Gastroenterol Res
Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access
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Volume 10, Number 2, April 2017, pages 65-69

IL-10 and IL-10 Receptor Mutations in Very Early Onset Inflammatory Bowel Disease

Lei Zhua, Tingting Shia, Chengdi Zhonga, Yingde Wanga, Michael Changb, Xiuli Liub, c

aDepartment of Gastroenterology and Hepatology, The First Affiliated Hospital of Dalian Medical University, Dalian City, China
bDepartment of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA
cCorresponding Author: Xiuli Liu, Department of Anatomic Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA

Manuscript accepted for publication December 15, 2016
Short title: IL-10 and IL-10 Receptor Mutations in VEO-IBD


Very early onset inflammatory bowel disease (VEO-IBD) is a unique disease entity with a complex genetic susceptibility in affected patients. Next-generation gene sequencing techniques have revealed various monogenetic mutations contributing to the pathogenesis of VEO-IBD, including interleukin 10 (IL-10) and IL-10 receptor (IL-10R) mutations. In this article, we reviewed the features of and effective therapeutic options for VEO-IBD with IL-10 and/or IL-10R mutations. The IL-10 signal pathway inhibits the release of several key cytokines and thereby has a significant anti-inflammatory effect in the gastrointestinal tract. Mutations of the genes encoding IL-10 and/or IL-10R have been detected in VEO-IBD patients among myriad populations throughout the world. VEO-IBD patients with IL-10 or IL-10R mutations often present with repeated bouts of bloody diarrhea, marked weight loss, growth retardation, and recurrent perianal problems, including abscesses, fistulas, and significant fissures. Moreover, some patients may have folliculitis and present with pulmonary infections. While the therapeutic efficacy of immunosuppressants is typically poor in these patients, allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to improve symptoms significantly. However, the long-term prognosis of VEO-IBD patients with IL-10 or IL-10R gene mutations treated with HSCT requires further exploration to verify the efficacy and safety of this treatment. We concluded that clinicians should recognize the clinical phenotype of VEO-IBD, as mutational analysis of the IL-10 pathway can support the diagnosis and prompt early treatment of this complicated disease.

Keywords: Interleukin-10; Interleukin-10 receptor; Gene mutation; Inflammatory bowel disease


Inflammatory bowel disease (IBD) is a heterogeneous family of chronic gastrointestinal inflammatory disorders encompassing ulcerative colitis (UC), Crohn’s disease (CD), and indeterminate colitis. The etiology and pathogenesis of these disorders have yet to be entirely elucidated. Studies increasingly reveal that the chronic inflammation of the gut in IBD is triggered by a variety of environmental factors in genetically susceptible individuals. Very early onset IBD (VEO-IBD) is defined as IBD with a disease onset before 6 years of age. Compared with adolescent- and adult-onset IBD, in which exogenous environmental factors are thought to play a larger role, genetic susceptibility may have more of an influence on the pathogenesis of VEO-IBD [1]. Genome-wide association studies (GWASs) have discovered 201 candidate loci of probable genetic mutations related to IBD; the most widely reported mutated gene codes for nucleotide-binding oligomerization domain-containing protein 2 (NOD2) [2]. GWAS is useful in detecting common genetic variants, but is not suitable for identifying low-frequency monogenetic variants, which seem to be more relevant to VEO-IBD [3]. In contrast, genetic linkage analysis and exome gene sequencing can overcome the limitations of GWAS. Until now, at least 58 susceptible genes were implicated in the pathogenesis of VEO-IBD by new gene sequencing techniques [4]. Among these susceptible genes, interleukin-10 (IL-10) and IL-10 receptor (IL-10R) gene mutations have been extensively investigated. This article aimed to review the current literature on the mutations of IL-10 and IL-10R in VEO-IBD.

Physiological Function of IL-10 in the Gut▴Top 

IL-10 is an important anti-inflammatory cytokine secreted by various cells, including monocytes, macrophages, T and B lymphocytes, dendritic cells, epithelial cells, and mast cells. IL-10 inhibits the release of tumor necrosis factor α [5] and thus is critical to the maintenance of immune homeostasis in gastrointestinal tract. The immune-modulating effect of IL-10 starts with its binding to IL-10R, which is a tetrameric receptor complex consisting of two α sub-units of IL-10 receptor 1 (IL-10R1), encoded by IL-10RA, and two β sub-units of IL-10 receptor 2 (IL-10R2), encoded by IL-10RB [6]. IL-10R1 only binds with IL-10, whereas the IL-10R2 sub-unit can bind with several other cytokines, such as IL-22, IL-26, IL-28 and IL-29 [7]. Once IL-10 binds its receptor, it activates Janus kinase 1 (JAK1) and tyrosine kinase 2 (Tyk2), leading to the phosphorylation of signal transducer and activator of transcription 3 (STAT-3), the activation of downstream target genes, and finally the expression of anti-inflammatory effectors [8]. The IL-10 and IL-10R signal pathway is briefly shown in Figure 1.

