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Case Reports
. 2018 Oct;38(7):787-793.
doi: 10.1007/s10875-018-0548-1. Epub 2018 Sep 25.

Impaired IL-12- and IL-23-Mediated Immunity Due to IL-12Rβ1 Deficiency in Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease

Nioosha Nekooie-Marnany  1 , Caroline Deswarte  2   3 , Vajiheh Ostadi  1 , Bahram Bagherpour  1 , Elaheh Taleby  1 , Mazdak Ganjalikhani-Hakemi  1 , Tom Le Voyer  2   3 , Hamid Rahimi  4 , Jérémie Rosain  2   3   5 , Zahra Pourmoghadas  6 , Saba Sheikhbahaei  1 , Razieh Khoshnevisan  1 , Daniel Petersheim  7 , Daniel Kotlarz  7 , Christoph Klein  7 , Stéphanie Boisson-Dupuis  2   3   8 , Jean-Laurent Casanova  2   3   8   9   10 , Jacinta Bustamante  2   3   5   8 , Roya Sherkat  11
Affiliations
Case Reports

Impaired IL-12- and IL-23-Mediated Immunity Due to IL-12Rβ1 Deficiency in Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease

Nioosha Nekooie-Marnany et al. J Clin Immunol. 2018 Oct.

Abstract

Purpose: Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM).

Methods: In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-γ, IL-12Rβ1 expression on T cell blasts, and sequenced candidate genes.

Results: We report four patients from Isfahan, Iran, ranging from 3 months to 26 years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rβ1 was completely abolished in the four patients with IL12RB1 mutations.

Conclusions: IL-12Rβ1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12Rβ1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12Rβ1-deficient patient, notified for the first time in this study.

Keywords: (BCG)-osis; Bacillus Calmette–Guérin vaccination; IL-12; Mendelian susceptibility to mycobacterial disease; interferon.

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Conflict of interest statement

Potential conflicts of interest

The authors have no conflict of interest to declare.

Figures

Figure 1:
Figure 1:. IL-12Rβ1 expression in the cells of IL-12Rβ1 patients.
A. T-cell blasts from c.1172delC (P1), c.1791+2T>G (P2,3) and C.C962A (P4) patients and from healthy control (C+) were stained with IL-12Rβ1-specific mAbs (solid line) and isotype control antibodies (dashed line). B. Expression of IL-12Rβ1 protein in patients were indicated by fluorescence intensity (MFI). A p-value <0.05, <0.01 and <0.001 in one way Anowa is indicated by *, ** and ** Respectively. ns, not significant. NS, not stimulated
Figure 2:
Figure 2:. The IL-12 and IFN-γ responses on whole blood activation.
A. Production of IFN-γ (pg/mL) in response to Bacille Calmette–Guérin (BCG) and BCG+IL-12 in whole blood cells was quantified in patients with IL-12Rβ1 deficiency (P1, P2, P3 and P4). B. Production of IL-12 was assessed in supernants of whole blood activation by BCG and BCG+IFN-γ activation. C. TNF production was indicated in response to Lipopolysacharide (LPS) and LPS + IFN-γ. 1.II is the sister of P.1, C- is an IL-12Rβ1 deficient, ns, not significant. NS, not stimulated
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