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Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis
- Source :
- Mucosal Immunology, 14(5), 1172-1182. SPRINGERNATURE, Mucosal Immunology, Mucosal Immunology, 14(5), 1172-1182. Nature Publishing Group
- Publication Year :
- 2021
- Publisher :
- SPRINGERNATURE, 2021.
-
Abstract
- 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.
- Subjects :
- CD4-Positive T-Lymphocytes
0301 basic medicine
Pancolitis
Immunology
Drug Resistance
Receptors, Antigen, T-Cell
Gene Expression
Lymphocyte Activation
Inflammatory bowel disease
Article
03 medical and health sciences
0302 clinical medicine
Gene Duplication
Gene duplication
Humans
Immunology and Allergy
Medicine
Genetic Predisposition to Disease
IL-2 receptor
Age of Onset
Colitis
Alleles
Genetic Association Studies
Chromosomes, Human, Pair 10
business.industry
Interleukin-2 Receptor alpha Subunit
FOXP3
Inflammatory Bowel Diseases
medicine.disease
Immunohistochemistry
030104 developmental biology
Genetic Loci
Case-Control Studies
Chromosomal region
Cytokines
Interleukin-2
030211 gastroenterology & hepatology
medicine.symptom
business
CD8
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 19330219
- Database :
- OpenAIRE
- Journal :
- Mucosal Immunology, 14(5), 1172-1182. SPRINGERNATURE, Mucosal Immunology, Mucosal Immunology, 14(5), 1172-1182. Nature Publishing Group
- Accession number :
- edsair.doi.dedup.....a002db7d270b9a537d87accc4d0b3ea0