Commentary on Mutations in Interleukin-10 Receptor and Clinical Phenotypes in Patients with Very Early-onset Inflammatory Bowel Disease

In this issue, Huang et al report the role of IL-10R in the very early-onset inflammatory bowel disease (VEO-IBD) population in China through a collaborative effort of 6 distinct hospitals, known as “The Chinese VEO-IBD Collaboration Group.” This timely and exciting article further supports the notion that VEO-IBD, in some cases, is a primary immunodeficiency. Inflammatory bowel disease (IBD) is a complex, polygenic, and environmentally triggered disease. Despite this complexity, it is becoming apparent that host genetics may play a more prominent role in some subpopulations of patients with IBD, particularly in very young children (those with onset at less than 5 years of age), known as VEO-IBD. Patients with VEO-IBD frequently present with a different phenotype, including extensive colonic involvement and more severe disease than older children and adults. The landmark article by Glocker et al in 2009 confirmed that VEO-IBD can be secondary to a single gene defect in a subset of patients with VEO-IBD. The authors identified loss of function mutations in IL-10RA/B in children with neonatal or infantile VEO-IBD, with a phenotype of severe enterocolitis and perianal disease.1 Since then, other defects in IL-10 and its receptors IL-10RA and IL-10RB have been reported in neonatal CD and enterocolitis.2 IL10 is an anti-inflammatory cytokine secreted by a variety of cells, including dendritic cells, natural killer cells, eosinophils, mast cells, macrophages, B cells, and CD4+ T cell subsets (including Th2, Th1, Th17, and Treg).3 IL-10 maintains homeostasis through the suppression of an excessive proinflammatory response4 and exerts its effect through binding to the IL-10 receptor, IL-10R, which is a tetrameric complex. It is composed of 2 distinct chains, 2 molecules of IL10R1 (α chain), and 2 molecules of IL10R2 (β chain). IL-10 binding to IL-10R activates the IL-10/JAK1/STAT3 cascade.5 STAT3 activates effector genes, which subsequently suppresses the proinflammatory genes. In addition to intestinal inflammation, IL-10 defects are associated with arthritis, folliculitis, and predisposition to lymphoma.6 The discovery of IL10R causative defects in these patients radically changed our view of the disease in these very young children, as a monogenic disease, often involving genes associated with primary immunodeficiencies. Perhaps more exciting was the finding that allogenic stem transplants and bone marrow transplants can be curative and life-saving treatments for some of these patients. Recent advances in sequencing technology, such as whole exome sequencing, has provided significant insight into the pathogenesis of VEO-IBD and has led to further discoveries of additional genes and pathways associated with the disease. These comprise defects of the epithelial barrier, phagocyte bacterial killing, B and T cell selection, activation, and migration, and hyperimmune and autoimmune inflammatory disorders.7,8 Primary immunodeficiencies with IBD phenotypes of these pathways include, but are not limited to, X-linked inhibitor of apoptosis,9,–11 common variable immunodeficiency, Wiskott–Aldrich syndrome, immunodysregulation, polyendocrinopathy and enteropathy, X-linked, and chronic granulomatous disease.12 Interestingly, bone marrow transplant can be curative for some of these monogenic causes of VEO-IBD, but is not appropriate in all cases. One such example is TTC7A mutation resulting in epithelial defects where bone marrow transplant can even worsen the IBD course. Therefore, it is critical to identify the causal gene when possible to appropriately counsel these unfortunate patients presenting with severe IBD early in life. With increased understanding of the disease process in VEO-IBD, we can begin to individualize our treatments to the specific patient, and use unconventional approaches that are not routinely part of the IBD therapeutic arsenal. This vital work by Huang et al is an important reminder that different geographical regions harbor distinct genetic contributions to the disease. Most genomic studies have focused on populations of European descent, and in 2009, this was true of up to 95% of genome-wide association studies.13 Since then, concerted effort was made to increase diversity in these studies, and in 2016, 20% of genome-wide association studies included individuals of non-European descent, including Asian populations. Similarly, whole exome sequencing databases have been successful in incorporating diverse populations.14 However, individuals of non-European descent are still underrepresented in many studies, which can lead to bias and inaccurate conclusions. Indeed, this work highlights some of these difficulties. The data presented in this article by Huang et al are intriguing, and the preliminary results showing this large cohort of patients with VEO-IBD caused by IL-10R defects may point to the unique genetic architecture in East Asia as compared to North America and Europe. The authors are reporting 16 mutations in IL-10R (6 already known and 10 novel) in 42 patients with VEO-IBD, all neonatal onset. To fully understand these results, particularly of those novel mutations, a large matched control cohort is critically needed. Although the causal role of some of these mutations is still unclear, in addition to validation with controls, a cohort of this size has not been previously described, and may lead to an exciting area of research in the genomics of IBD. More importantly, this may translate to an improved understanding of the disease and ultimately allow for better care of children with VEO-IBD.