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）家族最近因其作为核小体蛋白的作用而引起了人们的兴趣。 在特定免疫细胞中介导基因沉默或激活的转录程序的染色质调节因子 细胞群人SP家族由4个成员- SP100、SP110、SP140和SP140 L组成，而人SP家族由4个成员- SP100、SP110、SP140和SP140 L组成。 小鼠SP家族包括SP 100、SP 110和SP 140。先天性和适应性免疫细胞谱系以及 因为非免疫细胞表达SP100和SP110，而SP140完全是免疫限制性的。结果 RNA测序分析显示，人SP家族成员在发育和生长过程中高度表达， 成熟B细胞、活化的CD 4+和CD 8 + T细胞以及骨髓谱系。SP也被鉴定为干扰素 （IFN）刺激基因（ISG），暗示它们参与病原体诱导的免疫、自身免疫和感染。 事实上，所有人类SP家族成员的突变都与自身免疫性，炎症性， 免疫缺陷和感染性疾病，强调了该蛋白质家族在免疫细胞中的重要作用 体内平衡和对感染的反应。然而，SP目前在免疫细胞背景下研究不足 调节，特别是在适应性免疫细胞中，它们在其中大量表达， 完全缺乏。我们最近确定了SP110和SP140作为两个新的候选下游介质， 转录因子干扰素调节因子5（IRF 5）通过T细胞受体（TCR）的scRNAseq- 来自Irf 5 +/+和Irf 5-/-同窝小鼠的刺激的原代鼠CD 4 + T细胞。IRF 5是一个关键的调解人， 和适应性免疫以及与多种炎症易感性相关的遗传风险因素， 和自身免疫性疾病;研究最充分的是系统性红斑狼疮（SLE）。的前提 该应用是SP 110和SP 140在IRF 5下游起作用以介导B和T细胞失调 常见于SLE患者，如T细胞活化增加，循环血浆水平升高 细胞和致病性自身抗体。在这个提议中，我们将1）测试SP110和SP140作用于 在IRF 5下游介导T和B细胞活化、增殖和效应子功能，以及2）确定 SP110和SP140在SLE患者的免疫细胞中失调，如果表达与IRF 5相关， 表达和/或活化、自身抗体产生和疾病活性。成功完成这些 研究将提供对适应性免疫细胞中SP 110和SP 140的功能的新的机理认识， 知识是完全缺乏的。此外，我们将提供一个了解这些因素如何 有助于免疫紊乱，这将为设计新的假定疗法提供理论基础。 与SP丢失或过度激活相关，因为SP提供了一种新的和更精细的治疗途径， 过度活跃的免疫反应。