STAT5 variants in the pathogenesis of inflammatory bowel disease

炎症性肠病（IBD），其两个主要实体克罗恩病和溃疡性结肠炎，是遗传和环境因素复杂相互作用的结果。遗传分析显示，在200多个遗传位点中存在ibd相关多态性。然而，将个体基因和多态性与IBD联系起来的机制仍然知之甚少。单个基因缺失与IBD相关的单基因型IBD的鉴定极大地促进了我们对IBD遗传途径的理解。具体来说，这项工作揭示了基于肠上皮缺陷、先天免疫或适应性免疫的IBD的巨大不同途径。此外，这些研究强调了IBD个性化治疗的新途径。筛查已知或新的单基因型IBD已成为临床诊断的一个重要方面，特别是对儿童和家族型IBD。通过这样的诊断，我们最近在一名患有严重早发性克罗恩病的女性患者中发现了信号换能器和转录激活因子（STAT） 5A （STAT5A E518K）的错义变异。STAT5A是一种在免疫中发挥重要作用的转录因子，但STAT5A的变异迄今尚未与单基因型IBD相关。功能研究表明STAT5A E518K与STAT5A表达和功能降低有关。为了研究其在体内的功能，我们利用了STAT5A E518残基及其侧翼区域在小鼠和内源性STAT5A位点携带该变体的工程小鼠中的保护。我们可以证明STAT5A E518K与免疫缺陷有关，并促进对化学诱导结肠炎的易感性。基于这些初步数据，我们的目标是表征这种和其他STAT5变异在IBD发病机制中的作用。具体来说，我们将(i)研究STAT5A E518K是否与携带STAT5A E518K的小鼠和患者肠上皮功能或粘膜免疫的改变相关；（ii）研究携带STAT5A E518K的小鼠是否对肠道炎症的化学、免疫和微生物触发因素表现出易感性；（iii）研究其他STAT5A和STAT5B变异在IBD发病机制中的作用。总之，这项工作将表征STAT5变异作为IBD的潜在单基因起源，并将确定STAT5与IBD之间的联系途径。

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.