Alteration of function and specificity of TFH in SLE

SLE 中 TFH 功能和特异性的改变

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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 GWAS 的数据，我们开发了一种小鼠模型来对 PRDM1 风险等位基因的表达模式进行表型复制。树突状细胞 (DC) 中选择性缺乏 BLIMP1 的小鼠（Prdm1 CKO 小鼠）发育系统性红斑狼疮 (SLE) 中滤泡辅助性 T 细胞 (TFH) 和自身抗体数量增加生发中心反应。只有雌性小鼠才会患病。中心假设为拟议的研究表明，BLIMP1 缺陷的 DC 会改变胸腺中 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，改变抗原呈递并与 BLIMP1 协同作用缺乏会导致 TFH 分化。以下目标将解决这些假设。目的 1 将确定雌性 Prdm1 CKO 小鼠中改变的 TFH 库是否在胸腺选择。我们将确定 BLIMP1 缺陷的 DC 是否会改变 TCR 的强度信号改变 T 细胞库。我们将探讨 TFH 在女性 Prdm1 CKO 中的功能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传导赋予 DC 和 TFH 的功能变化。这些研究应针对特定的 SLE 患者提出治疗策略，并且在这种疾病中推进精准医学，许多人都认为临床治疗的失败试验反映出对患者异质性的认识不足。