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

基本信息

批准号：
7871645
负责人：
Jill Marie Kramer
金额：
$ 13.31万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7871645
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&apos 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

项目摘要

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）：作为具有免疫学博士学位的口腔病理学，Kramer博士对具有口服表现的自身免疫性疾病感兴趣，并选择研究Sjogren综合征（SS）。尽管她的远程目标是指导自己的实验室，教学和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Feinstein医学研究所（FIMR）的临床医生Rothstein博士的指导下实现这些目标。因此，FIMR非常重视转化研究，并将提供一个丰富的协作环境，以在其中进行她的拟议项目。此外，她将参加课程和研讨会，还将根据她的职业发展计划参加会议。由于她已经成功完成了一个具有挑战性的DDS/PhD计划，因此她准备实现自己的目标，并正在与拥有B细胞生物学专业知识的经验丰富的导师合作。 Kramer博士的提议着重于SS，SS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。 SS（PSS）的主要形式主要影响唾液和泪腺，而次级形式（SSS）与其他自身免疫结缔组织疾病结合发生。 SS患者表现出增加的牙齿衰减，难以说话和咀嚼，并且也有许多系统并发症。许多类型的免疫细胞在自身免疫的发展和进展中至关重要，该建议将特别关注B细胞。尽管B细胞在SS中显然很重要，但它们对疾病起始和进展的贡献尚不清楚。该提案的第一个目的旨在获得对SS病因的基本理解。在此目标中，我们将检查负责SS自身抗体产生的特定B细胞子集以及免疫球蛋白基因使用和细胞特异性。在特定目标2和3中，我们将寻求确定SS中创新的治疗靶标。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。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，我们将将这些研究扩展到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。我们将确定表达高水平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鉴定迄今为止在SS中定义较差的基本疾病机制，以及用于治疗该疾病的创新治疗靶标，这可能会导致患有SS患者的口腔和系统健康的显着改善。公共卫生相关性：Sjogren综合征（SS）是一种令人衰弱的自身免疫性疾病，发生在0.6％的人口中，主要影响产生泪水和唾液的腺体，但也会引起许多系统性问题。该建议旨在评估自身抗体和影响疾病B细胞运动的因素。这项研究可能会导致鉴定基本疾病机制，以及疾病发育的生物标志物和新型B细胞靶向治疗剂，这些疗法将改善SS发病机理，从而改善患病患者的口服和系统健康。