Mendelian susceptibility to mycobacterial disease: IFN-γ-driven immunity collapse underlies heterogeneous infections

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare inborn error of immunity characterized by heightened susceptibility to low-virulence non-tuberculous mycobacteria. Despite the widespread application of next-generation sequencing, the molecular etiology of approximately 50% of patients remains elusive. To date, 22 genes have been implicated, all converging on the IL-12/23-IFN-γ circuit, underscoring its non-redundant role in controlling intracellular pathogens. Isolated MSMD is characterized by a selective predisposition to one or more mycobacterial and related infections. But syndromic MSMD's clinical phenotypes are highly heterogeneous; apart from mycobacterial infections, patients may suffer from viral, bacterial, or fungal diseases, and can additionally manifest auto-inflammation, malignancy, or cutaneous involvement. Current MSMD management mainly hinges on prolonged antimicrobial therapy or align with recombinant human interferon-γ (rhIFN-γ), although allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative yet high-risk option; gene editing is still experimental. Priorities are early high-risk identification, targeted intervention and full-process management.