Figure 1.
Click for large image
Figure 1. Diagram of IL-10 and IL-10R pathway.
Mutations in IL-10 and IL-10R in VEO-IBD▴Top 

Defects in the encoding regions of IL-10 and IL-10R genes lead to disturbances of the anti-inflammatory response. The dysfunction of this IL-10 and IL-10R signal pathway in humans can cause severe enterocolitis [9], as seen in some cases of VEO-IBD. Since the initial report in 2009 by Glocker et al [10], more than 60 cases of IL-10 or IL-10R gene mutated VEO-IBD have been documented in the literature. Most of the cases were reported in Europe, where IL-10R mutations were more predominant than IL-10 mutations. In 22 cases reported in East Asia, 21 cases had IL-10RA mutations, and only one case had an IL-10RB mutation, in contrast to European cases, in which the numbers of IL-10RA and IL-10RB mutated cases were somewhat more equivalent (Table 1). Cases of IL-10 and IL-10R mutated VEO-IBD in the literature are summarized in Table 1 [10-27].

Table 1.
Click to view
Table 1. Cases of VEO-IBD with mutated IL-10, IL-10RA, or IL-10RB reported in the literature [10-27]

Until now, most cases of IL-10 and/or IL-10R mutations have been scattered reports, and multi-center and global epidemiological data are lacking. Pediatric IBD patients (defined as younger than 16 years) account for approximately 20-25% of all IBD patients. About 5% of all IBD patients are less than 10 years old, and approximately 1% are less than 2 years of age [1]. Approximately 15% of pediatric IBD patients can be classified as VEO-IBD [27]. Although IL-10 and/or IL-10R mutations occur in VEO-IBD, the exact prevalence is not known. In small cohorts of VEO-IBD, the frequency of IL-10 and/or IL-10R varied significantly. For example, one report from the United Kingdom showed that five of 62 patients (8.1%) with IBD younger than 2 years old were verified to have IL-10 or IL-10R mutation [28]. One study from Germany reported that 16 of 66 (24.2%) IBD patients younger than 5 years old had IL-10 or IL-10R mutations [13]. In the United States, only six of 125 (4.8%) VEO-IBD patients showed IL-10 mutations [24]. Meanwhile, VEO-IBD cases from Asian countries tend to have higher rate of IL-10/IL-10R mutations. For example, one study from Korea reported that seven of 14 IBD patients (50%) diagnosed within 1 year of age had IL-10RA mutations [20]. The prevalence of IL-10R mutations was also strikingly high in VEO-IBD cases from China. According to a report by Xiao et al [27], 38.5% of VEO-IBD cases from China are positive for IL-10RA or IL-10RB mutations. This high frequency of IL-10 and/or IL-10R mutations in China is probably due to the small size of the cohort as there were only 13 VEO-IBD cases in this study. Regardless, the currently available data from case series suggest that the frequency of IL-10 and/or IL-10R gene mutations should not be low. Multi-center studies are needed to determine the frequency and role of IL-10 and/or IL-10R mutations in VEO-IBD and to accurately identify the clinical phenotype of IL-10 and/or IL-10R mutated VEO-IBD. Such information could potentially be used in the future to guide the screening of VEO-IBD patients with IL-10 and/or IL10-R mutations.

Clinical Features of IL-10 or IL-10R Mutation-Associated VEO-IBD▴Top 

Compared with adult-onset IBD, the clinical manifestations of VEO-IBD are different. VEO-IBD has a more severe clinical course and is more resistant to immunosuppressive therapy. VEO-IBD patients with IL-10 or IL-10R mutations have even more complicated, severe, and intractable disease. These patients have repeated bouts of bloody diarrhea, marked weight loss, growth retardation, and recurrent perianal inflammation with abscesses, fistulas, and significant fissures [29]. Furthermore, folliculitis and refractory pneumonia are frequent complications in patients with IL-10RB mutations which interrupt the binding of IL-10R1 and IL-22, finally leading to disturbances in skin and lung epithelial immunity due to abnormal IL-22 signaling pathway [13, 25].

In addition to the severe and intractable nature of VEO-IBD with IL-10 or IL-10R mutations, this disease is also resistant to a variety of immunosuppressive therapies, including azathioprine, methotrexate, corticosteroid, and infliximab, either as single agent therapies or in combination. Treatment with the above agents usually results in no or only mild improvement of clinical manifestations. A few patients have had to undergo bowel resection and ileostomy or colostomy due to poor treatment efficacy and resistance to therapy [22]. Given the fact that IL-10 acts predominantly on hematopoietic and immune cells, allogeneic hematopoietic stem cell transplantation (HSCT) has been attempted as a curative therapy for VEO-IBD patients with IL-10 or IL-10R mutations [10, 13, 17, 19, 23, 25, 30]. The initial results appear to support the therapeutic role of HSCT in VEO-IBD patients with IL-10 or IL-10R mutations. However, experience is limited, as it was only used in a few patients with a relatively short follow-up period. HSCT remains a promising therapeutic modality, but additional studies are required to address its long-term safety and efficacy in VEO-IBD patients with IL-10 or IL-10R mutations.


VEO-IBD is a rare disease with a high probability of harboring monogenetic mutations, such as IL-10 or IL-10R mutations. It is important for clinicians to recognize the phenotype of IL-10 gene or IL-10R gene mutated VEO-IBD and prompt genetic testing to aid in the early diagnosis and treatment of these patients. In patients with IL-10 gene or IL-10R gene mutated VEO-IBD who are refractory to standard medical therapy, allogeneic HSCT may be an efficacious treatment option in a clinical trial setting.




CD: Crohn’s disease; GWAS: genome-wide association study; HSCT: hematopoietic stem cell transplantation; IBD: inflammatory bowel disease; IL: interleukin; NOD2: nucleotide-binding oligomerization domain-containing protein 2; STAT-3: signal transducer and activator of transcription 3; UC: ulcerative colitis; VEO-IBD: very early onset inflammatory bowel disease

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