Alteration of function and specificity of TFH in SLE

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。

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.