Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3⁺, and Foxp3^neg CD4⁺ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4⁺ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4⁺ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

单一基因突变易患极早发性炎症性肠病 (VEO-IBD)。在这里，我们在一名患有难治性全结肠炎的 2 岁女孩中发现了 10p15.1 染色体区域（包括IL2RA基因座）的从头重复，该女孩通过结肠切除术得到缓解。引人注目的是，在患者处于临床缓解且未接受药物治疗的情况下，在结肠切除术后，与健康对照相比，外周血 CD4:CD8 比率显着升高，循环效应记忆、Foxp3 ⁺和 Foxp3^阴性CD4 ^{+ T 细胞的 CD25 表达增加。}这种高 CD25 表达增加了 IL-2 信号，增强了 CD4 ⁺T 细胞受体 (TCR) 刺激后 T 细胞衍生的 IFNγ 分泌。使用 JAK1/3 抑制剂托法替尼恢复 CD25 表达可在体外控制 TCR 诱导的 IFNγ 分泌。由于患病的结肠组织而非未受影响的十二指肠主要包含具有显着 IFNγ 特征的 CD4 ⁺ T 细胞，我们假设局部微生物刺激可能引发了结肠疾病。总的来说，我们发现IL2RA基因座的重复与 VEO-IBD 相关，并表明增加的 IL-2 信号传导易导致结肠肠道炎症。