A genetic database and clinical findings for immunodeficiency due to mutations in interleukin-10, interleukin-10 receptor A, and interleukin-10 receptor B genes
Abstract
Defects in interleukin (IL)-10 cytokine and receptors are associated with severe immune dysregulation, with affected patients presenting mainly with very early onset inflammatory bowel disease (VEO-IBD), arthritis, and skin manifestations such as dermatitis and folliculitis. We have created a database of published mutations in the genes encoding for IL-10, IL-10 receptor A (IL-10RA), and IL-10 receptor B (IL-10RB). All published mutations were reviewed and clinical as well as laboratory phenotypes recorded. Many variants in these genes are reported to be associated with IBD, as well as other diseases and pathologies. However, in this review we have focused on mutations considered harmful to the gene product and which lead to the classic presentation of VEO-IBD. This database can assist clinicians in the diagnosis of patients with specific features of immunodeficiency. A yearly update of new mutations and phenotypes will be performed.
Statement of novelty: The presented database and short review is the first extensive collection of reported mutations and the clinical features of Very Early Onset IBD due to IL10 related genes.
Introduction
Interleukin (IL)-10 is an important anti-inflammatory mediator. Deleterious defects in IL-10 cytokine and receptors are associated with severe immune dysregulation, with affected patients presenting mainly with the phenotype of very early onset inflammatory bowel disease (VEO-IBD). Other prominent features include skin manifestations, such as dermatitis and folliculitis, and in some patients arthritis may be significant (Glocker et al. 2009).
Inflammatory bowel disease is a group of several disorders afflicting mainly the gastrointestinal tract, alongside the well characterized Crohn’s disease and Ulcerative Colitis, there is a group of patients with very early onset inflammatory bowel disease (VEO-IBD), which is encountered by pediatricians and gastroenterologists worldwide. These patients present with severe gastrointestinal involvement, eczema, arthritis and sometimes infections. As many as 20% carry mutations in IL-10, IL-10 receptor A (IL-10RA), or IL-10 receptor B (IL-10RB). These defects are considered primary immunodeficiency diseases and carry a poor prognosis if left untreated. Unfortunately, response to conventional IBD treatment regimens is poor, thus, hematopoietic stem cell transplantation (HSCT) is considered a curative treatment for these patients.
Immunologic studies
The routine immune workup in the majority of patients is unremarkable. 2 studies reported changes in immunoglobulins; in 2 cases IgG was low, and in 1 case IgA or IgG was elevated. As for lymphocyte surface markers, 1 study reported reduced numbers of FOXP3 expressing CD4 lymphocytes in both blood and tissue (Kelsen et al. 2015) and another study reported low CD4/CD8 ratio (Engelhardt et al. 2013). Lymphocyte proliferation assay results have been reported to be normal.
Clinical features
VEO-IBD, which is refractory to conventional treatment modalities, is the most significant finding, with most reports describing the disease as beginning during the very first months of life. Severe perianal disease with fistula formation and severe colitis, and in some patients oral aphtous lesions, all appeared in infants younger than 6 months. In many cases, this was described during the first 3 months of life and progressed rapidly. One interesting report of a patient from Korea described a relatively late presentation at the age of 6 years without the common finding of severe perianal disease. The pathogenic mutation occurred before the splice site, resulting in skipping and fusion of exon 3 and 5 of the IL10 RA gene (Oh et al. 2016).
All known treatments for IBD, such as steroids, immunomodulators, and anti-tumor necrosis factor (TNF) therapy failed to achieve substantial effects. In many patients, surgical treatment was undertaken to alleviate some of the symptoms. In as much as a third of patients, a prominent feature is arthritis affecting the large joints. Eczema and folliculitis are also very common and this may involve large portions of body area.
Malignancy with B cell lymphoma in patients with IL-10 defects have been reported by Neven et al. (2013). These involved mostly non-Epstein-Barr virus (EBV)-related B cell lymphomas, and occurred after several years of disease (around 5 years). Most were treated and cured, although 1 patient was reported to experience several recurrences, and was cured after HSCT. The exact mechanism has not been elucidated, although it may well be related to IL-10 regulatory, or rather, lack of regulatory activity in these patients. All had non-EBV-related diffuse large B cell lymphoma. The current consensus for treating these patients is with HSCT, however, in some patients not all manifestations resolve post-transplant, such as in the case reported by Kim et al. (2014). This group of patients reinforces the need for early diagnosis and curative treatment with HSCT.
Other less frequent findings including autoimmune hepatitis, idiopathic thrombocytopenic purpura (ITP), pyoderma gangrenosum, Gram-negative sepsis, and recurrent pneumonia were all described in sporadic patients (see Table 1).
Table 1:
Note: VEO-IBD, very early onset inflammatory bowel disease, consisting frequently with severe inflammation, severe perianal disease with fistulae. Patients often suffer from FTT, failure to thrive; 3′UTR, untranslated region; AI, autoimmune; JML, juvenile myelogenous leukemia; ITP, immune thrombocytopenic purpura.
There are, however, some limitations in our attempt to summarize this large group of patients (Table 1). Since the discovery of this group of diseases, the increasing availability of diagnostic tools, as well as early diagnosis and treatment, has changed the natural course and phenotype of these inherited defects. Furthermore, the mutations and patients presented here are by no means a reflection of the extent of this group of diseases or their prevalence. It is reasonable to conclude that once a mutation is found in a population, many more patients will be identified by direct sequencing of the known mutation, rather than whole exome sequencing, and therefore may not be reported.
Summary
VEO-IBD related to mutations in IL-10 and IL-10 receptors have a unique presentation and carry a grave prognosis, unless diagnosed early and treated appropriately. The current main curative treatment is HSCT, with good results reported by several centers.
The subject of polymorphisms in these genes was not covered in this manuscript, but is an important issue (Moran et al. 2013). Undoubtedly, some of these changes cause increased susceptibility to IBD and are worth studying in further detail. We have focused on the changes that were studied biologically and were proven to be a direct cause for IBD.
In this short review, we have collated all reported mutations found in several journal databases with a short description of the patients’ ethnicity, main immunological features and most important their clinical presentation. We hope this increases awareness to the spectrum of the disease, and the importance of early diagnosis and treatment.
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LymphoSign Journal
Volume 4 • Number 2 • June 2017
Pages: 80 - 85
History
Received: 3 November 2016
Accepted: 12 February 2017
Accepted manuscript online: 20 March 2017
Version of record online: 20 March 2017
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© 2017.
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Amarilla B.Mandola, YotamEshel, and AmitNahum. 2017. A genetic database and clinical findings for immunodeficiency due to mutations in interleukin-10, interleukin-10 receptor A, and interleukin-10 receptor B genes. LymphoSign Journal.
4(2): 80-85. https://doi.org/10.14785/lymphosign-2016-0014
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