Cytokine Signaling and Primary Immunodeficiency

细胞因子代表大量分泌的蛋白质，调节细胞生长和分化。这些因子在调节免疫和炎症反应、调节淋巴样细胞的发育和分化方面尤为重要。细胞因子还调节免疫稳态、耐受性和记忆力。毫不奇怪，细胞因子在类风湿性关节炎、系统性红斑狼疮、炎症性肠病和牛皮癣等自身免疫性疾病的发病机制中起着关键作用。了解细胞因子作用的分子基础有助于深入了解免疫介导性疾病的发病机制，并提供新的治疗靶点。 我们发现了JAK3，一种通过结合共同伽马链的细胞因子GC(IL-2、IL-4、IL-7、IL-9、IL-15和IL-21)进行信号传递所必需的激酶。我们发现JAK3的突变会导致一种称为严重联合免疫缺陷(SCID)的原发性免疫缺陷疾病。我们有一个临床方案，允许我们评估疑似JAK3缺乏症患者。今年没有新的患者入选。 NIH科学家最近的研究表明，另一种原发免疫缺陷综合征，约伯氏综合症或高免疫球蛋白E综合征是由STAT3突变引起的。基于我们在小鼠身上的研究，我们调查了人类STAT3突变是否与Th17分化受损有关。我们发现，患有约伯氏综合症的患者就是这种情况。STAT3的突变是高IgE综合征(HIEs)的基础，但STAT3在发病机制中的作用一直受到与STAT3胚系缺失相关的致命性的阻碍。此外，导致IgE过度产生的机制尚不清楚。我们发现，表达HIEs-STAT3等位基因的转基因小鼠概括了HIEs的一些方面，包括升高的血清IgE。令人惊讶的是，突变的B细胞在体外激活后表现出Ig生殖系转录和开关重组的增加，表明高IgE缺陷是B细胞固有的。利用ChIP-和mRNA-Seq，我们发现STAT3直接调节B细胞Id2的表达，Id2是一种开关抑制物。异位Id2的表达恢复了正常的Ig转录和重组，认为未能诱导Id2是导致这种疾病高IgE的一个重要机制 我们还采用了新技术，开始在全基因组范围内定义STAT3靶点。具体地说，我们使用染色质免疫沉淀和大规模并行测序来全面枚举Th17细胞中的STAT3靶基因。我们发现STAT3与参与Th17细胞分化、细胞激活、增殖和存活的多个基因结合，调节表达和表观遗传修饰。因此，STAT3在炎症和动态平衡中协调T细胞功能的多个关键方面。

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.