Cytokine Signaling and Primary Immunodeficiency

细胞因子代表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以及调节淋巴发育和分化中特别重要。毫不奇怪，细胞因子在自身免疫性疾病如类风湿性关节炎、系统性红斑狼疮、炎症性肠病和银屑病的发病机制中至关重要。相反，影响细胞因子和细胞因子信号通路的突变是多种原发性免疫缺陷的基础。 我们发现了人Jak 3，这是一种通过结合常见γ链gc（IL-2、IL-4、IL-7、IL-9、IL-15和IL-21）的细胞因子进行信号传导所必需的激酶。我们发现Jak 3突变导致一种原发性免疫缺陷疾病，称为严重联合免疫缺陷（SCID）。我们有一个临床方案，允许我们评估疑似Jak 3缺陷的患者。今年没有新的患者入组。 在激活受体相关的Jaks后，信号转导的下一步是激活也可以结合激活的细胞因子受体的潜伏的胞质转录因子。这些因子被称为STAT（信号转导和转录激活因子）。STAT蛋白在免疫细胞中的功能一直是该实验室二十年来的重点。NIH科学家最近的工作揭示了另一种原发性免疫缺陷综合征，Job或高免疫球蛋白E综合征，是由于STAT 3突变。基于我们的小鼠研究，我们研究了人类中STAT 3的突变是否与受损的Th 17分化相关。我们发现这种情况在约伯综合征患者。STAT 3突变是高IgE综合征（HIES）的基础，但由于与STAT 3种系缺失相关的致死性，STAT 3在发病机制中的作用一直受到阻碍。此外，负责IgE过度产生的机制是未知的。为了更好地了解这种复杂的原发性免疫缺陷，我们建立了一个小鼠模型。我们发现表达HIES-Stat 3等位基因的转基因小鼠重现了HIES的各个方面，包括血清IgE升高。突变体B细胞显示出在离体活化后增加的IG种系转录和开关重组，表明高IgE缺陷是B细胞固有的。目前，我们正在研究STAT 3在造血细胞和基质细胞中的相对作用。利用这些小鼠，我们正在进行骨髓移植实验。这些结果可能对HIES患者具有重要意义。 我们还采用新技术开始在全基因组范围内定义STAT 3靶标。具体来说，我们已经使用染色质免疫沉淀和大规模平行测序，全面枚举STAT 3靶基因在Th 17细胞。我们发现，STAT 3绑定到多个基因参与Th 17细胞分化，细胞活化，增殖和生存，调节表达和表观遗传修饰。因此，STAT 3协调炎症和稳态中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, and in regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Conversely, mutations that affect cytokines and cytokine signal pathways underlie a variety of primary immunodeficiencies. We discovered human 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. After activation of receptor-associated Jaks, the next step in signal transduction is the activation of latent, cytosolic transcription factors that can also bind activated cytokine receptors. These factors are called STATs (signal transducers and activators of transcription). The function of STAT proteins in immune cells has been a focus of this lab for two decades. 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 mouse studies, we investigated whether 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. To better understand this complicated primary immunodeficiency, we generated a mouse model of the disease. We found that transgenic mice expressing a HIES-Stat3 allele recapitulate aspects of HIES, including elevated serum IgE. Mutant B cells display increased Ig germline transcription and switch recombination upon ex-vivo activation, demonstrating that the hyper-IgE defect is B cell intrinsic. At present, we are dissecting the relative roles of STAT3 in hematopoietic versus stromal cells. Using these mice, we are performing bone marrow transplantation experiments. These results may have important implications for patients with HIES. 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.