Severe Early-Onset Inflammatory Bowel Disease Caused by IL10 Receptor Deficiency Can Be Cured by Allogeneic Hematopoietic Stem Cell Transplantation.

Abstract 713

In spite of recent genome-wide association studies, the molecular pathophysiology of many human auto-inflammatory diseases such as enterocolitis remains largely unknown.

Here, we discover the first fully penetrant monogenetic defect causing inflammatory bowel disease (IBD) in humans. Using homozygosity mapping and candidate gene sequencing, we identified three distinct, homozygous mutations in IL10RA, encoding the IL10R1 protein, and IL10RB, encoding the IL10R2 protein, in patients with severe and refractory enterocolitis. IL10R1 is a specific receptor for IL10, whereas IL10R2 is a shared cytokine receptor unit for IL10, IL22, IL26, and IFNλ. The striking similarity of the clinical phenotype between patients with IL10RA and IL10RB deficiency, respectively, suggests that defective IL10-mediated signaling, and not IL22, IL26, or IFNλ dependent effects, is the critical reason for disease.

Deleterious missense mutations in IL10RA abrogate IL10-induced signaling, as shown by deficient phosphorylation of STAT3 at the residue tyrosine 705 in primary patient cells and in HeLa cells engineered to express mutant IL10R1. Mutations in IL10RB introduced a premature stop codon. Defective expression of IL10R2 on the cell surface and deficient STAT3 signaling could be reconstituted by lentiviral gene transfer. As a consequence of defective STAT3 signal transduction in response to IL10 stimulation, IL10R-deficient primary cells showed increased secretion of TNFαa and various other proinflammatory cytokines unresponsive to IL10-dependent negative feedback regulation (TGFβ1, IL1αa, IL1β, IL2, IL6, IL6sR, RANTES, MCP1, MIP1αa, and MIP1β). We are currently assessing whether other IBD patients with early-onset IBD show defects in IL10-mediated signal transduction.

In view of the therapy refractory course of disease and the critical role of IL10 signaling on cells of the hematopoietic system, we have successfully treated two IBD patients with IL10 receptor deficiency by hematopoietic stem cell transplantation (HSCT) without overt side effects. This proof-of-principle suggests that allogeneic HSCT may represent a novel therapeutic approach to treat defined subgroups of IBD patients.

In summary, our results suggest that IL10 receptor defects constitute monogenetic causes for severe, early-onset IBD patients, proving that a lack of IL10-mediated negative feedback signaling perturbs homeostasis of the intestinal immune system.