Cytokine Signaling and Primary Immunodeficiency

细胞因子是调节细胞生长和分化的大量分泌蛋白。这些因子在调节免疫和炎症反应、调节淋巴细胞的发育和分化中尤为重要。细胞因子也调节免疫稳态、耐受性和记忆。毫不奇怪，细胞因子在自身免疫性疾病如类风湿关节炎、系统性红斑狼疮、炎症性肠病和牛皮癣的发病机制中起着至关重要的作用。了解细胞因子作用的分子基础为了解免疫介导疾病的发病机制提供了重要的见解，并提供了新的治疗靶点。

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.