Cytokine Signaling and Primary Immunodeficiency

细胞因子信号传导和原发性免疫缺陷

基本信息

批准号：
8344727
负责人：
John O'Shea
金额：
$ 19.16万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8344727
关键词：
Alleles Autoimmune Diseases B-Lymphocytes Binding Cell Differentiation process Cell physiology Cells Clinical Protocols Cytokine Signaling Defect Development Disease Dominant-Negative Mutation Enrollment Epigenetic Process Failure Gene Targeting Genes Genetic Recombination Genetic Transcription Homeostasis Human IgE Immune Immune response Immunoglobulin Switch Recombination Immunologic Deficiency Syndromes Inflammation Inflammatory Bowel Diseases Inflammatory Response Interleukin 2 Receptor Gamma Interleukin-15 Interleukin-2 Interleukin-4 Interleukin-7 Interleukin-9 Janus kinase Job&apos s Syndrome Laboratories Lymphoid Mediating Memory Messenger RNA Modification Molecular Mus Mutation Occupations Pathogenesis Patients Phosphotransferases Proteins Psoriasis Receptor Activation Rheumatoid Arthritis Role STAT3 gene Scientist Serum Severe Combined Immunodeficiency Systemic Lupus Erythematosus T-Lymphocyte Transgenic Mice United States National Institutes of Health Work base cell growth chromatin immunoprecipitation cytokine genome-wide inhibitor/antagonist insight mouse model mutant new technology new therapeutic target

项目摘要

Cytokines represent a large number of secreted proteins that regulate cell growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, regulating lymphoid development and differentiation. Cytokines also regulate immune homeostasis, tolerance, and memory. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. We discovered Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have a clinical protocol that allows us to evaluate patients with suspected Jak3 deficiency. No new patients were enrolled this year. Recent work by NIH scientists has revealed that another primary immunodeficiency syndrome, Job's or Hyperimmunoglobulin E syndrome is due to STAT3 mutations. Based on our studies in the mouse, we investigated if mutations of STAT3 in humans are associated with impaired Th17 differentiation. We found this to be the case in patients with Job's syndrome. Mutations of STAT3 underlie hyper-IgE syndrome (HIES), but deciphering STAT3s role in pathogenesis has been hampered by the lethality associated with germline deletion of Stat3. Furthermore, the mechanisms responsible for IgE hyperproduction are unknown. We show that transgenic mice expressing a HIES-Stat3 allele recapitulate aspects of HIES, including elevated serum IgE. Surprisingly, mutant B cells display increased Ig germline transcription and switch recombination upon ex-vivo activation, demonstrating the hyper-IgE defect is B cell intrinsic. Using ChIP- and mRNA-Seq we show that Stat3 directly regulates B cell expression of Id2, an inhibitor of - switching. Ectopic Id2 expression restores normal Ig transcription and recombination, arguing that failure to induce Id2 is an important mechanism underlying the hyper-IgE aspect of this disease We have also employed new technology to begin to define STAT3 targets genome-wide. Specifically, we have used chromatin immunoprecipitation and massive parallel sequencing to comprehensively enumerate STAT3 target genes in Th17 cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation, and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis.

细胞因子代表了调节细胞生长和分化的大量分泌蛋白。这些因素对于调节免疫和炎症反应，调节淋巴发育和分化尤为重要。细胞因子还调节免疫稳态，耐受性和记忆力。毫不奇怪，细胞因子在自身免疫性疾病（例如类风湿关节炎，全身性红斑狼疮，炎症性肠病和牛皮癣）的发病机理中至关重要。了解细胞因子作用的分子基础为免疫介导疾病的发病机理提供了重要的见解，并提供了新的治疗靶标。我们发现了JAK3，这是一种通过结合常见γ链GC（IL-2，IL-4，IL-7，IL-7，IL-9，IL-9，IL-15和IL-21）的细胞因子信号传导所必需的激酶。我们发现JAK3的突变导致原发性免疫缺陷障碍称为严重的免疫缺陷（SCID）。我们有一个临床方案，使我们能够评估怀疑JAK3缺乏症的患者。今年没有新患者入学。 NIH科学家最近的工作表明，另一种原发性免疫缺陷综合症，JOB或高免疫球蛋白E综合症是由于STAT3突变引起的。根据我们在小鼠中的研究，我们研究了人类中Stat3的突变是否与TH17分化受损有关。我们发现，在乔布综合症患者中是这种情况。 STAT3的突变是高IGE综合征（HIE），但是与STAT3的生殖线缺失相关的致死性阻碍了破译STAT3在发病机理中的作用。此外，负责IgE超生产的机制尚不清楚。我们表明，表达HIES-STAT3等位基因的转基因小鼠概括了HIE的方面，包括升高的血清IgE。出乎意料的是，突变B细胞在活体激活后显示出Ig系的转录和开关重组，这表明超级不足是B细胞的固有性。使用芯片和mRNA-seq，我们表明STAT3直接调节ID2的B细胞表达，ID2是 - 开关的抑制剂。异位ID2表达恢复了正常的Ig转录和重组，认为未能诱导ID2是该疾病超级范围的重要机制我们还采用了新技术来开始定义全基因组的STAT3目标。具体而言，我们已经使用染色质免疫沉淀和大规模平行测序来全面列举Th17细胞中的STAT3靶基因。我们发现，与参与Th17细胞分化，细胞活化，增殖和生存的多个基因结合的STAT3，可以调节表达和表观遗传修饰。因此，STAT3在炎症和稳态中策划了T细胞功能的多个关键方面。