P095 Consequences of an IL2RA locus duplication in a very early onset inflammatory bowel disease patient

• Published in: Journal of Crohn's and colitis 2018-01, Vol.12 (supplement_1), p.S141-S142
• Main Authors: Joosse, M, Charbit-Henrion, F, Raatgeep, H, Lindenbergh-Kortleve, D J, Costes, L M, Nugteren, S, Malan, V, Nowak, J, Mearin, M L, Escher, J, Cerf-Bensussan, N, Samsom, J N
• Format: Article
• Language: English
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjx180.222

Abstract Background Rare single genetic mutations can predispose to very early onset inflammatory bowel disease (VEO IBD). These monogenic forms of IBD inform on key functional defects that drive intestinal inflammation. Here, we studied the functional consequences of an IL2RA locus duplication in a VEO IBD patient who presented with severe treatment-resistant colitis. Methods Whole exome sequencing and comparative genome hybridisation was performed on peripheral blood of the patient and her parents. Frequency and phenotype of immune cells were determined in peripheral blood and intestinal tissue by flow cytometry and immunohistochemistry. Functional changes in circulating T cells were assessed using in vitro activation assays. Results The patient presented with severe diarrhoea and bloody stools at 2 years of age. Endoscopically, the entire colon was severely inflamed. As the disease was resistant to standard and biological therapy a subtotal colectomy was performed which resulted in a striking clinical improvement without further need for immunosuppressive therapy. Genetic analyses identified a de novo 446 kb duplication of the 10p15.1 chromosomal region, including the IL2RA locus. As IL-2 has an important role in T-cell survival and proliferation, we hypothesised that the IL2RA duplication results in aberrant T-cell function. Indeed, after colectomy, the patient still had an increased CD4 to CD8 ratio in peripheral blood and an increased IL2RA expression on circulating effector memory, Foxp3+ and Foxp3neg CD4+ T cells. Isolated patient CD4+ T cells were intrinsically activated as evidenced by STAT5 phosphorylation, proliferation and Ki67 expression. In agreement with increased IL2RA surface expression, the patient CD4+ T cells were more sensitive to low-dose IL-2 when compared with healthy controls. To understand why the intestinal inflammation was limited to the colon, we compared uninflamed duodenal biopsies with inflamed colonic tissue. The colon, but not the duodenum, was infiltrated with proliferating CD3+ T cells in lamina propria and in the epithelial layer. Inflamed colonic tissue contained numerous Tbet+ cells and expressed high levels of IFNG mRNA. IL-2 may potentiate inflammation as it increased IFNγ production of activated CD4+ T cells in vitro. Crucially, inhibiting IL-2 signalling with the JAK1/3 inhibitor tofacitinib ablated IFNγ secretion and restored normal IL2RA expression on CD4+ T cells. Conclusions To our knowledge this is the first