Impaired in-vitro responses to IL-12 and IFN-γ in Iranian patients with Mendelian susceptibility to mycobacterial disease

Abstract

Introduction

Diagnosis of specific molecular defects of Mendelian susceptibility to mycobacterial diseases (MSMD) patients is important with respect to their clinical outcomes and their response to therapy. The aim of this study was to perform functional tests on blood samples of a group of patients who were suspected of having MSMD.

Methods

This study was performed on 11 cases who had mycobacterial infections and suspected MSMD. Whole blood cell culture was performed in presence of different stimulators. The supernatants were assayed for IFN-γ, IL-12p40 by ELISA method.

Results

All patients presented with complications of BCG vaccine in the form of localised lymphadenitis or disseminated BCG infection and chronic mycobacterial osteomyelitis. Infections with Salmonella species occurred in two patients. In-vitro studies showed that 10 cases had impaired response to IL-12. However, the baseline levels of IL-12p40 were normal, while one of our patients may have a potential IFN-γ signalling defect or an IL-12p40 defect.

Conclusions

Early detection of MSMD and commencing of appropriate combination therapy could prevent severe or even fatal complications of uncontrolled mycobacterial infections.

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.