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Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

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. S...

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Autores principales: Joosse, Maria E., Charbit-Henrion, Fabienne, Boisgard, Remy, Raatgeep, Rolien (H.) C., Lindenbergh-Kortleve, Dicky J., Costes, Léa M. M., Nugteren, Sandrine, Guegan, Nicolas, Parlato, Marianna, Veenbergen, Sharon, Malan, Valérie, Nowak, Jan K., Hollink, Iris H. I. M., Mearin, M. Luisa, Escher, Johanna C., Cerf-Bensussan, Nadine, Samsom, Janneke N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379074/
https://www.ncbi.nlm.nih.gov/pubmed/34226674
http://dx.doi.org/10.1038/s41385-021-00423-5
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author Joosse, Maria E.
Charbit-Henrion, Fabienne
Boisgard, Remy
Raatgeep, Rolien (H.) C.
Lindenbergh-Kortleve, Dicky J.
Costes, Léa M. M.
Nugteren, Sandrine
Guegan, Nicolas
Parlato, Marianna
Veenbergen, Sharon
Malan, Valérie
Nowak, Jan K.
Hollink, Iris H. I. M.
Mearin, M. Luisa
Escher, Johanna C.
Cerf-Bensussan, Nadine
Samsom, Janneke N.
author_facet Joosse, Maria E.
Charbit-Henrion, Fabienne
Boisgard, Remy
Raatgeep, Rolien (H.) C.
Lindenbergh-Kortleve, Dicky J.
Costes, Léa M. M.
Nugteren, Sandrine
Guegan, Nicolas
Parlato, Marianna
Veenbergen, Sharon
Malan, Valérie
Nowak, Jan K.
Hollink, Iris H. I. M.
Mearin, M. Luisa
Escher, Johanna C.
Cerf-Bensussan, Nadine
Samsom, Janneke N.
author_sort Joosse, Maria E.
collection PubMed
description 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.
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spelling pubmed-83790742021-09-02 Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis Joosse, Maria E. Charbit-Henrion, Fabienne Boisgard, Remy Raatgeep, Rolien (H.) C. Lindenbergh-Kortleve, Dicky J. Costes, Léa M. M. Nugteren, Sandrine Guegan, Nicolas Parlato, Marianna Veenbergen, Sharon Malan, Valérie Nowak, Jan K. Hollink, Iris H. I. M. Mearin, M. Luisa Escher, Johanna C. Cerf-Bensussan, Nadine Samsom, Janneke N. Mucosal Immunol Article 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. Nature Publishing Group US 2021-07-05 2021 /pmc/articles/PMC8379074/ /pubmed/34226674 http://dx.doi.org/10.1038/s41385-021-00423-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Joosse, Maria E.
Charbit-Henrion, Fabienne
Boisgard, Remy
Raatgeep, Rolien (H.) C.
Lindenbergh-Kortleve, Dicky J.
Costes, Léa M. M.
Nugteren, Sandrine
Guegan, Nicolas
Parlato, Marianna
Veenbergen, Sharon
Malan, Valérie
Nowak, Jan K.
Hollink, Iris H. I. M.
Mearin, M. Luisa
Escher, Johanna C.
Cerf-Bensussan, Nadine
Samsom, Janneke N.
Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
title Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
title_full Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
title_fullStr Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
title_full_unstemmed Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
title_short Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
title_sort duplication of the il2ra locus causes excessive il-2 signaling and may predispose to very early onset colitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379074/
https://www.ncbi.nlm.nih.gov/pubmed/34226674
http://dx.doi.org/10.1038/s41385-021-00423-5
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