In the patients' cells, the allele is dominant-negative for γ-activated factor-mediated responses to interferon-γ, but not for interferon-stimulated gene factor-3-mediated responses to interferon-α/β, accounting for the clinical phenotype of Mendelian susceptibility to mycobacterial diseases without severe viral diseases.
Individuals with inherited disorders of interferon gamma (IFN-gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections.
Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-gamma-receptor (IFNgammaR1) deficiency: mutational analysis and evaluation of therapeutic options.
MSTs expanded from patients with primary immunodeficiency (PID) and invasive mycobacterial infections showed activity against mycobacterial antigens in only two of seven subjects, whereas both patients with IFN-γ autoantibodies recognized mycobacterial antigens.
Mutations of the gene encoding the signal transducing molecule STAT1, which impairs the ability to respond to IFNgamma, and mutations of the gene encoding TYK2 (which is associated with a failure to respond to IL12), are both rare genetic defects predisposing to mycobacterial infections.
On the other hand, patients with inborn errors in the IL12/IFNγ circuit may develop disseminated mycobacterial infections following perinatal BCG vaccination.
Patient had recurrence of mycobacterial disease during antibiotic therapy for which subcutaneous IFN-γ was added as a modality of treatment for resistant MAC infection.
Patients with IFN-γR deficiencies and other immune deficits predisposing to mycobacterial disease seem to have an increased risk of malignancies, especially those related to viral infections.
Previous studies identified the variant IFNG+874A/T (rs2430561) in the first intron of the gene in association with mycobacterial infection, especially tuberculosis and leprosy.
Rare disorders of either chain of the IFN-γ receptor, but not of IFN-γ itself, have been shown to confer predisposition to mycobacterial disease in patients otherwise normally resistant to most viruses.
Recently, recessive mutations in the interferon-gamma-receptor receptor ligand-binding chain, interferon-gamma-receptor signalling chain, IL-12 p40 subunit and IL-12-receptor beta 1 chain genes have been identified in a number of patients with disseminated mycobacterial infection.
Significant associations between mycobacterial infection and TNF-α production after stimulating peripheral blood mononuclear cells with LPS alone and with IFN-γ plus LPS were identified.
The interferon-gamma (IFN-gamma)/interleukin-12 (IL-12) pathway is a pivotal player in the immune system and is central to controlling mycobacterial infections.
The interleukin (IL)-12/interferon(IFN)γ axis plays an important role in the control of mycobacterial diseases as demonstrated by the increased susceptibility to mycobacterial species in patients with an inborn error of the IL-12-dependent IFNγ immunity.
The structure reveals the mechanism underlying deficits in IFNγ responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNγR2, which impairs assembly of the full signalling complex.