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J Clin Immunol. 2019 Feb 4. doi: 10.1007/s10875-019-0593-4. [Epub ahead of print]

Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

Author information

1
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, 4th Floor, Building no.3, Children's Medical Center, Gharib St, Keshavarz Blvd, 14185-863, Tehran, IR, 14194, Iran.
2
Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
3
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, EU, France.
4
Imagine Institute, Paris Descartes University, Paris, EU, France.
5
Howard Hughes Medical Institute, New York, NY, USA.
6
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New York, NY, USA.
7
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, EU, France.
8
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, EU, France. jacinta.bustamante@inserm.fr.
9
Imagine Institute, Paris Descartes University, Paris, EU, France. jacinta.bustamante@inserm.fr.
10
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New York, NY, USA. jacinta.bustamante@inserm.fr.
11
Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, EU, France. jacinta.bustamante@inserm.fr.
12
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, 4th Floor, Building no.3, Children's Medical Center, Gharib St, Keshavarz Blvd, 14185-863, Tehran, IR, 14194, Iran. mmoin@sina.tums.ac.ir.

Abstract

PURPOSE:

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).

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

IL-12Rbeta1; Immunodeficiency; interferon-gamma; interleukin-12

PMID:
30715640
DOI:
10.1007/s10875-019-0593-4

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