Alteration of function and specificity of TFH in SLE

SLE 中 TFH 功能和特异性的改变

• 批准号: 10650347
• 负责人: Betty Diamond
• 金额: $ 55.16万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10650347
• 关键词: Affect; Agreement; Anti-DNA Antibodies; Antigen Presentation; Antigen Presentation Pathway; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Separation; Cell physiology; Cells; Chronic; Clinical Trials; Coculture Techniques; Complex; Data; Dendritic Cells; Development; Disease; Disease Progression; Disease model; Estradiol; Estrogen Receptors; Estrogens; Failure; Female; Frequencies; Gender; Gene Expression; Gene Expression Profile; Genes; Genetic Predisposition to Disease; Glomerulonephritis; Gonadal Steroid Hormones; Helper-Inducer T-Lymphocyte; Heterogeneity; Hormonal; ITGAX gene; Immune; Immune System Diseases; In Vitro; Individual; Knowledge; LoxP-flanked allele; Modeling; Mus; Mutation; PRDM1 gene; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Peripheral; Persons; Phenocopy; Play; Receptor Signaling; Regulation; Reporter; Risk Factors; Role; Selective Estrogen Receptor Modulators; Sex Chromosomes; Signal Transduction; Specificity; Spleen; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T cell regulation; T-Lymphocyte; T-cell receptor repertoire; Testing; Therapeutic; Thymus Gland; antigen processing; autoreactive B cell; autoreactive T cell; autoreactivity; conditional knockout; disease phenotype; effector T cell; genetic risk factor; genome wide association study; hormone regulation; in vivo; insight; lupus prone mice; lupus-like; mouse model; nanoparticle; novel therapeutics; patient subsets; precision medicine; receptor-mediated signaling; response; risk variant; systemic autoimmune disease; thymocyte; young woman

Project Summary/ Abstract Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease and pathogenic mechanisms are not well understood. Based on data from SLE patients and GWAS, we developed a mouse model to phenocopy the expression pattern of the PRDM1 risk allele. Mice with a selective deficiency of BLIMP1 in dendritic cells (DCs) (Prdm1 CKO mice) develop SLE with an increased number of T follicular helper cells (TFH) and autoantibodies arising in a germinal center response. Only female mice develop disease. The central hypothesis for the proposed studies is that BLIMP1-deficient DCs alter the selection of T cells in the thymus. We further hypothesize that estrogen and estrogen-receptor mediated signaling play a critical role in BLIMP1-deficient DC function, altering antigen presentation and synergizing with BLIMP1 deficiency to skew to TFH differentiation. The following aims will address these hypotheses. Aim 1 will determine if the altered TFH repertoire in female Prdm1 CKO mice is determined during thymic selection. We will identify whether BLIMP1-deficient DCs alter the strength of TCR signaling to alter the T cell repertoire. We will explore the function of TFH in female Prdm1 CKO mice and female control mice, and their activation of autoreactive B cells. Aim 2 will investigate functional changes in DCs and TFH conferred by estrogen receptor signaling. These studies should suggest therapeutic strategies in a defined subset of SLE patients, and advance precision medicine in a disease where many agree that the failure of clinical trials reflects an inadequate understanding of patient heterogeneity.

项目摘要/摘要 系统性红斑狼疮(SLE)是一种慢性复杂的自身免疫性疾病。 致病机制尚不清楚。根据SLE患者和GWA的数据， 我们开发了一个小鼠模型来复制PRDM1风险等位基因的表达模式。 树突状细胞(DC)BLIMP1选择性缺陷小鼠(Prdm1 CKO小鼠) 系统性红斑狼疮伴T滤泡辅助细胞(TFH)和自身抗体增加 生发中心反应。只有雌性老鼠才会患上疾病。这一理论的核心假设是 建议的研究是，BLIMP1缺陷的DC改变了胸腺中T细胞的选择。我们 进一步假设雌激素和雌激素受体介导的信号在 BLIMP1缺陷的DC功能、抗原提呈改变及与BLIMP1的协同作用 虚证偏向TFH分化。以下目标将解决这些假设。目标 1将确定雌性Prdm1 CKO小鼠的TFH改变谱系是否在 胸腺选择。我们将确定BLIMP1缺陷的DC是否会改变TCR的强度 发出信号来改变T细胞库。我们将探讨TFH在女性Prdm1CKO中的作用 小鼠和雌性对照小鼠，以及它们自身反应性B细胞的激活。目标2将 研究雌激素受体信号转导对DC和TFH功能的影响。这些 研究应该建议在确定的SLE患者亚组中的治疗策略，以及 在许多人都同意临床治疗失败的疾病中推进精准医学 试验反映了对患者异质性的不充分理解。