Immune Dysregulation Resulting From Impaired Interleukin-10 And The Interleukin-10 Receptor Signaling: A Systematic Review of 284 Monogenic Patients

Purpose: Interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiency are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). Methods: We systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. Results: We assessed 284 patients (44.1% female) with IL-10 and/or IL-10R deficiencies who were predominantly from China (41.0%), Italy (14.1%), and South Korea (8.6%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL-10 deficiency and in 38.8% of patients with IL-10R deficiency (23.4% of patients with IL-10RA, and 79.4% of patients with IL-10RB deficiency). The most prevalent mutations in IL-10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL-10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Autoimmunity and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (18.1%), and colitis (15.7%). Patients with IL-10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60%), while IL-10 deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30% underwent hemopoietic stem cell transplantation, 61.5% surgery, and 87% immunosuppressive treatment. The ten-year survival rate was higher in patients with IL-10 deficiency than in patients with IL-10R deficiency.Conclusion: IL-10/IL-10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. No clear genotype-phenotype correlation was present among these patients. The high prevalence of distinct clinical manifestations reported in IL-10RA- and IL-10RB-deficient patients might be attributable to the interaction between the target tissue and cytokines other than IL- 10 capable of binding to IL-10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcome.