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,... Show moreSingle 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 IFN gamma secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFN gamma secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4(+) T cells with a prominent IFN gamma-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. Show less
Charbit-Henrion, F.; Parlato, M.; Hanein, S.; Duclaux-Loras, R.; Nowak, J.; Begue, B.; ... ; Cerf-Bensussan, N. 2021
