Implications for Speckled proteins 110 and 140 in adaptive immunity

斑点蛋白 110 和 140 对适应性免疫的影响

• 批准号: 10726020
• 负责人: Betsy J Barnes
• 金额: $ 16.75万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10726020
• 关键词: Acute Promyelocytic Leukemia; Amino Acids; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Blood Cells; Blood Vessels; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Lineage; Cell physiology; Cells; Chromatin; Communicable Diseases; Development; Disease; Family member; Functional disorder; Gene Activation; Gene Silencing; Genes; Genetic Risk; Genetic Transcription; Haplotypes; Homeostasis; Human; Hyperactivity; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Deficiency Syndromes; Infection; Inflammatory; Interferons; Knowledge; Leukocytes; Link; Mature B-Lymphocyte; Mediating; Mediator; Metabolic; Mus; Mutation; Myelogenous; Natural Immunity; Neuropathy; Nuclear; Nuclear Family; Pathogenesis; Patients; Phenotype; Pilot Projects; Plasma Cells; Population; Predisposition; Primary biliary cirrhosis; Production; Proliferating; Protein Family; Proteins; Rare Diseases; Reader; Regulation; Reporting; Review Literature; Risk; Role; Specific qualifier value; Specificity; Supporting Cell; Systemic Lupus Erythematosus; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; adaptive immune response; adaptive immunity; design; genetic risk factor; immunoregulation; inhibitor; insight; interest; member; novel; null mutation; pathogen; pathogenic autoantibodies; programs; recruit; response; risk variant; systemic autoimmune disease; transcription factor; transcriptome sequencing

The Speckled protein (SP) family of nuclear body proteins has recently garnered interest for their role(s) as chromatin regulators that mediate transcriptional programs of gene silencing or activation in specified immune cell populations. The human SP family consists of 4 members - SP100, SP110, SP140 and SP140L, whilst the mouse SP family comprises Sp100, Sp110, and Sp140. Both innate and adaptive immune cell lineages as well as non-immune cells express SP100 and SP110, whereas SP140 is entirely immune-restricted. Results from RNA sequencing analysis revealed that human SP family members are highly expressed in developing and mature B cells, activated CD4+ and CD8+ T cells, and myeloid lineages. SPs were also identified as interferon (IFN)-stimulated genes (ISGs), implicating them in pathogen-induced immunity, autoimmunity and infection. Indeed, mutations in all human SP family members are associated with autoimmune, inflammatory, immunodeficiency, and infectious diseases, highlighting essential roles for this family of proteins in immune cell homeostasis and response to infections. However, SPs are currently understudied in the context of immune cell regulation, and particularly in adaptive immune cells, in which they are abundantly expressed, and knowledge is completely lacking. We recently identified SP110 and SP140 as two new candidate downstream mediators of the transcription factor interferon regulatory factor 5 (IRF5) through scRNAseq of T cell receptor (TCR)- stimulated primary murine CD4+ T cells from Irf5+/+ and Irf5-/- littermate mice. IRF5 is a key mediator of both innate and adaptive immunity and a genetic risk factor associated with susceptibility to a wide variety of inflammatory and autoimmune diseases; the most well-studied being systemic lupus erythematosus (SLE). The premise of this application is that SP110 and SP140 act downstream of IRF5 to mediate B and T cell dysregulation commonly seen in patients with SLE, such as increased T cell activation, elevated levels of circulating plasma cells and pathogenic autoantibodies. In this proposal, we will 1) test the hypothesis that SP110 and SP140 act downstream of IRF5 to mediate T and B cell activation, proliferation, and effector function and 2) determine if SP110 and SP140 are dysregulated in immune cells of SLE patients and if expression correlates with IRF5 expression and/or activation, autoantibody production, and disease activity. Successful completion of these studies will provide new mechanistic insight into the function(s) of SP110 and SP140 in adaptive immune cells, in which knowledge is completely lacking. Further, we will provide an understanding of how these factors contribute to immune disorders that will provide rationale for the design of new putative therapies for diseases associated with SP loss or over-activation, as SPs offer a novel and more refined therapeutic avenue for taming hyper-active immune responses.

核体蛋白的斑点蛋白（SP）家族最近对其作用引起了人们的兴趣 介导基因沉默或激活的转录程序的染色质调节剂 细胞种群。人类SP家族由4个成员组成-SP100，SP110，SP140和SP140L，而 鼠标SP家族包括SP100，SP110和SP140。先天和适应性免疫细胞谱系也 由于非免疫细胞表达SP100和SP110，而SP140完全受到免疫限制。结果 RNA测序分析表明，人类SP家族成员在发展和 成熟的B细胞，激活的CD4+和CD8+ T细胞以及髓样谱系。 SP也被确定为干扰素 （IFN）刺激的基因（ISGS），将它们与病原体诱导的免疫，自身免疫和感染有关。 实际上，所有人类SP家族成员的突变都与自身免疫性，炎症性， 免疫缺陷和传染病，突出了该蛋白质在免疫细胞中的重要作用 稳态和对感染的反应。但是，目前在免疫细胞的背景下对SP进行了研究 调节，尤其是在自适应免疫细胞中大量表达的调节，知识是 完全缺乏。我们最近将SP110和SP140确定为两个新的候选候选者下游调解人 通过T细胞受体（TCR） - 来自IRF5+/+和IRF5 - / - 同窝型小鼠的刺激的原代鼠CD4+ T细胞。 IRF5是两个先天的关键调解人 以及自适应免疫力和与多种炎症易感性相关的遗传危险因素 和自身免疫性疾病；最精心研究的是系统性的红斑狼疮（SLE）。前提 该应用是IRF5下游的SP110和SP140 ACT介导B和T细胞失调 在患有SLE的患者（例如T细胞激活升高）中，循环血浆的水平升高 细胞和致病自身抗体。在此提案中，我们将1）检验以下假设：SP110和SP140 ACT IRF5的下游介导T和B细胞激活，增殖和效应子功能以及2）确定是否是否 SP110和SP140在SLE患者的免疫细胞中失调，如果表达与IRF5相关 表达和/或激活，自身抗体产生和疾病活性。这些成功完成 研究将提供有关自适应免疫细胞中SP110和SP140功能的新机械洞察力， 知识完全缺乏。此外，我们将对这些因素如何理解 为免疫疾病做出贡献，这些免疫疾病将为设计新推定疗法的设计提供理由 与SP损失或过度激活相关，因为SPS提供了一种新颖，更精致的治疗途径来驯服 超活动免疫反应。