IL-12Rbeta1 deficiency corresponding to concurrency of two diseases, mendelian susceptibility to mycobacterial disease and Crohn's disease

Abstract

Background: The interleukin-12 receptor beta1 (IL-12Rbeta1) deficiency is a primary immunodeficiency (PID), affecting the immunological pathway of interleukin 12/interferon- gamma (IL12/IFN-gamma) axis and interleukin 23 receptor (IL23R). Defect in this pathway is mainly affecting the cellular immunity-related disorders. IL-12Rbeta1 is a receptor chain of both the IL-12 and the IL-23 receptors and thus, deficiency of IL-12Rbeta1 abolishes both IL-12 and IL-23 signaling. Material and methods: In this study, we performed whole exon sequencing and confirmatory Sanger sequencing in IL-12Rbeta1. Evaluation of the IL12/IFN-gamma axis was performed by assessment of patients' whole blood cell to IL12/IFN-gamma responding. Total and surface IL-12Rbeta1expression was evaluated, in peripheral blood mononuclear cells (PBMCs) and T cell- derived PBMCs, and Th17 count was assessed. Results: In the present study, we described a c.1791 + 2T > G mutation at a splicing site position in IL-12Rbeta1, using whole exome sequencing, and confirmed with targeted Sanger sequencing in a 26- year-old patient with Mendelian susceptibility to mycobacterial disease (MSMD) and Crohn's disease (CD). Complete lack of IL-12Rbeta1 protein expression was detected in patient's PBMCs, compared to the healthy control. Furthermore, no IL-12Rbeta1 protein was expressed on the cell surface. Interestingly, IL-12Rbeta1-mutant cells showed an impaired response to IL12, and Bacillus Calmette-Guerin stimulation, confirming that the mutation is causative in this patient. Conclusion: A 3'splicing site mutation in IL12Rbeta1, can be corresponding to the abolished expression of IL12Rbeta1 in patients' cells, and associated with an impaired IL12-mediated signaling, which may lead not only to MSMD, but also to inflammatory bowel disease (IBD).