Altered T follicular helper responses in human autoimmune diseases

人类自身免疫性疾病中滤泡辅助 T 反应的改变

• 批准号: 8732917
• 负责人: Hideki Ueno
• 金额: $ 7.84万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732917
• 关键词: Address; Antigen-Presenting Cells; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Assay; Blood; Blood Cells; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; Cells; Collaborations; Data; Disease; Functional disorder; Gene Expression; Generations; Genes; Goals; Helper-Inducer T-Lymphocyte; Human; ITGAX gene; Immune; Inflammatory; Knowledge; Lead; Medical; Memory; Methods; Microdissection; Molecular Profiling; Mus; Natural Immunity; Newly Diagnosed; Pathogenesis; Pathway interactions; Patients; Phenotype; Prevention; Protocols documentation; Regulatory T-Lymphocyte; STAT4 gene; Sampling; Signal Transduction; Site; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF4 gene; Thymus Gland; Tissues; Tonsil; adaptive immunity; cytokine; memory CD4 T lymphocyte; new therapeutic target; novel; response

Generation of autoantibodies is a hallmark of autoimmune diseases. Recent data in humans and mice show that overrepresentation of T follicular helper (Tfh) cells, a CD4+ T cell subset specialized in helping B cells in germinal centers (GCs), is associated with autoimmunity. Yet, the immune mechanisms that cause exaggerated Tfh response in human autoimmune diseases remain largely unknown. Our preliminary studies suggest a common mechanism associated with exaggerated Tfh responses in human autoimmune disease. We identified two candidate factors derived from antigen-presenting cells promoting Tfh responses. Altered Tfh response in autoimmune diseases might be also associated with dysregulated of T follicular regulatory (Tfr) cells that originate from thymus-derived regulatory T cells (Tregs). In this Collaborative Project, we hypothesize that Altered APCs promotes Tfh response while suppressing Tfr response thereby contributing to the pathogenesis of human autoimmune diseases. We will share our established methods for the studies of human Tfh cells to other Centers, so that newly diagnosed untreated patients with a broad range of autoimmune diseases can be analyzed across the Centers. The specific aims are AIM 1: To determine the alteration in Tfh cell subsets in blood in autoimmune diseases. AIM 2: To determine the alteration in Tfh cells and CD11c+ APCs in inflammatory tissues in autoimmune diseases. AIM 3: To determine whether APCs in inflammatory tissues are capable of inducing naive and memory CD4+ T cells to differentiate into Tfh cells, and AIM 4: To determine whether and how Tfr response is altered in autoimmune diseases. In conclusion, we might be able to reveal immunological pathways that cause altered Tfh/GC response shared by different autoimmune diseases as well as unique one to each disease.

自身抗体的产生是自身免疫性疾病的标志。最近在人类和老鼠身上的数据显示， 滤泡辅助性T细胞（Tfh）的过度表达，一种专门帮助B细胞的CD 4 + T细胞亚群， 与自身免疫相关的是老年痴呆症中心（GC）。然而，免疫机制， 人类自身免疫性疾病中过度的Tfh应答在很大程度上仍然未知。我们的初步研究 提示与人类自身免疫性疾病中过度Tfh应答相关的共同机制。 我们确定了两个候选因素来自抗原呈递细胞促进Tfh反应。改变 自身免疫性疾病中的Tfh反应也可能与T细胞滤泡调节因子的失调有关。 (Tfr)来源于胸腺衍生的调节性T细胞（TCFs）的细胞。在这个合作项目中，我们 假设改变的APC促进Tfh应答，同时抑制Tfr应答， 人类自身免疫性疾病的发病机制。我们将分享我们建立的研究方法 人类Tfh细胞的其他中心，使新诊断的未经治疗的患者与广泛的 可以在各个中心分析自身免疫性疾病。具体目标是目标1： 自身免疫性疾病中血液中Tfh细胞亚群的改变目的2：检测转铁蛋白（Tfh）的变化 细胞和CD 11 c + APC在自身免疫性疾病的炎症组织中的表达。目标3：确定是否 炎性组织中的APC能够诱导幼稚和记忆性CD 4 + T细胞分化为CD 4 + T细胞。 Tfh细胞和AIM 4：确定Tfr反应是否以及如何在自身免疫性疾病中改变。在 结论，我们可能能够揭示导致Tfh/GC反应改变的免疫途径， 不同的自身免疫性疾病以及每种疾病的独特之处。