients demonstrate increased tooth decay, have difficulty speaking and chewing, and have many systemic complications as well. Many types of immune cells are essential in the development and progression of autoimmunity, and this proposal will focus B cells in particular. While B cells are clearly important in SS, their contribution to disease initiation and progression is not well understood. The first aim of this proposal seeks to gain a fundamental understanding of SS etiology. In this aim, we will examine the anatomic location and the specific B cells subsets responsible for autoantibody production in SS, as well as immunoglobulin gene usage and fine antibody specificity. In specific aims 2 and 3, we will seek to identify innovative therapeutic targets in SS. Specifically; we will determine whether inhibition of a specific mediator that drives B cell recruitment, termed CXCL13, will ameliorate the pathology observed in SS. We will neutralize CXCL13 in an SS mouse model and evaluate disease severity. Moreover, we will extend these studies to pSS patients to determine whether serum and/or salivary CXCL13 levels correlate with disease severity. Finally, we will examine the CXCL13 receptor in SS. We will determine whether subsets expressing high levels of this receptor produce autoantibodies preferentially, and whether expression of this receptor is influenced by inflammatory mediators that are present in SS. Results from these studies will likely result in the identification of fundamental disease mechanisms that are poorly defined in SS to date, and innovative therapeutic targets for the treatment of this disease that may result in significant improvements in the both the oral and systemic health of patients afflicted with SS.