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Mendelian susceptibility to mycobacterial disease: recent discoveries

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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.

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Acknowledgements

I thank Jean-Laurent Casanova, Stéphanie Boisson-Dupuis, Jérémie Rosain, Anna-Lena Neehus and Laurent Abel for helpful discussions and support. I thank both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions. The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institute of Allergy and Infectious Diseases Grant no. 5R37AI095983, the Rockefeller University, the St. Giles Foundation, National Institute of Health and Medical Research (INSERM), Paris University, the Foundation for Medical Research (FRM), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency under the “Investments for the future” program (Grant no. ANR-10-IAHU-01) ANR-GENMSMD (ANR-16-CE17-0005-01 for JB), SRC 2017 (for JB) and ECOS Nord (C14S011 and C19S01-63407 for JB).

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  1. Imagine Institute, Paris University, Paris, France

    Jacinta Bustamante

  2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France

    Jacinta Bustamante

  3. Study Center for Primary Immunodeficiencies, AP-HP, Necker Children Hospital, Paris, France

    Jacinta Bustamante

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Bustamante, J. Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum Genet 139, 993–1000 (2020). https://doi.org/10.1007/s00439-020-02120-y

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