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.

原发性干燥综合征（pSS）是一种全身性慢性炎症性自身免疫性疾病，其特征为 眼睛干燥和口干。 pSS 的基本组织病理学特征包括 T 细胞和 B 细胞的局灶性浸润 在唾液腺和泪腺中，导致组织损伤和慢性炎症。在某些情况下， 组织病理学变化通过称为淋巴的过程发展成三级淋巴组织或器官（TL） 新发生。 TLO 的细胞组成和组织类似于脾脏和淋巴结。 TLO 可能是招募具有淋巴归巢能力（幼稚和中枢记忆）的 T 细胞的地方 细胞）以及它们的激活、增殖和分化发生。 CD4+ T 细胞协调免疫 应答可分为辅助性 T 细胞 (Th)1、Th2 和 Th17 细胞以及具有调节性的 CD4+ T 细胞 功能包括叉头框 P3 (FOXP3) 阳性调节性 T 细胞 (Treg)。尽管 T 细胞及其 pSS 的唾液组织中发现了细胞因子，但尚不清楚哪种类型的 T 细胞在该过程中起主导作用。 发病机制。该项目调查了这样的假设：pSS 患者的平衡发生了改变 由慢性炎症和淋巴新生引起的 Th17 和 Treg 免疫反应 Th17 细胞和 Treg 的分化和功能缺陷基于 Th17 细胞有效的事实 诱导炎症，而 Treg 抑制炎症。另外，这两种细胞类型都与自身免疫相关，并且具有 炎症环境下细胞分化的相互关系。假设将是 解决方法： 1) 目标 1. 确定 pSS 中的 TLO 是否可以作为抗原呈递位点 诱导自身抗体、耐受或激活，重点关注 Treg 和 Th17 细胞； 2) 目标 2. 确定是否 pSS 患者外周血中 Th17 和 Treg 免疫反应的平衡发生改变 继发于 Th17 细胞和 Treg 分化和功能缺陷； 3) 目标 3. 确定是否 外周血中 Th17 和 Treg 免疫反应平衡的改变与新鲜血液中的 TLO 相关 pSS 患者的小唾液组织。这些研究将为发病机制和机制提供新的线索 治疗自身免疫性疾病，包括 pSS。