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）：Sjogren的综合征（SJS）是一种自身免疫性疾病，其特征是由于慢性免疫攻击主要针对唾液和泪腺，导致唾液和泪腺（干肉眼）和嗜血杆菌（干眼睛）（干眼睛）。虽然可能会参与其他许多组织（例如，尤其感兴趣的gl道，皮肤，肺，肺部和肌肉系统，肾脏，膀胱和阴道），尤其感兴趣的是各种感觉，周围，颅和骨髓病神经病，在SJS患者中近20％都会发展出近20％的感觉。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作中起关键作用。尽管在没有B细胞淋巴瘤形成的情况下，通常不认为SJS是致命疾病，但随着疾病进展，患者的生活质量越来越降低。人类和动物模型中SJS自身免疫性的一个特征是在唾液和泪腺中形成类似生发的中心，称为淋巴细胞灶（LF）。 LF和LF评分虽然临床疾病的重要诊断标准并不总是与疾病的严重程度相关，这表明对LF内细胞的性质和功能普遍缺乏了解；但是，LF必须包含有关自身免疫反应的重要信息，该信息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专注于定义唾液腺LF内形成的白细胞种群的性质，并确定这些细胞种群是否确定了SJS自身免疫涉及的疾病机制。为了解决这些问题，提前了两个具体目的：（1）定义和表征IL-23的分泌和CD4+ TH17记忆T细胞种群渗透在c57BL/6.NOD-4ECF AEC2 AEC2小鼠模型的SJS样疾病过程中渗透唾液腺的唾液腺，并确定（2）确定CD4+ TH1+ TH1+ TH1+ TH1的+-27+ TH1。 C57BU6.NOD-.AECF AEC2鼠标模型中的SJS。拟议的研究代表了为SJS研究未来职业准备主要研究者的核心活动，而结果有望通过更好地定义与SJS相关表现形式发作的更好的因素来为人类的未来转化研究建立基础。在SJS小鼠模型中定义和表征LF的白细胞种群的结果以及在研究过程中开发的技术将确定使用人类标本的过渡研究的可行性。本研究将进一步提供有关白细胞种群及其产物在腺体中的动态相互作用的重要数据，从而导致了与长期疾病状态相关的免疫病理生理表现和并发症。