Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease
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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients).
We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients.
Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8 months and 3.7 years. The remaining patients were alive at the last follow-up and were aged between 2 and 13 years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations.
We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.
KeywordsImmunodeficiency interleukin-12 interferon-gamma IL-12Rbeta1
We would like to thank the patients and their families. We also thank Yelena Nemirovskaya, Cecile Patissier, and Céline Desvallées for their assistance. We would like to thank Nastaran Sabetkish and Fatemeh Talebian for English editing of the manuscript. This research was funded in part by a grant from the National Institute of Allergy and Infectious Diseases grant number 5R01AI089970, The Rockefeller University, the St. Giles Foundation, 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 (ANR) under the “Investments for the future” (grant number ANR-10-IAHU-01) and ANR-GENMSMD (ANR-16-CE17-0005-01 for JB). This project has been granted and supported by Immunology, Asthma and Allergy Research Institute under the supervision of Tehran University of Medical Sciences (grant number: 89-33-1/253-1).
The authors have no financial relationships relevant to this article to disclose.
Compliance with Ethical Standards
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 ethics committee of Tehran University of Medical Sciences (TUMS). The experiments described here were performed in Iran and France, in accordance with local regulations, and with the approval of the TUMS for Immunology, Asthma and Allergy Research Institute (IAARI), Tehran-Iran; and for Necker Hospital for Sick Children, France.
Written informed consent was obtained from the patients.
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