Interleukin-10 receptor (IL10R) plays a critical role in immune regulation by mediating anti-inflammatory effects of IL-10 through STAT3 phosphorylation and downstream signaling. While biallelic mutations in IL10RA are well established as causative of very early onset inflammatory bowel disease (VEO-IBD) and severe immune dysregulation, the clinical relevance and functional consequences of heterozygous variants remain poorly defined.
We report a multi-generational Argentinean family with three affected individuals—two males and one female—from distinct branches, all carrying a heterozygous nonsense variant in IL10RA (c.787C>T; p.Arg263*). Clinical phenotypes ranged from VEO-IBD to common variable immunodeficiency with autoimmunity. In contrast, heterozygous relatives without overt disease showed either normal immune profiles or mild immunological alterations.
The p.Arg263* variant introduces a premature stop codon in the penultimate exon, within 50 bp of the exon–exon junction, and is predicted to escape nonsense-mediated decay. Consistently, Western blot analysis of peripheral blood mononuclear cells demonstrated expression of a truncated IL10Rα protein in both patients and asymptomatic mothers, with higher protein levels in symptomatic individuals, supporting a dose-dependent dominant-negative effect. Patient-derived peripheral blood mononuclear cells (PBMCs) showed diminished STAT3 phosphorylation upon IL-10 stimulation. Furthermore, LPS stimulation induced elevated secretion of pro-inflammatory cytokines (IL-6, TNF-α) in both patients and healthy donors; however, only in healthy controls did IL-10 co-stimulation effectively suppress cytokine production. This regulatory effect was absent in patient cells, suggesting a defect in IL-10–mediated immune suppression. In vitro reporter assays using HEK293T cells co-transfected with wild-type or mutant IL10RA constructs demonstrated reduced STAT3-GFP activation in the presence of the mutant receptor, consistent with a dominant-interfering mechanism.
These findings support a dominant-negative effect of the IL10RA p.Arg263* variant. This case expands the spectrum of IL-10R–associated immune dysregulation and suggests that heterozygous truncating variants may underlie dominant inheritance patterns. Functional testing is essential for variant interpretation and patient care.
