Tpl2 regulation of pDC function and SLE pathogenesis

Tpl2 对 pDC 功能和 SLE 发病机制的调节

• 批准号: 10064466
• 负责人: Wendy T Watford
• 金额: $ 16.61万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064466
• 关键词: Ablation; Address; Adrenal Cortex Hormones; Affect; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Biochemical; Bone Marrow; Cell physiology; Cells; Cellular biology; Chimera organism; Clinical; Data; Dendritic Cells; Deposition; Development; Disease; Disease Progression; Dose; Drug Targeting; FRAP1 gene; Funding Mechanisms; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Goals; Health; Human; Immune; Immune Tolerance; Immune signaling; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferons; Intervention; Laboratory Research; Link; Lupus; MAP3K8 gene; Malignant Neoplasms; Modeling; Molecular; Mus; Nuclear Translocation; Nucleic Acids; Outcome; Output; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phosphotransferases; Plasma Cells; Prevalence; Production; Protein-Serine-Threonine Kinases; Psoriasis; Regulation; Research; Ribosomal Protein S6 Kinase; Role; STAT4 gene; Signal Transduction; Signal Transduction Pathway; Source; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic Intervention; Virus Diseases; autoreactive B cell; autoreactive T cell; chronic autoimmune disease; cytokine; genetic signature; genome wide association study; human disease; immune function; immunoregulation; imprint; in vivo; innovation; interferon therapy; lupus-like; macrophage; mouse model; novel; novel strategies; overexpression; peripheral blood; phosphoproteomics; receptor; response; risk variant; side effect; spatiotemporal; symptom management; therapeutic target; young woman

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.

摘要 系统性红斑狼疮(SLE)是一种痛苦的慢性自身免疫性疾病，估计影响高达 每10万人中有150人，年轻女性患病率增加。它是由正常免疫功能紊乱引起的。 导致自身反应性T细胞激活、自身反应性B细胞扩张、循环的耐受机制 自身抗体和免疫复合体沉积。目前的治疗方法主要包括大剂量皮质类固醇 以及免疫抑制药物，这些药物有助于控制症状，但无法解决根本原因，而且 与不良副作用有关。因此，需要新的免疫治疗干预措施。I型IFN 分泌它们的浆细胞样树突状细胞(PDC)已经成为发病机制中的关键角色。 系统性红斑狼疮。大多数SLE患者的免疫细胞都印有I型干扰素基因签名。因此，封锁 对于I型干扰素，它们的受体和pDC正被积极用于SLE和其他疾病的免疫治疗 带有干扰素签名的自身免疫性疾病。尽管pDC具有重要的免疫功能， 对它们控制干扰素产生的分子“线路”的了解相对较少，这构成了一种障碍 开发新型的PDC靶向免疫疗法。在此，我们提供了丝氨酸-苏氨酸 Tpl2(也称为MAP3K8或CoT)是TLR诱导的pDC产生I型干扰素的重要途径。 活着。本应用程序的目的是了解pDC如何唯一地需要Tpl2作为核酸- 诱导干扰素的产生，并确定PDCs中Tpl2的表达是否影响SLE的发病。这 将在两个目标中进行审查。目的1将原代小鼠pDC的体外生化分析与 无偏向磷酸蛋白质组学方法研究Tpl2促进的生化机制 PDC产生I型干扰素。目标2将使用一种创新的混合骨髓嵌合体方法来确定 PDC中Tpl2的表达在SLE小鼠模型发展中的作用.预期的结果 提出的研究是对PDC核酸的分子机制(S)的更好理解 感应和干扰素的产生。这一信息将促进新的免疫治疗方法来调节 干扰素和/或pDC用于治疗系统性红斑狼疮和可能的其他人类干扰素疾病。