Regulation of Tfh function in autoimmunity by TSLP

TSLP 对自身免疫中 Tfh 功能的调节

• 批准号: 10571867
• 负责人: Steven F Ziegler
• 金额: $ 21.66万
• 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: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571867
• 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 Separation; Cell physiology; Cells; Childhood; Chronic; Clinical; 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; 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; autoreactive B cell; autoreactivity; 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.

项目摘要 生发中心（GCS）是动态免疫微构造，在继发性淋巴机中膨胀 感染或免疫期间的组织。 GC也可以在没有明显免疫或 可检测的促进感染（称为赞助GC，SPT-GCS）。与诱导的GC相反 在免疫或抗病原体反应期间，SPT-GCs响应内源性抗原和 部分贡献了慢性自身免疫性。 SPT-GC在自身免疫性的小鼠中得到增强，并且更频繁 在没有可检测的病原体或明显的免疫挑战的情况下。 SPT-GC暴露了与 狼疮易发的核反应性自身抗体滴度和许多从SPT-GC分离的GC B细胞 在宽松的小鼠中，自动反应性。 SPT-GC中的TFH细胞和CGC B细胞在 调节高亲和力自身抗体的产生。 在患有多种自身免疫性疾病的患者中，还发现了SPT-GC 全身性红斑狼疮（SLE），类风湿关节炎（RA），多发性硬化症（MS），Sjogren综合征 （SS）和1型糖尿病（T1D）。例如，小儿SLE患者的循环循环次数升高 GC B细胞和成年SLE患者暴露于循环TFH细胞增加。这些数据表明重要角色 SPT-GC在致病性自身抗体产生中发挥作用。 尽管SPT-GC与自身免疫的相关性很明显，但控制其发展的因素 保持晦涩。我们发现细胞因子胸腺基质淋巴蛋白（TSLP）起着重要作用 在SPT-GC的开发中。 TSLP和TSLPR缺陷小鼠的SPT数量急剧减少 GC和现有的那些似乎是残留的。与此观察一致，我们还发现TSLP 信号对于TFH的分化至关重要。从总体上讲，这些数据证明了 SPT和诱导GC的形成和功能中的TSLP。我们将通过确定 TSLP在TFH开发和功能中（AIM 1），并确定TFH特异性TSLP信号在 自身免疫性俯卧小鼠。