Immune-pathophysiology of lymphocytic foci in Sjogren's syndrome

干燥综合征淋巴细胞病灶的免疫病理生理学

• 批准号: 7587561
• 负责人: Cuong Q Nguyen
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587561
• 关键词: 12p; Address; Affect; Androgens; Animal Model; Anxiety; Appearance; Applications Grants; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Cell Lymphomas; B-Lymphocytes; Bladder; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cephalic; Chronic; Clinic Visits; Clinical; Connective Tissue Diseases; Data; Dementia; Dendritic Cells; Development; Diagnostic; Disease; Disease Progression; Disease susceptibility; Equilibrium; Estrogens; Exocrine Glands; Fibromyalgia; Functional disorder; Future; Gland; Goals; Gonadal Steroid Hormones; Helper-Inducer T-Lymphocyte; Human; Immune; Impaired cognition; In Vitro; Infiltration; Interleukin-17; Kidney; Lacrimal gland structure; Lead; Leukocytes; Lung; Lymphocyte; Memory Loss; Mental disorders; Mus; Nature; Neuropathy; Patients; Peripheral; Play; Population; Principal Investigator; Quality of life; Relative (related person); Reporting; Research; Research Personnel; Role; Salivary; Salivary Glands; Sensory; Severity of illness; Sialadenitis; Signal Transduction Pathway; Site; Sjogren' s Syndrome; Skin; Specimen; Symptoms; System; T memory cell; Technology; Time; Tissues; Vagina; Viral Vector; Woman; Xerophthalmia; Xerostomia; base; career; depression; eye dryness; insight; interest; interleukin-23; macrophage; men; mouse model; muscular system; novel; prevent; programs; sexual dimorphism; therapeutic target; translational study

DESCRIPTION (provided by applicant): Sjogren's syndrome (SjS) is an autoimmune disease characterized by loss of exocrine function as a result of a chronic immune attack primarily against the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). While a number of other tissues may become involved (e.g., the Gl tract, skin, the lungs, the vasculature and muscular systems, kidneys, bladder and vagina), of particular interest are the various sensory, peripheral, cranial and myelopathic neuropathies that develop in nearly 20% of SjS patients. Recent studies suggest that B cells and autoantibodies play a critical role in onset of exocrine glandular dysfunction. Although SjS is generally not considered a lethal disease in the absence of B cell lymphoma formation, patients have an increasingly diminished quality of life with disease progression. One feature of SjS autoimmunity in both humans and animal models is the formation of germinal-like centers in the salivary and lacrimal glands, referred to as lymphocytic foci (LF). LF and LF scores, while important diagnostic criteria for clinical disease, do not always correlate with disease severity, indicating a general lack of understanding about the nature and function of cells within LF; yet, LF must contain important information about the autoimmune response that ultimately results in exocrine glandular dysfunction and eventually destruction. Thus, the fundamental goal of the research proposed herein is to focus on defining the nature of the leukocyte populations forming within LF of the salivary glands and determine if these cell populations identify disease mechanisms involved in SjS autoimmunity. To address these issues, two specific aims are advanced: (1) Define and characterize the IL-23 secreting and CD4+ TH17 memory T cell populations infiltrating the salivary glands during development of SjS-like disease in the C57BL/6.NOD-4ecf Aec2 mouse model of SjS, and (2) Determine the possible regulatory potential of IL-27 on the CD4+ TH17 memory T cell populations for preventing development of SjS in the C57BU6.NOD-.Aecf Aec2 mouse model. The proposed research represents the core activity in preparing the principal investigator for a future career in SjS research, while the results are expected to establish the basis for future translational studies to humans by better defining factors underlying development and onset of SjS-associated manifestations. Results defining and characterizing leukocytic populations of LF in a mouse model of SjS, together with technologies developed during the conduct of the studies will establish the feasibility for transitional studies using human specimens. The present studies will further provide important data on the dynamic interactions of leukocytic populations and their products within the glands resulting in the immuno-pathophysiological manifestations and complications associated with long-term disease states.

描述（由申请人提供）：干燥综合征（SjS）是一种自身免疫性疾病，其特征是由于主要针对唾液腺和泪腺的慢性免疫攻击导致外分泌功能丧失，从而导致口干症（口干）和干眼症（干眼症）。虽然许多其他组织可能会参与其中（例如，胃肠道、皮肤、肺、脉管系统和肌肉系统、肾、膀胱和阴道），特别感兴趣的是在近20%的SjS患者中发展的各种感觉、外周、颅和脊髓病变神经病。最近的研究表明，B细胞和自身抗体在外分泌腺功能障碍的发病中起关键作用。虽然在没有B细胞淋巴瘤形成的情况下，SjS通常不被认为是一种致死性疾病，但随着疾病进展，患者的生活质量越来越低。在人类和动物模型中，SjS自身免疫的一个特征是在唾液腺和泪腺中形成生殖样中心，称为淋巴细胞灶（LF）。LF和LF评分，而重要的临床疾病的诊断标准，并不总是与疾病的严重程度，表明一般缺乏了解的性质和功能的细胞内LF，然而，LF必须包含重要的信息，自身免疫反应，最终导致外分泌腺功能障碍，并最终破坏。因此，本文提出的研究的基本目标是重点定义唾液腺LF内形成的白细胞群体的性质，并确定这些细胞群体是否识别了SjS自身免疫相关的疾病机制。为了解决这些问题，提出了两个具体目标：（1）在SjS的C57 BL/6.NOD-4 ecf Aec 2小鼠模型中，定义并表征在SjS样疾病的发展过程中浸润唾液腺的IL-23分泌性和CD 4 + TH 17记忆T细胞群，和（2）确定IL-27对CD 4 + TH 17记忆T细胞群的可能调节潜力，以防止C57BU6.NOD-.AecfAec2小鼠模型中SjS的发展。拟议的研究代表了主要研究者为SjS研究的未来职业生涯做准备的核心活动，而结果预计将通过更好地定义SjS相关表现的发展和发病的潜在因素，为未来对人类的转化研究奠定基础。结果定义和表征LF的白细胞群体在小鼠模型的SjS，连同技术开发过程中的研究进行将建立过渡性研究，使用人类标本的可行性。目前的研究将进一步提供重要的数据动态相互作用的白细胞群体和他们的产品在腺体内导致免疫病理生理表现和并发症与长期疾病状态。