STAT5 variants in the pathogenesis of inflammatory bowel disease

炎症性肠病(IBD)是一种由遗传因素和环境因素共同作用的疾病，主要包括克罗恩病和溃疡性结肠炎两种疾病。遗传分析发现了200多个遗传座位上与IBD相关的多态。然而，将单个基因和多态与IBD联系起来的机制仍然知之甚少。单个基因缺失与IBD相关的单基因IBD的鉴定，极大地促进了我们对IBD遗传途径的理解。具体地说，这项工作揭示了基于肠道上皮缺陷、先天免疫或获得性免疫的巨大不同的IBD途径。此外，这些研究突出了IBD个性化治疗的新途径。筛选已知或新的单基因IBD已成为临床诊断的一个重要方面，尤其是对儿科和家族性IBD。通过这种诊断，我们最近可以在一名严重的早发性克罗恩病女性患者中发现信号转导和转录激活因子(STAT)5A(STAT5A E518K)的错义变体。STAT5A是一种在免疫中起重要作用的转录因子，但到目前为止，STAT5A的变异还没有与单基因形式的IBD相关联。功能研究表明，STAT5A E518K与STAT5A的表达和功能降低有关。为了研究它在体内的功能，我们利用了STAT5A E518残基及其侧翼区域在小鼠和在内源性STAT5A基因座上携带这种变体的工程小鼠中的保守。我们可以证明STAT5A E518K与免疫缺陷有关，并促进了对化学诱导的结肠炎的易感性。基于这些初步数据，我们的目标是确定该STAT5和其他STAT5变异在IBD发病机制中的作用。具体地说，我们将(I)研究STAT5A E518K是否与小鼠和携带STAT5A E518K的患者的肠道上皮功能或粘膜免疫变化有关；(Ii)研究携带STAT5A E518K的小鼠是否表现出对化学、免疫和微生物触发肠道炎症的易感性；以及(Iii)研究其他STAT5A和STAT5B变异在IBD发病机制中的作用。总之，这项工作将确定STAT5变体是IBD的潜在单基因起源，并将确定将STAT5与IBD联系起来的途径。

Inflammatory bowel disease (IBD), with its two main entities Crohn's disease and ulcerative colitis, results from a complex interplay of genetic and environmental factors. Genetic analyses revealed IBD-associated polymorphisms in more than 200 genetic loci. However, the mechanisms which link individual genes and polymorphisms to IBD are still poorly understood. The identification of monogenic forms of IBD in which the loss of individual genes is associated with IBD, has tremendously contributed to our understanding of genetic pathways to IBD. Specifically, this work has revealed vastly different pathways to IBD based on defects in the intestinal epithelium, innate immunity or adaptive immunity. Moreover, these studies have highlighted new avenues to personalized treatment of IBD. The screening for known or novel monogenic forms of IBD has become an important aspect of clinical diagnostics, particularly for pediatric and familial forms of IBD. Through such diagnostics, we could recently identify a missense variant in signal transducer and activator of transcription (STAT) 5A (STAT5A E518K) in a female patient with severe, early-onset Crohn's disease. STAT5A is a transcription factor with important roles in immunity, but variants in STAT5A have so far not been linked to monogenic forms of IBD. Functional investigations demonstrated that STAT5A E518K was associated with reduced STAT5A expression and function. To investigate its function in vivo, we capitalized on conservation of the STAT5A E518 residue and its flanking region in mice and engineered mice carrying this variant in the endogenous Stat5a locus. We could demonstrate that STAT5A E518K is associated with defects in immunity and promotes susceptibility to chemically induced colitis. Based on these preliminary data, we aim to characterize the role of this and other STAT5 variants in the pathogenesis of IBD. Specifically, we will (i) investigate whether STAT5A E518K is associated with alterations in intestinal epithelial function or mucosal immunity in mice and in the patient carrying STAT5A E518K; (ii) study whether mice carrying STAT5A E518K exhibit susceptibility to chemical, immunological, and microbial triggers of intestinal inflammation; and (iii) investigate the roles of other STAT5A and STAT5B variants in the pathogenesis of IBD. Together, this work will characterize STAT5 variants as a potential monogenic origin of IBD and shall identify the pathways that link STAT5 to IBD.