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

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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.

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Acknowledgements

We would like to thank the patients and their families for their collaboration and their participation in the present study. Finally, we would like to thank Dr. Hamid Zarkesh for her great help and invaluable advice.

Financial Support

This study was supported by Isfahan University of Medical Sciences. The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institute of Allergy and Infectious Diseases (grant number 5R01AI089970); the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (grant number 8UL1TR000043); The Rockefeller University; the St. Giles Foundation; the Institut National de la Santé et de la Recherche Médicale (INSERM); Paris Descartes University; Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID); the French National Research Agency under the “Investments for the future” (grant number ANR-10-IAHU-01), ANR-GENMSMD (ANR-16-CE17–0005-01 for JB); and the German Academic Exchange Service (DAAD).

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Author notes

  1. Jacinta Bustamante and Roya Sherkat contributed equally to this work.

Authors and Affiliations

  1. Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

    Nioosha Nekooie-Marnany, Vajiheh Ostadi, Bahram Bagherpour, Elaheh Taleby, Mazdak Ganjalikhani-Hakemi, Saba Sheikhbahaei, Razieh Khoshnevisan & Roya Sherkat

  2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, EU, France

    Caroline Deswarte, Tom Le Voyer, Jérémie Rosain, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova & Jacinta Bustamante

  3. Paris Descartes University, Paris, EU, France

    Caroline Deswarte, Tom Le Voyer, Jérémie Rosain, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova & Jacinta Bustamante

  4. Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran

    Hamid Rahimi

  5. Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris AP-HP, Necker Hospital for Sick Children, Paris, EU, France

    Jérémie Rosain & Jacinta Bustamante

  6. Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

    Zahra Pourmoghadas

  7. Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-Universität München, Munich, EU, Germany

    Daniel Petersheim, Daniel Kotlarz & Christoph Klein

  8. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Stéphanie Boisson-Dupuis, Jean-Laurent Casanova & Jacinta Bustamante

  9. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  10. Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris AP-HP, Necker Hospital for Sick Children, Paris, EU, France

    Jean-Laurent Casanova

Authors
  1. Nioosha Nekooie-Marnany
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  2. Caroline Deswarte
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  3. Vajiheh Ostadi
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  4. Bahram Bagherpour
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  18. Jacinta Bustamante
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  19. Roya Sherkat
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Corresponding author

Correspondence to Roya Sherkat.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants

Informed consent for participation in this study was obtained in accordance with local regulations, with approval from the IRB. The experiments described here were performed in Iran and in France, in accordance with local regulations, and with the approval of the IRB for Isfahan Immunodeficiency Research Center (IIRC), Iran, and for Necker Hospital for Sick Children, France.

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Written informed consent was obtained from the patients.

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Nekooie-Marnany, N., Deswarte, C., Ostadi, V. et al. Impaired IL-12- and IL-23-Mediated Immunity Due to IL-12Rβ1 Deficiency in Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease. J Clin Immunol 38, 787–793 (2018). https://doi.org/10.1007/s10875-018-0548-1

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