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: 10242226
• 负责人: Wendy T Watford
• 金额: $ 19.33万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242226
• 关键词: Ablation; Address; Adrenal Cortex Hormones; Affect; Antigen-Antibody Complex; Autoantibodies; Autoimmune; Autoimmune Diseases; 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; Immunosuppressive Agents; 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; 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.

抽象的 系统性红斑狼疮 (SLE) 是一种痛苦的慢性自身免疫性疾病，估计会影响最多 150/100,000人中年轻女性患病率较高。它是由于正常免疫系统受到破坏造成的 耐受机制导致自身反应性 T 细胞激活、自身反应性 B 细胞扩增、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皮质类固醇 以及有助于控制症状但无法解决根本原因的免疫抑制药物 与不良副作用有关。因此，需要新的免疫治疗干预措施。 I 型干扰素 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角色 系统性红斑狼疮。大多数 SLE 患者的免疫细胞都带有 I 型 IFN 基因特征。因此，封锁 I 型 IFN、其受体和 pDC 正在积极寻求作为 SLE 和其他疾病的免疫疗法 带有干扰素特征的自身免疫性疾病。尽管 pDC 具有重要的免疫功能， 人们对它们控制干扰素产生的分子“线路”知之甚少，这构成了障碍 开发新型 pDC 靶向免疫疗法。在此，我们提供证据表明丝氨酸-苏氨酸 激酶 Tpl2（也称为 MAP3K8 或 COT）对于 TLR 诱导 pDC 产生 I 型 IFN 至关重要 体内。本应用的目的是了解 pDC 如何独特地需要 Tpl2 来获取核酸。 诱导 IFN 产生并确定 pDC 中 Tpl2 表达是否影响 SLE 发病机制。这 将在两个目标中进行审查。目标 1 将原代小鼠 pDC 的离体生化分析与 无偏见的磷酸化蛋白质组学方法来描绘 Tpl2 促进的生化机制 pDC 中 I 型 IFN 的产生。目标 2 将使用创新的混合骨髓嵌合体方法来确定 pDC 内 Tpl2 表达对 SLE 小鼠模型发展的贡献。预期结果 拟议的研究是为了更好地理解控制 pDC 核酸的分子机制 传感和干扰素产生。这些信息将有助于新的免疫治疗方法的调节 用于治疗 SLE 和可能的其他人类干扰素病的 IFN 和/或 pDC。