<p>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<sup>+</sup>, and Foxp3<sup>neg</sup> CD4<sup>+</sup> T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4<sup>+</sup> 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<sup>+</sup> 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.</p>

doi.org/10.1038/s41385-021-00423-5, hdl.handle.net/1765/136215
Mucosal Immunology
Erasmus MC: University Medical Center Rotterdam

M.E. (Linda) Joosse, Fabienne Charbit-Henrion, Remy Boisgard, HC (Rolien) Raatgeep, DJ (Dicky) Lindenbergh - Kortleve, LMM (Léa) Costes, … J.N. (Janneke) Samsom. (2021). Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis. Mucosal Immunology, 14(5), 1172–1182. doi:10.1038/s41385-021-00423-5