Regulation of Tfh function in autoimmunity by TSLP

TSLP 对自身免疫中 Tfh 功能的调节

• 批准号: 10441850
• 负责人: Steven F Ziegler
• 金额: $ 25.95万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441850
• 关键词: Adult; Affinity; Antibiotics; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Childhood; Chronic; Clinical; Clinical Data; Clinical Trials; Clone Cells; Complement Receptor; Data; Development; Diabetes Mellitus; Disease; Exhibits; Fc Receptor; Follicular Dendritic Cells; Generations; Genes; Genetic; Germ-Free; Grant; Helper-Inducer T-Lymphocyte; House mice; Human; Immune; Immunization; Immunoglobulin Class Switching; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulin Variable Region; Infection; Insulin-Dependent Diabetes Mellitus; Intervention; Joints; Lupus; Mediating; Mind; Mouse Strains; Multiple Sclerosis; Mus; Nuclear; Nuclear Antigens; Organ; Pancreas; Patients; Play; Point Mutation; Production; Property; RNA; Receptor Activation; Regulation; Rheumatoid Arthritis; Role; SLEB1 gene; Sampling; Signal Transduction; Sjogren' s Syndrome; Structure; Structure of germinal center of lymph node; Synovial Fluid; Systemic Lupus Erythematosus; T-Lymphocyte; TSLP gene; Testing; Thymus Gland; aluminum sulfate; antigen processing; autoreactivity; base; cytokine; ds-DNA; insight; lupus prone mice; lupus-like; lymph nodes; pathogen; pathogenic autoantibodies; pre-clinical; response; secondary lymphoid organ

Project Summary Germinal centers (GCs) are dynamic immune microarchitectures that expand in secondary lymphoid organs during infection or immunization. GCs can also develop in the absence of overt immunization or detectable adventitious infection (called spontaneous GCs, Spt-GCs). As opposed to induced GCs that form during immunization or anti-pathogen responses, Spt-GCs develop in response to endogenous antigens and contribute, in part, to chronic autoimmunity. Spt-GCs are enlarged and more frequent in autoimmune-prone mice in the absence of detectable pathogens or overt immune challenge. Spt-GCs exhibit a linear correlation with nuclear-reactive autoantibody titers in lupus-prone mice and many GC B cells isolated from Spt-GCs developed in SLE-prone mice are autoreactive. Both Tfh cells and CGC B cells within the Spt-GCs play essential roles in regulating high-affinity autoantibody production. Spt-GCs have also been detected in patients with several different autoimmune diseases including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Sjogren’s syndrome (SS) and Type 1 diabetes (T1D). For example, pediatric SLE patients have elevated numbers of circulating pre- GC B cells and adult SLE patients exhibit increased circulating Tfh cells. These data indicate the important roles that Spt-GCs play in pathogenic autoantibody production. While the correlation of Spt-GCs with autoimmunity is clear, the factors that control their development remain obscure. We have found that the cytokine thymic stromal lymphopoietin (TSLP) plays a significant role in the development of Spt-GCs. TSLP- and TSLPR-deficient mice have dramatically reduced numbers of Spt- GCs, and those that exist appear to be vestigial. Consistent with this observation, we have also found that TSLP signaling is critical for the differentiation of Tfh. Taken as a whole, these data demonstrate an important role for TSLP in Spt- and induced-GC formation and function. We will test this hypothesis by determining the role of TSLP in Tfh development and function (Aim 1), and determine the role of Tfh-specific TSLP signaling in autoimmune prone mice.

项目概要 生发中心 (GC) 是在二级淋巴中扩展的动态免疫微结构 感染或免疫期间的器官。 GC 也可能在没有明显免疫或未进行公开免疫的情况下发生。 可检测的外来感染（称为自发性GC，Spt-GC）。与诱导 GC 形成相反 在免疫或抗病原体反应期间，Spt-GC 响应内源性抗原而发展， 部分导致慢性自身免疫。在有自身免疫倾向的小鼠中，Spt-GC 增大且更频繁 在没有可检测到的病原体或明显的免疫挑战的情况下。 Spt-GC 表现出线性相关性 狼疮易感小鼠中的核反应性自身抗体滴度以及从 Spt-GC 中分离出的许多 GC B 细胞均已开发出来 在易患 SLE 的小鼠中，存在自身反应性。 Spt-GC 内的 Tfh 细胞和 CGC B 细胞在 调节高亲和力自身抗体的产生。 在患有几种不同自身免疫性疾病的患者中也检测到了 Spt-GC，包括 系统性红斑狼疮 (SLE)、类风湿性关节炎 (RA)、多发性硬化症 (MS)、干燥综合征 (SS) 和 1 型糖尿病 (T1D)。例如，儿科 SLE 患者的循环前体细胞数量增加。 GC B 细胞和成年 SLE 患者表现出循环 Tfh 细胞增加。这些数据表明了重要作用 Spt-GC 在致病性自身抗体产生中发挥作用。 虽然 Spt-GC 与自身免疫的相关性很明显，但控制其发展的因素 保持模糊。我们发现细胞因子胸腺基质淋巴细胞生成素（TSLP）发挥着重要作用 Spt-GC 的开发。 TSLP 和 TSLPR 缺陷小鼠的 Spt- 数量显着减少 GC 以及那些现存的似乎已经退化了。与这一观察结果一致，我们还发现 TSLP 信号传导对于 Tfh 的分化至关重要。总的来说，这些数据显示了重要作用 TSLP 在 Spt- 和诱导-GC 的形成和功能中的作用。我们将通过确定以下角色来检验这一假设： TSLP 在 Tfh 发育和功能中的作用（目标 1），并确定 Tfh 特异性 TSLP 信号传导在 Tfh 发育和功能中的作用 自身免疫易感小鼠。