Autosomal recessive 333 base pair interleukin 10 receptor alpha subunit deletion in very early-onset inflammatory bowel disease

Abstract

BACKGROUND Interleukin 10 receptor alpha subunit (IL10RA) dysfunction is the main cause of very early-onset inflammatory bowel disease (VEO-IBD) in East Asians. AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations. METHODS From May 2016 to September 2020, four young patients with clinically diagnosed VEO-IBD were recruited. Before hospitalization, using targeted gene panel sequencing and trio-whole-exome sequencing (WES), three patients were found to harbor a IL10RA mutation (c.301C>T, p.R101W in one patient; c.537G>A, p.T179T in two patients), but WES results of the fourth patient were not conclusive. We performed whole-genome sequencing (WGS) on patients A and B and reanalyzed the data from patients C and D. Peripheral blood mononuclear cells (PBMCs) from patient D were isolated and stimulated with lipopolysaccharide (LPS), interleukin 10 (IL-10), and LPS + IL-10. Serum IL-10 levels in four patients and tumor necrosis factor-α (TNF-α) in the cell supernatant were determined by enzyme-linked immunosorbent assay. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and Ser727 in PBMCs was determined by western blot analysis. RESULTS The four children in our study consisted of two males and two females. The age at disease onset ranged from 18 d to 9 mo. After hospitalization, a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data. Patient D was homozygous for the 333 bp deletion. All four patients had elevated serum IL-10 levels. In vitro , IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-α production induced by LPS. Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS + IL-10 in both healthy subjects and in patient D. CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD, whereas the WES results were inconclusive.

A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis

“…333-bp deletion in IL10RA was recognized to contribute to four cases of clinically diagnosed VEO-IBD with inconclusive IL10RA mutations. Most importantly, they confirmed that typical clinical manifestations and increased serum levels of IL-10 strongly indicate the existence of IL-10R dysfunction [237]. GWASs have additionally documented common polymorphisms in the IL-10 pathway as risk factors for IBD in adults [238].…”

“…IL-22 is a member of the IL-10 family and is produced by Th-17 cells, γδ T cells, and newly described innate lymphoid cells (ILCs) [248]. IL-22 is crucial for maintaining intestinal epithelial homeostasis and barrier function, providing protective effects in IBD [237]. IL-22 and IL-18 serve crucial functions in the delicate cytokine balance that determines host defense and inflammation particularly at biological barriers.…”

Inflammatory proteins may mediate the causal relationship between gut microbiota and inflammatory bowel disease: A mediation and multivariable Mendelian randomization study

“…[ 53 ] Notably, although our data mainly come from European populations, previous studies have found that IL-10RA dysfunction is a major cause of very early-onset IBD (VEO-IBD) in East Asian populations, where a potential mechanism might be a novel 333-bp deletion in IL10RA. [ 54 ] Mentioning this aims to highlight the importance of genetic background in IBD onset and the potential differences among various populations. Furthermore, it suggests that future research should more broadly explore the diversity of IBD pathogenesis mechanisms across different genetic backgrounds.…”