Abstract
BackgroundMendelian Susceptibility to Mycobacterial Disease (MSMD) is a primary immunodeficiency (PID) characterised by a predisposition to infection by weakly-pathogenic mycobacteria. In countries with a high prevalence of tuberculosis (TB), individuals with MSMD are also prone to infections by Mycobacterium tuberculosis. Several MSMD-associated genes have been described, all resulting in a disruption of IL-12 and IFN-γ cytokine axis, which is essential for control of mycobacterial infections. An accurate molecular diagnosis, confirmed by phenotypic and functional immune investigations, is essential to ensure that the patient receives optimal treatment and prophylaxis for infections. The aim of this study was to implement a set of functional assays to assess the integrity of the IL-12-IFN-γ cytokine pathways in patients presenting with severe, persistent, unusual and/or recurrent TB, mycobacterial infections or other clinical MSMD-defining infections such as Salmonella.MethodsBlood was collected for subsequent PBMC isolation from 16 participants with MSMD-like clinical phenotypes. A set of flow cytometry (phenotype and signalling integrity) and ELISA-based (cytokine production) functional assays were implemented to assess the integrity of the IL-12-IFN-γ pathway.ResultsThe combination of the three assays for the assessment of the integrity of the IL-12-IFN-γ pathway was successful in identifying immune deficits in the IL-12-IFN-γ pathway in all of the participants included in this study.ConclusionsThe data presented here emphasise the importance of investigating PID and TB susceptibility in TB endemic regions such as South Africa as MSMD and other previously described PIDs relating to TB susceptibility may present differently in such regions. It is therefore important to have access to in vitro functional investigations to better understand the immune function of these individuals. Although functional assays alone are unlikely to always provide a clear diagnosis, they do give an overview of the integrity of the IL-12-IFN-γ pathway. It would be beneficial to apply these assays routinely to patients with suspected PID relating to mycobacterial susceptibility. A molecular diagnosis with confirmed functional impairment paves the way for targeted treatment and improved disease management options for these patients.
Highlights
South Africa is among the countries with the highest burden of tuberculosis (TB) [1] and primary immunodeficiencies (PIDs) that relate to susceptibility to mycobacterial infection, such as Mendelian Susceptibility to Mycobacterial Disease (MSMD), are of particular relevance
Non-tuberculous mycobacterial infections were confirmed in only 1 case, PID01 (M. avium)
The overall goal of this study was to determine whether the combination of functional assays, which have previously been used in isolation to describe MSMD related defects, could be applied to aid in the diagnosis of suspected MSMD in South Africa where these patients generally have a different clinical presentation (SPUR TB) than what was originally defined as MSMD (BCG and non-tuberculous Mycobacteria)
Summary
South Africa is among the countries with the highest burden of tuberculosis (TB) [1] and primary immunodeficiencies (PIDs) that relate to susceptibility to mycobacterial infection, such as Mendelian Susceptibility to Mycobacterial Disease (MSMD), are of particular relevance. Fifteen MSMD-associated genes have been described, and mutations in these MSMD-associated genes are associated with a disruption in IFN-γ immunity, which is essential for the control of mycobacterial infections [2, 3, 6, 9,10,11,12,13,14,15,16]. The heterogeneity of these genes result in at least 30 distinct disorders, which vary in their mode of inheritance and clinical presentation [12,13,14]. The aim of this study was to implement a set of functional assays to assess the integrity of the IL-12-IFN-γ cytokine pathways in patients presenting with severe, persistent, unusual and/or recurrent TB, mycobacterial infections or other clinical MSMD-defining infections such as Salmonella
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