Targeting OCA-B in multiple sclerosis

项目摘要 开发新的治疗方法来阻止多发性硬化症（MS），同时保持有益的免疫功能完整 这是该领域的一个主要目标。T细胞是MS发病机制的中心驱动因素。我们的工作表明， 转录辅助调节子OCA-B（基因符号Pou 2af 1）在刺激的原代CD 4 + T细胞中被诱导， 在那里它与其同源转录因子Oct 1对接以调节免疫调节靶基因，包括 Il 2、Il 17 a、Ifng和Csf 2（Gmcsf）。有趣的是，OCA-B仅驱动这些基因的表达升高， 在一个非常狭窄的条件下。OCA-B缺陷型T细胞的初级刺激导致很少的基因表达。 表达变化，然而，在培养物中静止后再刺激这些细胞导致基因表达 500倍或以上的变化。这些结果表明，OCA-B控制基因表达特异性下， 抗原再相遇的条件。我们确定了分子机制，其中包括去除 抑制性染色质修饰，否则积累以稳定沉默基因表达。重复 抗原暴露是自身免疫的必要特征。在体内，OCA-B缺失导致T细胞发育 和原发性病原体反应完整，但损害了CD 4 + T细胞记忆的建立。在两种小鼠中 和人类，具有记忆样表型的T细胞可以是包括MS在内的自身免疫的基础。 研究确定了Ocab/Pou 2af 1基因座以及OCA-B和Oct 1结合位点的多态性， MS司机这些发现表明了一个潜在的“治疗窗口”，在这个窗口中，靶向这一途径可以被治疗。 用于治疗MS，同时保留T细胞发育和初级免疫应答。因此，我们有 表明Oct 1的T细胞特异性缺失阻断了实验性免疫缺陷病毒的临床和分子表现， 自身免疫性脑脊髓炎（EAE），同时保持对嗜神经病毒的免疫反应完整。OCA-B's 淋巴限制性表达模式，以及OCA-B生殖系缺陷小鼠的生存能力和生育能力，使其成为一种 与Oct 1相比，更有希望的潜在药物靶点。我们的初步数据表明，T细胞特异性OCA- B缺失还保护小鼠免受经典EAE，并保护自身免疫倾向的非肥胖糖尿病（NOD） 来自复发EAE模型的小鼠，特别是在复发期。我们的首要假设是OCA-B 调节自身反应性、促炎性Th 1/Th 17 CD 4 + T细胞中的关键基因，以驱动MS发病机制。我们 将通过关注OCA-B必要性和充分性的两个具体目标实现研究目标： 目的1：明确OCA-B促进EAE发病的细胞和分子基础。 目的2：检测OCA-B在EAE发病机制中的作用。

PROJECT SUMMARY Developing new treatments to block multiple sclerosis (MS) while keeping beneficial immune function intact constitutes a major goal in the field. T cells are central drivers of MS pathogenesis. Our work shows that the transcriptional co-regulator OCA-B (gene symbol Pou2af1) is induced in stimulated primary CD4+ T cells, where it docks with its cognate transcription factor Oct1 to regulate immunomodulatory target genes including Il2, Il17a, Ifng, and Csf2 (Gmcsf). Interestingly, OCA-B drives the elevated expression of these genes only under a very narrow range of conditions. Primary stimulation of OCA-B deficient T cells results in few gene expression changes, however re-stimulating these cells after resting in culture results in gene expression changes of 500-fold or more. These results indicate that OCA-B controls gene expression specifically under conditions of antigen reencounter. We identified the molecular mechanism, which involves the removal of inhibitory chromatin modifications that otherwise accumulate to stably silence gene expression. Repeated antigen exposures are a necessary feature of autoimmunity. In vivo, OCA-B loss leaves T cell development and primary pathogen responses intact, but impairs the establishment of CD4+ T cell memory. In both mice and humans, T cells with memory-like phenotypes can underlie autoimmunity including MS. Human GWAS studies identify polymorphisms at the Ocab/Pou2af1 locus, as well as in binding sites for OCA-B and Oct1, as MS drivers. These findings suggest a potential “therapeutic window” in which targeting this pathway can be used to treat MS while preserving T cell development and primary immune responses. Consistently, we have shown that T cell-specific deletion of Oct1 blocks clinical and molecular manifestations of experimental autoimmune encephalomyelitis (EAE) while keeping immune responses to neurotropic viruses intact. OCA-B’s lymphoid-restricted expression pattern, and the viability and fertility of OCA-B germline null mice, make it a more promising potential drug target compared to Oct1. Our preliminary data indicate that T cell-specific OCA- B deletion also protects mice from classical EAE, and protects autoimmune-prone non-obese diabetic (NOD) mice from a relapsing EAE model, specifically at the relapse phase. Our overarching hypothesis is that OCA-B regulates key genes in autoreactive, pro-inflammatory Th1/Th17 CD4+ T cells to drive MS pathogenesis. We will realize the objectives of the study via two specific aims focused on OCA-B necessity and sufficiency: Aim 1: Determine the cellular and molecular basis of OCA-B promotion of EAE pathogenesis. Aim 2: Test OCA-B’s sufficiency in EAE pathogenesis.