ImmunologyTier 1Medical Sciences concept

IL-12/IFN-gamma axis defects and susceptibility to mycobacterial infection

Core concept

```

Macrophage phagocytoses mycobacterium

  • -> IL-12 (p40+p35) released
  • -> IL-12R-beta1/beta2 on T and NK cells
  • -> STAT4 -> Th1 differentiation
  • -> IFN-gamma
  • -> IFN-gamma-R1/R2 on macrophage -> JAK1/JAK2 -> STAT1 -> GAS elements
  • -> inc phagosome-lysosome fusion, inc reactive nitrogen species, inc killing, granuloma maintenance

```

  • Break any step -> Mendelian Susceptibility to Mycobacterial Disease (MSMD)
  • The phenotype is remarkably narrow: weakly virulent mycobacteria (BCG, environmental NTM), Salmonella, and not the broad infection susceptibility of a combined immunodeficiency

Key detail

DefectInheritancePhenotype
IL12RB1ARCommonest MSMD gene worldwide; BCG-osis, NTM, salmonellosis; variable penetrance, many survive to adulthood
IL12B (p40)ARAs above
IFNGR1 / IFNGR2 completeARMost severe - early disseminated BCG/NTM, poorly formed, multibacillary "lepromatous-like" granulomas, does not respond to IFN-gamma
IFNGR1 partial (dominant negative)ADMilder, tuberculoid granulomas, osteomyelitis, responds to IFN-gamma
STAT1 loss-of-functionAR/ADMycobacterial +/- viral susceptibility (STAT1 also serves IFN-alpha/beta)
STAT1 GAIN-of-functionADChronic mucocutaneous candidiasis (Th17 suppressed) - the mirror image, and a common exam distractor
CYBB, NEMO, RORC, TYK2, ISG15, SPPL2AVariousOther MSMD genes
  • Acquired phenocopy: anti-IFN-gamma neutralising autoantibodies
    • Adult-onset disseminated NTM, salmonella and other intracellular infection
    • *Strongly associated with HLA-DRB116:02/DQB105:02 and with people of South-East Asian origin*
    • In an adult with disseminated NTM and no HIV, this is the diagnosis to think of
  • The same axis is the target of anti-TNF therapy: TNF is required to maintain granuloma integrity -> infliximab/adalimumab -> reactivation TB, often disseminated or extrapulmonary

Clinical relevance

  • Disseminated BCG after routine vaccination, or NTM disease in a child with a normal HIV test, mandates MSMD work-up
    • Lymphocyte subsets are typically normal - request functional testing (IFN-gamma production after IL-12 stimulation, STAT1 phosphorylation) and genetic panel
    • A normal FBC and normal immunoglobulins do not exclude MSMD
  • Do not give BCG (or any live vaccine) to a sibling until MSMD is excluded
  • Treatment: prolonged multi-drug antimycobacterial therapy, adjunctive subcutaneous IFN-gamma where the receptor is intact, HSCT for complete IFN-gammaR deficiency
  • Anti-IFN-gamma autoantibody syndrome - antimycobacterials plus B-cell depletion (rituximab)
  • Screen and treat latent TB before starting anti-TNF therapy - this axis is why

Correlations1 exam ›

  • Granuloma formation - cell types and mechanism
  • NF-kB pathway defects and immunodeficiency
  • Multidrug-resistant tuberculosis; non-tuberculous mycobacteria
  • Biologic drug treatments - anti-TNF and infection risk
  • Chronic granulomatous disease

4 of 4 sections written · drafted 2026-09-04