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Il-12Rβ1 Deficiency Corresponding to Concurrency of Two Diseases, Mendelian Susceptibility to Mycobacterial Disease and Crohn's Disease Publisher



Khoshnevisan R1 ; Nekooeimarnany N2 ; Klein C3 ; Kotlarz D3 ; Behnam M1 ; Ostadi V1, 2 ; Yaran M2 ; Rezaei A1, 2 ; Sherkat R2
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Authors Affiliations
  1. 1. Immunology Department, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Aquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany

Source: Journal of Clinical Tuberculosis and Other Mycobacterial Diseases Published:2019


Abstract

Background: The interleukin-12 receptor β1 (IL-12Rβ1) deficiency is a primary immunodeficiency (PID), affecting the immunological pathway of interleukin 12/interferon- γ (IL12/IFN-γ) axis and interleukin 23 receptor (IL23R). Defect in this pathway is mainly affecting the cellular immunity-related disorders. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptors and thus, deficiency of IL-12Rβ1 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-12Rβ1. Evaluation of the IL12/IFN-γ axis was performed by assessment of patients’ whole blood cell to IL12/IFN-γ responding. Total and surface IL-12Rβ1expression 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-12Rβ1, 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-12Rβ1 protein expression was detected in patient's PBMCs, compared to the healthy control. Furthermore, no IL-12Rβ1 protein was expressed on the cell surface. Interestingly, IL-12Rβ1-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 IL12Rβ1, can be corresponding to the abolished expression of IL12Rβ1 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). © 2019
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