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 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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http://dx.doi.org/10.1038/s41385-021-00423-5 | DOI Listing |
Proc Natl Acad Sci U S A
June 2024
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.
Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types.
View Article and Find Full Text PDFJ Reprod Immunol
June 2024
The First Clinical College, Shandong University of Traditional Chinese medicine, Jinan, China; Reproductive and Genetic Center of Integrated Traditional and Western Medicine, Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, China. Electronic address:
Purpose: Observational studies have linked cytokines to the occurrence of female and male infertility. However, it is not clear how biomarkers of inflammation are causally related to infertility. To explore whether genetic variants in circulating cytokines are associated with the pathogenesis of infertility, we performed two-sample Mendelian randomization (MR) analysis.
View Article and Find Full Text PDFGenetic variants associated with human autoimmune diseases commonly map to non-coding control regions, particularly enhancers that function selectively in immune cells and fine-tune gene expression within a relatively narrow range of values. How such modest, cell-type-selective changes can meaningfully shape organismal disease risk remains unclear. To explore this issue, we experimentally manipulated species-conserved enhancers within the disease-associated locus and studied accompanying changes in the progression of autoimmunity.
View Article and Find Full Text PDFFront Immunol
June 2023
Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China.
Background: Epidemiological studies have linked various circulating cytokines to cardiovascular disease (CVD), which however remains uncertain whether these relationships represent causality or are due to bias. To address this question, we conducted a Mendelian randomization (MR) analysis to systematically investigate the causal effects of circulating cytokine levels on CVD development.
Methods: This study leveraged the summary statistic from respective genome-wide association study (GWAS) of 47 cytokines and four types of CVD.
J Crohns Colitis
January 2023
Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Background And Aims: Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear.
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