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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：
10437692
负责人：
Betty Diamond
金额：
$ 54.76万
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/10437692
关键词：
Address Affect 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 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 Genetic Predisposition to Disease Glomerulonephritis Gonadal Steroid Hormones Helper-Inducer T-Lymphocyte Heterogeneity Hormonal ITGAX gene Immune Immune System Diseases In Vitro Individual Knowledge Mus Mutation PRDM1 gene 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 autoreactivity base 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.

项目总结/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，致病机制还不清楚。根据SLE患者和GWAS的数据，我们开发了一种小鼠模型来表型复制PRDM 1风险等位基因的表达模式。树突状细胞（DC）中BLIMP 1选择性缺陷的小鼠（Prdm 1 CKO小鼠） SLE伴T滤泡辅助细胞（TFH）数量增加和自身抗体产生，老年中枢反应。只有雌性老鼠才会发病。关于这个问题的中心假设目前提出的研究是BLIMP 1缺陷型DC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传导在 BLIMP 1缺陷型DC功能，改变抗原呈递并与BLIMP 1协同作用缺乏倾向于TFH分化。以下目标将解决这些假设。目的 1将确定雌性Prdm 1 CKO小鼠中改变的TFH库是否在胸腺选择我们将确定BLIMP 1缺陷的DC是否改变TCR的强度，信号传导以改变T细胞库。我们将探讨TFH在女性Prdm 1 CKO中的作用小鼠和雌性对照小鼠，以及它们自身反应性B细胞的活化。目标2将研究雌激素受体信号传导所赋予的DC和TFH的功能变化。这些研究应在确定的SLE患者亚组中提出治疗策略，在一种疾病中推进精确医学，许多人认为，试验反映了对患者异质性的理解不足。