Mendelian susceptibility to mycobacterial disease: recent discoveries

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. Affected patients are highly and selectively susceptible to weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines. Since 1996, disease-causing mutations have been reported in 15 genes, with allelic heterogeneity leading to 30 genetic disorders. Here, we briefly review the progress made in molecular, cellular, immunological, and clinical studies of MSMD since the last review published in 2018. Highlights include the discoveries of new genetic etiologies of MSMD: autosomal recessive (AR) complete deficiencies of (1) SPPL2a, (2) IL-12Rβ2, and (3) IL-23R, and (4) homozygosity for TYK2 P1104A, resulting in selective impairment of responses to IL-23. The penetrance of SPPL2a deficiency for MSMD is high, probably complete, whereas that of IL-12Rβ2 and IL-23R deficiencies, and TYK2 P1104A homozygosity, is incomplete, and probably low. SPPL2a deficiency has added weight to the notion that human cDC2 and Th1* cells are important for antimycobacterial immunity. Studies of IL-12Rβ2 and IL-23R deficiencies, and of homozygosity for P1104A TYK2, have shown that both IL-12 and IL-23 are required for optimal levels of IFN-γ. These recent findings illustrate how forward genetic studies of MSMD are continuing to shed light on the mechanisms of protective immunity to mycobacteria in humans.

Figure 1.. Number of patients with identified mutation in the genes involved in Mendelian susceptibility to mycobacterial disease (MSMD).

Patients with isolated or syndromic MSMD have been included in this figure, indicating in the X-axis the total number according to the different deficiency (Y-axis). The figure included the total number of patients with mutated genes of MSMD published between 1996 and 2019.