IL10RA – Inflammatory Bowel Disease

Interleukin-10 receptor α (IL-10R1), encoded by IL10RA, is a critical modulator of intestinal immune homeostasis. Loss-of-function variants in IL10RA disrupt anti-inflammatory signaling and lead to severe early-onset inflammatory bowel disease (IBD). This autosomal recessive disorder presents within the first months of life with protracted diarrhea, colitis, perianal disease and failure to thrive. Recognition of this monogenic form is crucial for prompt genetic diagnosis and management, including curative hematopoietic stem cell transplantation.

Biallelic IL10RA variants have been identified in multiple unrelated families. In a cohort of 66 early-onset IBD patients, 16 carried homozygous or compound heterozygous IL10RA coding or splice-site mutations, all with complete penetrance and consistent clinical presentation ([PMID:22549091]). In unrelated consanguineous pedigrees, three distinct homozygous IL10RA mutations segregated with disease in four affected children, confirming recessive inheritance ([PMID:19890111]).

Case reports and small series describe a spectrum of variant classes in IL10RA, including missense (e.g., c.301C>T (p.Arg101Trp)), nonsense, frameshift, splice-site, and intronic changes. Affected individuals display uniform resistance to standard therapies, highlighting the necessity of molecular testing in very early-onset IBD.

Functional studies demonstrate that IL10RA mutations abrogate IL-10–induced STAT3 phosphorylation and downstream anti-inflammatory feedback. Aberrant splicing, misfolding, and impaired surface expression of IL-10R1 have been shown by immunoblot, flow cytometry, and confocal microscopy. These assays establish a clear mechanism of loss of signaling capacity linked to the clinical phenotype ([PMID:19890111]; [PMID:22549091]).

Allogeneic hematopoietic stem cell transplantation restores IL-10R–mediated signaling and induces sustained clinical remission in affected children, providing definitive proof of pathogenicity. Transplantation outcomes underscore the value of early genetic diagnosis for therapeutic decision-making.

Key Take-home: IL10RA deficiency is a definitive, autosomal recessive cause of very early-onset IBD. Genetic testing for IL10RA should be prioritized in infants with refractory colitis, and prompt HSCT offers curative potential.

References

• Gastroenterology • 2012 • Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. PMID:22549091
• The New England Journal of Medicine • 2009 • Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. PMID:19890111

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