Autoantibodies and B Cell Chemotaxis in Sjogren's Syndrome

干燥综合征中的自身抗体和 B 细胞趋化性

• 批准号: 8292245
• 负责人: Jill Marie Kramer
• 金额: $ 5.05万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-12-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292245
• 关键词: Affect; Anatomy; Antibody Specificity; Arthritis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; Biological Markers; CXCL13 gene; Cells; Cellular biology; Chemotaxis; Connective Tissue Diseases; Dental caries; Development; Development Plans; Disease; Doctor of Philosophy; Educational process of instructing; Environment; Etiology; Failure; Functional disorder; Gland; Goals; Health; Human; Immune; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunology; Individual; Inflammation Mediators; Inflammatory; Institutes; Institution; Kinetics; Knowledge; Laboratories; Lacrimal gland structure; Ligands; Location; Lymphoid Tissue; Mastication; Mediating; Mediator of activation protein; Medical Research; Mentors; Mentorship; Modeling; Mononuclear; Oral; Oral Manifestations; Oral Pathology; Pathogenesis; Pathology; Patient Care; Patients; Play; Population; Production; Research; Role; Saliva; Salivary; Salivary Glands; Scientist; Secondary to; Serum; Severities; Severity of illness; Signal Transduction; Site; Sjogren' s Syndrome; Source; Specificity; Therapeutic; Tissues; Translational Research; Up-Regulation; Work; autoreactive B cell; autoreactivity; career development; cell motility; chemokine; cytokine; experience; human CXCL13 protein; innovation; interest; mouse model; novel; programs; public health relevance; receptor; receptor expression; skills; symposium; therapeutic target; trafficking

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. Public Health Relevance: Sjogren's syndrome (SS) is a debilitating autoimmune disease that occurs in 0.6% of the population, and primarily affects the glands that produce tears and saliva, but causes many systemic problems as well. This proposal seeks to evaluate autoantibodies and a factor affecting B cell movement in disease. This study will likely result in the identification of fundamental disease mechanisms, as well as biomarkers for disease development and novel B cell targeted therapeutics that will ameliorate SS pathogenesis, leading to improvements in oral and systemic health for afflicted individuals.

描述（由申请人提供）：作为一名拥有免疫学博士学位的口腔病理科住院医师，Kramer 博士对具有口腔表现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、教学并参与学术机构内的患者护理，但她的近期目标是获得独立进行自身免疫研究所需的知识和技能。她将在费恩斯坦医学研究所 (FIMR) 一位卓有成就的临床科学家 Rothstein 博士的指导下实现这些目标。因此，FIMR 非常重视转化研究，并将提供丰富的协作环境来开展她提出的项目。此外，她还将根据自己的职业发展计划参加课程和研讨会，并参加会议。她已经做好了实现目标的准备，因为她已经成功完成了具有挑战性的 DDS/PhD 项目，并且现在正在与一位在 B 细胞生物学方面拥有丰富专业知识的经验丰富的导师一起工作。 Kramer 博士的建议重点关注 SS，这是一种罕见的自身免疫性疾病，主要影响产生眼泪和唾液的腺体。原发性 SS (pSS) 主要影响唾液腺和泪腺，而继发性 (sSS) 则与其他自身免疫性结缔组织疾病同时发生。 SS 患者蛀牙增多，说话和咀嚼困难，并且还有许多全身并发症。许多类型的免疫细胞对于自身免疫的发生和进展至关重要，该提案将特别关注 B 细胞。虽然 B 细胞在 SS 中显然很重要，但它们对疾病发生和进展的贡献尚不清楚。本提案的第一个目标是寻求对 SS 病因学的基本了解。为此，我们将检查 SS 中负责自身抗体产生的解剖位置和特定 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。具体来说;我们将确定抑制驱动 B 细胞募集的特定介质（称为 CXCL13）是否会改善 SS 中观察到的病理学。我们将在 SS 小鼠模型中中和 CXCL13 并评估疾病的严重程度。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，我们将检查 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到 SS 中存在的炎症介质的影响。这些研究的结果可能会确定迄今为止在 SS 中尚不清楚的基本疾病机制，以及治疗该疾病的创新治疗靶点，从而可能显着改善 SS 患者的口腔和全身健康。 公共健康相关性：干燥综合征 (SS) 是一种使人衰弱的自身免疫性疾病，发生于 0.6% 的人口，主要影响产生眼泪和唾液的腺体，但也会引起许多全身问题。该提案旨在评估自身抗体和影响疾病中 B 细胞运动的因素。这项研究可能会确定基本疾病机制、疾病发展的生物标志物和新型 B 细胞靶向疗法，从而改善 SS 发病机制，从而改善患病个体的口腔和全身健康。