Laboratory evaluation of the IFN-γ circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease

Abstract

The integrity of the interferon (IFN)-γ circuit is necessary to mount an effective immune response to intra-macrophagic pathogens, especially Mycobacteria. Inherited monogenic defects in this circuit that disrupt the production of, or response to, IFN-γ underlie a primary immunodeficiency known as Mendelian susceptibility to mycobacterial disease (MSMD). Otherwise healthy patients display a selective susceptibility to clinical disease caused by poorly virulent mycobacteria such as BCG (bacille Calmette-Guérin) vaccines and environmental mycobacteria, and more rarely by other intra-macrophagic pathogens, particularly Salmonella and M. tuberculosis. There is high genetic and allelic heterogeneity, with 19 genetic etiologies due to mutations in 10 genes that account for only about half of the patients reported. An efficient laboratory diagnostic approach to suspected MSMD patients is important, because it enables the establishment of specific therapeutic measures that will improve the patient's prognosis and quality of life. Moreover, it is essential to offer genetic counseling to affected families. Herein, we review the various genetic and immunological diagnostic approaches that can be used in concert to reach a molecular and cellular diagnosis in patients with MSMD.

Inherited human IFN-γ deficiency underlies mycobacterial disease

“…Furthermore, the retroviral transduction of P1 cells with the WT IFNG cDNA rescued the cellular phenotype, whereas transduction with an empty plasmid or vector (EV) did not ( Figure 4A). We studied the functional consequences of the homozygous IFNG mutation in primary lymphocytes by measuring cytokine secretion in whole-blood assays (72,73). After stimulation with BCG plus IL-12, the whole blood of healthy controls secreted large amounts of IFN-γ.…”

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

“…Informed consent forms were signed by patients and/or their parents, as requested and approved by the institutional review board. Whole-blood activation was performed as previously described [39, 40]. IFN-γ secretion was assessed with phytohemagglutinin (PHA)-IL-2 activated T cells.…”

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

“…Other infectious diseases have also been reported, albeit more rarely . Acquired and inherited immunodeficiencies conferring a predisposition to mycobacterial diseases in the context of other infections must first be excluded, before a diagnosis of MSMD can be reached . The most severe forms of MSMD lead to early‐onset, disseminated, persistent, life‐threatening mycobacterial disease, whereas the least severe forms can have a late onset, be relatively circumscribed, spontaneously improve with age, or even remain clinically silent because of incomplete penetrance .…”