Alteration of function and specificity of TFH in SLE

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。

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.