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 Foxp3neg 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.
|Number of pages||11|
|Early online date||5 Jul 2021|
|Publication status||Published - Sept 2021|
Bibliographical noteFunding Information:
The authors declare no competing financial interests. This work was supported by ERC-2013-AdG-339407-IMMUNOBIOTA and Inserm grant n°ANR-10-LABX-62-IBEID to N.C.B. M.J. was supported by the Netherlands Organization for Scientific Research grant 2013/09420/BOO. L.M.M.C. was funded by SSWO grants (SSWO 608, S16-23) and a research fellowship from the Dutch Sophia Research Foundation. S.V. was funded by the Dutch Sophia Research Foundation SSWO grant (S14-17). J.K.N. was supported by a grant from the Polish National Science Centre (2015/16/T/NZ5/ 00168). F.C.H. was supported by a fellowship from INSERM and acknowledges the members of the GENIUS group (GENetically ImmUne mediated enteropathieS) from ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition), www.genius-group.org.
© 2021, The Author(s).