Variants in Interferon Lambda are Associated with Infantile-Onset Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestine that affect children and adults. The etiology is multifactorial with the contribution of genetic, immune, microbial, and environmental risk factors with a substantial involvement of host:microbial cross-talk in the lumen. Whether and how antiviral responses contribute to IBD pathogenesis is under intense investigation. Here, we identified two unrelated patients diagnosed with very early onset IBD (VEOIBD) with rare variants in type III Interferons (IFNs), also known as interferon lambdas (IFN{lambda}s), a group of IFNs that play key roles in the protection against enteric viruses. The first patient was found to have homozygous variants in both IFNL2 and IFNL3, the genes encoding, IFN-{lambda}2 and IFN-{lambda}3, respectively. The second patient was found to have inherited compound heterozygous variants in IFNL3, with one of the two alleles bearing the same variant as the first patient. Functional analyses revealed that the proteins coded for by these variant IFN-{lambda} genes exhibited defects in the induction of IFN signaling. More detailed assessment of the variants identified in Patient 1 demonstrated defects in their ability to bind to IFN-{lambda} receptor 1 (IFNLR1), as well as their ability to induce heterodimerization of IFNLR1 and IL10RB, which together compromise the functional receptor for IFN-{lambda} (IFNLR). These patient-encoded IFN-{lambda} variants also exhibit defects in the ability to induce robust downstream IFN-stimulated genes (ISGs) in patient-derived intestinal organoids. All in all, we demonstrate that VEOIBD is associated with variants in IFN-{lambda}s and defective induction of downstream IFN signaling.