Functional Testing of the IL-12/IFN-γ Circuit

The integrity of the IL-12/IFN-γ circuit is necessary to mount an effective immune response against intramacrophagic pathogens, especially Mycobacteria. Inherited monogenic defects in this circuit, which disrupts the production of, or response to, IFN-γ underlie a group of inborn errors of immunity known as Mendelian Susceptibility to Mycobacterial Disease (MSMD). Otherwise healthy patients with MSMD 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 intramacrophagic pathogens, particularly Salmonella and M. tuberculosis. An efficient laboratory diagnostic approach to patients with suspected MSMD is important, enabling the establishment of specific therapeutic measures that will improve patient's prognosis and quality of life. Herein, we review the various diagnostic approaches that can be used in concert to reach a molecular and cellular diagnosis in patients with defects on the IL-12/INF-γ circuit. We have included classic functional and genetic assays, advanced functional analysis and specific-disease tests. A diagnostic algorithm is proposed.