STAT3 is a cytokine-signaling transcription factor critical for gene regulation. Gain-of-function (GOF) mutations in STAT3 are associated with lymphoproliferation, autoimmune cytopenias, increased susceptibility to infection, early-onset solid-organ autoimmunity, short stature, and eczema. We studied the JAK/STAT signaling pathway gene expression and the cytokine profile in two families carrying STAT3-GOF variants to shed light on the STAT3-GOF-associated variable expressivity, including the identification of disease markers. Considering 92 target genes, KIT and IL2RA were downregulated only in patients with high clinical penetrance, while CXCL8 was markedly downregulated for all of them. Unlike previous studies, SOCS3—a STAT3 inhibitor—was not upregulated in patients. In addition, low levels of IL-2 and a reduced numbers of Tregs cells were strikingly prevalent in patients. This study shows a disruptive role of STAT3-GOF variants in the regulatory axis activities CXCL8/STAT3, KIT/STAT3, IL2/CD25/Treg, which, by slightly different mechanisms, underlie the broad clinical spectrum seen in the studied patients. In addition, we suggest the investigation of CXCL8 as a biomarker for identifying STAT3-GOF mutation.

STAT3 是一种对基因调控至关重要的细胞因子信号转导转录因子。STAT3中的功能获得 (GOF) 突变与淋巴增殖、自身免疫性血细胞减少、感染易感性增加、早发性实体器官自身免疫、身材矮小和湿疹有关。我们研究了携带STAT3 -GOF 变体的两个家族中的 JAK/STAT 信号通路基因表达和细胞因子谱，以阐明STAT3 -GOF 相关的可变表达性，包括疾病标志物的鉴定。考虑到 92 个靶基因，KIT和IL2RA仅在临床外显率高的患者中下调，而CXCL8对所有这些都显着下调。与之前的研究不同，SOCS3 （一种 STAT3 抑制剂）在患者体内没有上调。此外，低水平的 IL-2 和减少的 Tregs 细胞数量在患者中非常普遍。该研究显示了STAT3 -GOF 变体在调节轴活性CXCL8 /STAT3、KIT /STAT3、IL2/CD25/Treg 中的破坏性作用，通过略有不同的机制，这些变异是在所研究患者中观察到的广泛临床谱的基础。此外，我们建议研究CXCL8作为识别STAT3 -GOF 突变的生物标志物。