We have shown that loss-of-function mutations in either IL10RA
can be found in children with severe, early-onset enterocolitis, findings that are consistent with the idea that a lack of negative-feedback signaling mediated by interleukin-10 perturbs homeostasis of the intestinal immune system. Since IL10R1 is expressed on many cells of the innate and adaptive immune system, further studies are needed to determine which types of cells are primarily responsible for the altered intestinal immunity. In contrast, IL10R2 is expressed not only on cells of the immune system but also on a wide range of nonimmune cells, such as epithelial cells and keratinocytes.38
Because IL10R2 is a component of the receptors for interleukin-10, -22, -26, -28A, -28B, and -29,38,39
defective signaling of any of these cytokines as a result of IL10R2 deficiency may have additive or synergistic effects. The presence of severe inflammatory bowel disease is the most prominent phenotype in patients with IL10R1 or IL10R2 deficiency. We therefore infer that a lack of interleukin-10 signaling is the principal malfunction and is a likely cause of inflammatory bowel disease in patients with IL10R2 deficiency. Nevertheless, interleukin-22 and interleukin-26 regulate immunity in the skin,40,41
suggesting that chronic folliculitis in IL10R2-deficient patients may be caused by irregular or diminished signaling by either interleukin-22 or interleukin-26.
Our findings are consistent with those regarding severe colitis in mice lacking either Il10
Expression of the murine gene encoding interleukin-22 in the appropriate cell types provides protection against colitis and is associated with the resolution of colitis in two distinct murine models,42,43
suggesting that some IL10R2-related functions may be independent of interleukin-10. Moreover, interleukin-22 induces the antimicrobial proteins REGIIIβ
and enhances mucus production in colonic epithelial cells, thereby maintaining the epithelial barrier function and preventing bacterial infections.42,44
We speculate that in the absence of an interleukin-10–mediated antiinflammatory response, the presence of intestinal commensal bacteria leads to activation of a fulminant immune response, resulting in a hyperinflammatory response with associated tissue damage. This may facilitate increased transmigration of intestinal bacteria and result in chronic intestinal lymphadenopathy or even organ-related abscesses.
Our limited search for mutations in IL10RA
in patients with inflammatory bowel disease indicated that loss-of-function mutations may be confined to very severe cases with an onset in infancy. A polymorphism in IL10
has been associated with the risk of colitis in a genomewide association study,11
and this finding has been replicated,45
suggesting that milder genetic variants affecting interleukin-10–dependent pathways may be involved in the pathophysiology of inflammatory bowel disease.
Our study provides an example of the power of molecular medicine to go from the bedside (for diagnosis) to the bench (for the discovery of mutations) and back to the bedside (for treatment). Because no conventional therapeutic approach was successful in our patients and given the role of interleukin-10 signaling in cells of the hematopoietic system, we attempted a curative approach by means of allogeneic stem-cell transplantation, which would have been ethically difficult to justify without knowledge of the monogenic cause. The sustained remission after stem-cell transplantation in the patient suggests that interleukin-10 signaling in hematopoietic cells rather than signaling through a pathway associated with interleukin-22, interleukin-26, or interferon-λ in nonhematopoietic cells was critical for the therapeutic effect.
In summary, mutations in the genes encoding the two polypeptide chains of the interleukin-10 receptor abrogate interleukin-10–mediated immunomodulatory signaling and are strongly associated with hyperinflammation of the intestine.