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Defects in the interferon-y/interleukin-12 dependent pathway: symptoms, diagnosis, treatment
Last reviewed: 07.07.2025
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Defects leading to disruption of the interferon-gamma (INF-y) and interleukin-12 (11-12)-dependent pathway are characterized by increased sensitivity to mycobacterial and some other infections (Salmonella, viruses).
Pathogenesis of defects of the interferon-y/interleukin-12 dependent pathway
Mycobacteria engulfed by macrophages stimulate the production of IL-12. IL-12 stimulates T-lymphocytes and NK cells and causes the production of INF-y. The latter activates macrophages and enhances the killing of mycobacteria. Defects in these cytokines, cellular receptors for them, and proteins that transmit signals from the receptor into the cell lead to specific sensitivity to certain pathogens.
Symptoms of interferon-y/interleukin-12 dependent pathway defects
Clinical manifestations in patients with various genetic defects are largely similar. After BCG vaccination, patients develop disseminated infection. In the absence of vaccination at an older age (1-3 years), pulmonary or generalized infections caused by meteotuberculosis mycobacteria or Salmonella are observed.
In all cases of mycobacterial infection, patients had fever, weight loss, lymphadenopathy, hepatosplenomegaly, and chronic anemia. Many patients had lesions of specific organs. In addition, several patients have described conditions such as bronchial asthma, vasculitis, and glomerulonephritis. However, it is not possible at this stage to establish a reliable pathogenetic connection between these conditions and the defect in the INF-y/IL-12 pathway.
Diagnostics
Patients with the above defects do not show quantitative and qualitative laboratory changes in the cellular and humoral links of immunity. The diagnosis is confirmed by identifying the corresponding mutation in patients with a typical clinical picture.
Treatment of defects of the interferon-y/interleukin-12 dependent pathway
HSCT is potentially the treatment of choice in these patients, but the relevant world experience is extremely limited. Patients should avoid contact with people suffering from tuberculosis, leprosy and other infections caused by intracellular pathogens. Preventive anti-tuberculosis therapy may be prescribed. BCG vaccination is strictly contraindicated in such patients. In case of mycobacterium infection, therapy is carried out with 4 drugs. It is necessary to determine the sensitivity of the pathogen with particular care, due to the high level of resistance in this group of pathogens. There are reports on the use of INF-alpha, as well as INF-a, IL-12 with a partial clinical effect.
Forecast
In case of infection with BCG or mycobacteria, the prognosis is extremely unfavorable. The prognosis largely depends on the dose of the infecting pathogen and early diagnosis.
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