Lymphoid neogenesis and CD4+T cell differentiation in primary Sjogren's syndrome

原发性干燥综合征中的淋巴新生和 CD4 T 细胞分化

• 批准号: 7687681
• 负责人: Insoo Kang
• 金额: $ 25.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687681
• 关键词: Address; Antigen Presentation; Antinuclear Antibodies; Archives; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biopsy; Boxing; CD4 Positive T Lymphocytes; CD4/CD8 ratio procedure; CD8B1 gene; Cell Differentiation process; Cells; Characteristics; Chronic; Defect; Dendritic Cells; Development; Diagnosis; Disease; Effector Cell; Environment; Epitopes; Equilibrium; Figs - dietary; Follicular Dendritic Cells; Frequencies; Fresh Tissue; Gene Expression; Generations; Helper-Inducer T-Lymphocyte; High Endothelial Venule; Homing; IL2RA gene; Immune; Immune Tolerance; Immune response; Immunity; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-10; Interleukin-17; Interleukin-4; Interleukin-6; Lacrimal gland structure; Lead; Ligands; Light; Link; Location; Lymphatic vessel; Lymphocyte; Lymphoid; Lymphoid Tissue; Measures; Mediating; Memory; Messenger RNA; Methods; Minor; Minor salivary gland structure; Organ; Paper; Pathogenesis; Pathologic; Patients; Phenotype; Population; Process; Production; Recruitment Activity; Regulation; Reporting; Role; Salivary; Salivary Glands; Secondary to; Site; Sjogren' s Syndrome; Spleen; Structure of germinal center of lymph node; Study models; Surrogate Markers; Syndrome; T memory cell; T-Lymphocyte; TALL-1 protein; Th1 Cells; Th2 Cells; Thymus Gland; Tissues; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Xerophthalmia; Xerostomia; base; cell type; chemokine; cohort; cytokine; eye dryness; interest; interleukin-23; lymph nodes; memory CD4 T lymphocyte; migration; peripheral blood; receptor

Primary Sjogren's syndrome (pSS) is a systemic chronic inflammatory autoimmune disease characterized by dry eyes and dry mouth. Essential histopathologic features of pSS include focal infiltrations of T and B cells in the salivary and lacrimal glands that lead to tissue injury and chronic inflammation. In some cases, the histopathologic changes develop into tertiary lymphoid tissues or organs (TLs) via a process called lymphoid neogenesis. TLOs resemble spleen and lymph nodes in their cellular composition and organization. TLOs may serve as a place where recruitment of T cells with lymphoid homing capacity (naive and central memory cells) as well as their activation, proliferation and differentiation occur. CD4+ T cells that orchestrate immune responses can be divided into T-helper (Th)1, Th2 and Th17 cells as well as CD4+ T cells with regulatory function including forkhead box P3 (FOXP3)-positive regulatory T cells (Treg). Although T cells and their cytokines are found in the salivary tissues of pSS, it is unknown which type of T cells has a leading role in the pathogenesis. This project investigates the hypothesis that patients with pSS have an altered balance of Th17 and Treg immune responses that is caused by chronic inflammation with lymphoid neogenesis and defect(s) in differentiating and functioning of Th17 cells and Treg based on the facts that Th17 cells potently induce inflammation while Treg suppress it. Plus, the both cell types are linked with autoimmunity and have a reciprocal relationship in cellular differentiation under inflammatory milieu. The hypothesis will be addressed with: 1) Aim 1. Determine if the TLOs in pSS could serve as sites of antigen presentation for induction of autoantibodies, tolerance or activation, focusing on Treg and Th17 cells; 2) Aim 2. Determine if patients with pSS have an altered balance of Th17 and Treg immune responses in the peripheral blood secondary to a defect(s) in Th17 cells and Treg differentiation and function; and 3) Aim 3. Determine if the altered balance of Th17 and Treg immune responses in peripheral blood correlates with TLOs in the fresh minor salivary tissues in patients with pSS. These studies will shed new light on the pathogenesis and treatment of autoimmune diseases including pSS.

原发性Sjogren综合征（PSS）是一种系统性的慢性炎症自身免疫性疾病，其为特征 眼睛干燥和嘴巴干燥。 PSS的基本组织病理学特征包括T和B细胞的局灶性浸润 在导致组织损伤和慢性炎症的唾液和泪腺中。在某些情况下， 组织病理学的变化通过称为淋巴样的过程发展成三级淋巴组织或器官（TLS） 新生成。 TLO在其细胞组成和组织中类似于脾脏和淋巴结。 tlos 可以用作募集具有淋巴样归巢能力的T细胞（幼稚和中央记忆 细胞）以及它们的激活，增殖和分化。策划免疫的CD4+ T细胞 可以将响应分为T-馆（Th）1，Th2和Th17细胞以及具有调节性的CD4+ T细胞 功能包括叉子盒P3（FOXP3） - 阳性调节T细胞（TREG）。尽管T细胞及其 细胞因子在PSS的唾液组织中发现，尚不清楚哪种类型的T细胞在 发病机理。该项目调查了PSS患者的平衡改变的假设 TH17和TREG免疫反应是由淋巴新生殖和慢性炎症引起的 基于Th17细胞有效的事实，Th17细胞和Treg的分化和功能缺陷 Treg抑制炎症，诱发炎症。另外，两种单元格类型都与自身免疫性相关 在炎症环境下细胞分化的相互关系。假设将是 以下方 诱导自身抗体，耐受性或激活，重点是Treg和Th17细胞； 2）目标2。确定是否 PSS患者的平衡状况改变了外周血中的Th17和Treg免疫反应 继发于Th17细胞和Treg分化和功能的缺陷。 3）目标3。确定是否是否 周围血液中Th17和Treg免疫反应的平衡改变与新鲜的TLO相关 PSS患者的次要唾液组织。这些研究将为发病机理和 包括PSS在内的自身免疫性疾病的治疗。