Tpl2 regulation of pDC function and SLE pathogenesis

摘要 系统性红斑狼疮（SLE）是一种疼痛的慢性自身免疫性疾病，估计影响高达 150/100，000人，年轻女性的患病率增加。这是由于正常免疫系统的破坏， 耐受机制导致自身反应性T细胞的活化、自身反应性B细胞的扩增、循环 自身抗体和免疫复合物沉积。目前的治疗主要包括高剂量的皮质类固醇 和免疫抑制药物，有助于控制症状，但未能解决根本原因， 与不良副作用有关。因此，需要新的免疫干预。I型ifn 分泌它们的浆细胞样树突状细胞（pDC）已成为发病机制中的关键参与者 关于SLE大多数SLE患者的免疫细胞都带有I型IFN基因标记。因此，封锁 I型IFN、它们的受体和pDC正被积极地用作SLE和其他疾病的免疫疗法。 带有干扰素标记的自身免疫性疾病尽管pDC具有重要的免疫功能， 相对而言，人们对它们控制IFN产生的分子“线路”知之甚少，这是一个障碍 开发新型pDC靶向免疫疗法。在此，我们提供的证据表明，丝氨酸-苏氨酸 激酶Tp 12（也称为MAP 3 K8或COT）是TLR诱导的I型IFN产生所必需的。 vivo.本申请的目的是理解pDC如何独特地需要Tp 12用于核酸扩增。 诱导IFN产生，并确定pDC中Tp 12表达是否影响SLE发病机制。这 将在两个目标中进行检查。目的1将联合收割机将原代鼠pDC的离体生物化学分析与 无偏见的磷酸蛋白质组学方法来描绘Tp 12促进 pDC中的I型IFN产生。AIM 2将使用创新的混合骨髓嵌合体方法来确定 pDC内Tp 12表达对鼠模型SLE发展的贡献。的预期成果 所提出的研究是对控制pDC核酸的分子机制的更好理解 感测和IFN产生。这些信息将促进新的免疫方法来调节 IFN和/或pDC用于治疗SLE和可能的其它人干扰素病。

Abstract Systemic lupus erythematosus (SLE) is a painful, chronic autoimmune disease estimated to affect up to 150/100,000 people with an increased prevalence in young women. It results from disruption in normal immune tolerance mechanisms leading to activation of autoreactive T cells, expansion of autoreactive B cells, circulating autoantibodies and immune complex deposition. Current treatments consist primarily of high dose corticosteroids and immunosuppressive drugs that help to manage symptoms but fail to address the underlying cause and are associated with adverse side effects. Therefore, novel immunotherapeutic interventions are needed. Type I IFNs and the plasmacytoid dendritic cells (pDCs) that secrete them have emerged as key players in the pathogenesis of SLE. Immune cells from most SLE patients are imprinted with a type I IFN gene signature. Therefore, blockade of type I IFNs, their receptors and pDCs are being actively pursued as immunotherapies for SLE and other autoimmune diseases imprinted with IFN signatures. Despite the important immunological functions of pDCs, relatively little is understood about their molecular ‘wiring’ that controls IFN production, which presents a barrier to developing novel pDC-targeted immunotherapies. Herein, we provide evidence that the serine-threonine kinase, Tpl2 (also known as MAP3K8 or COT), is essential for TLR-induced type I IFN production by pDCs in vivo. The objective of this application is to understand how Tpl2 is uniquely required by pDCs for nucleic acid- induced IFN production and to determine whether Tpl2 expression in pDCs influences SLE pathogenesis. This will be examined in two Aims. Aim 1 will combine ex vivo biochemical analysis of primary murine pDCs with unbiased phosphoproteomics approaches to delineate the biochemical mechanisms by which Tpl2 promotes type I IFN production in pDCs. Aim 2 will use an innovative mixed bone marrow chimera approach to determine the contribution of Tpl2 expression within pDCs to SLE development a murine model. The expected outcome of the proposed studies is a better understanding of the molecular mechanism(s) governing pDC nucleic acid sensing and IFN production. This information will facilitate novel immunotherapeutic approaches to modulate IFNs and/or pDCs for treating SLE and possibly other human interferonopathies.