Original articleImpaired in-vitro responses to IL-12 and IFN-γ in Iranian patients with Mendelian susceptibility to mycobacterial disease
Introduction
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare group of disorders,1 characterised by severe clinical disease, either disseminated or localised and recurrent, caused by weakly virulent mycobacterial species, such as bacillus Calmette-Guerin (BCG) vaccines and non-tuberculous environmental mycobacteria.2, 3, 4 Patients with MSMD are also susceptible to more severe disease caused by non-typhoidal as well as typhoidal salmonella serotypes.2, 5
The interleukin (IL)-12/Interferon (IFN)-γ dependent signalling pathway has a central role in controlling mycobacterial infections. Therefore molecular defects in this pathway could lead to an increased susceptibility to mycobacterial diseases.
It has been reported that ten genes have been identified as causing MSMD when they harbour germline mutations, namely IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1, IKBKG, CYBB, TYK2, IRF8 and ISG15.6, 7, 8 Defects in IFNGR1, IFNGR2 and STAT1 are associated with impaired cellular responses to IFN-γ, whilst defects in IL12B, IL12RB1, and NEMO are associated with impaired IL-12/IL-23-dependent IFN-γ production. Most MSMD patients have either autosomal recessive mutations in IL-12RB1 or autosomal dominant mutations in IFN- γ R1.9 IL12RB1 gene mutations are the most common genetic aetiology of MSMD, which are reported in about 40% of affected patients.10 It seems that there is heterogeneity in clinical presentation of the patients with MSMD according to their specific genetic defects. Patients with IL-12RB1 deficiency are usually susceptible to less severe mycobacterial infections, caused by weakly virulent mycobacterial species, such as BCG vaccines and non-tuberculous, environmental mycobacteria, later in their lives.11, 12
Diagnosis of specific molecular defects of MSMD patients is important with respect to their clinical outcomes and their response to therapy. In this study, serologic tests were performed on blood samples of a group of patients who were suspected of having MSMD, which showed impaired response to recombinant IL-12 (most probably IL-12RB1-deficiency) in the studied cases.
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Patients
Eleven unrelated patients (six male and five female) who had mycobacterial infections were enrolled in this study (Table 1). All the patients were Iranian and were of Persian descent. All these patients had mycobacterial infections and MSMD was suspected after exclusion of other immunodeficiency disorders such as severe combined immunodeficiency and chronic granulomatous disease.
This study was conducted according to the principles expressed in the Helsinki Declaration. Informed consent was
Characteristics of patients
The characteristics of 11 enrolled cases that were suspected MSMD are presented in Table 1. In eight patients, the parents were consanguine. Ten patients had been inoculated with BCG at birth as per the national BCG vaccination programme, but one patient had not been inoculated because of positive history of disseminated BCG infection and death in two siblings of her family. Seven patients suffered from infectious complications of BCG vaccine in the form of localised lymphadenitis or
Discussion
BCG is one of the first vaccines developed in medicine. Considering its efficiency in preventing the occurrence of severe forms of tuberculosis, its inoculation is recommended within the vaccination programme of the countries endemic for tuberculosis, including Iran. However, several complications, ranging from regional disease (BCG-itis) to disseminated disease (BCG-osis) have also been reported, especially in cases with underlying immunodeficiency.3, 13, 14, 15Although susceptibility to
Patients’ data protection
Confidentiality of Data. The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.
Right to privacy and informed consent
The authors have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence is in possession of this document.
Protection of human subjects and animals in research
The authors declare that the
Conflict of interest
The authors have no conflict of interest to declare.
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Cited by (7)
Primary Immunodeficiency Diseases and Bacillus Calmette-Guérin (BCG)-Vaccine–Derived Complications: A Systematic Review
2020, Journal of Allergy and Clinical Immunology: In PracticeEvaluation of interleukin-12 receptor β1 and interferon gamma receptor 1 deficiency in patients with disseminated BCG infection
2019, Allergologia et ImmunopathologiaCitation Excerpt :Since discovering the IFN-γ receptor gene defect as a condition associated with mycobacterial infection in 1996, several genes have been recognized in which their mutations can lead to susceptibility of mycobacterial infections. Among them, IL-12Rβ1 gene seems to be the most common genetic etiology of MSMD.13 Although there is not a defined genetic etiology in about half of all the patients with MSMD,21 flow cytometry has proved to be useful in patients with genetic defects associated with MSMD by focusing on the assessment of specific surface protein expression and cell function analysis.1
Characterization of two novel mutations in IL-12R signaling in MSMD patients
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