Anti-IFN-γ autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection.
We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-γ, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-γR2 or STAT1 deficiency.
By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes-granulocyte, in particular-reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease.
AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained.
Interferon-γ (IFN-γ) is a key molecule of T helper 1 (Th1)-immune response against tuberculosis (TB), and rare genetic defects of IFN-γ receptors cause disseminated mycobacterial infection.
This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients.
This case demonstrates the link between mycobacterial disease and IFN-γ pathway deficiency, the diagnosis of which facilitates more accurate therapy and genetic counseling.
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.
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.
However, despite these well-recognized predispositions to clinical disease with tuberculosis and nontuberculous mycobacteria, the genetic disorders that are relatively specific for mycobacterial infection with nontuberculous bacteria and bacille Calmette Guerin (BCG) involve the innate immune pathways, and all engage interferon gamma and IL-12 production, signaling, and availability.
Interferon-gamma is the most important cytokine in resistance to mycobacterial diseases and common variants of interferon-gamma gene could be related to tuberculosis susceptibility.
Interferon-gamma (IFN-gamma) plays a key role in the host defense response against mycobacterial disease, and a complete or partial deficiency in IFN-gamma receptor 1 (IFN-gammaR1) or IFN-gamma receptor 2 (IFN-gammaR2) has been reported to contribute to susceptibility to disseminated infection with non-tuberculous mycobacteria (NTM).
Human host genetic factors in nontuberculous mycobacterial infection: lessons from single gene disorders affecting innate and adaptive immunity and lessons from molecular defects in interferon-gamma-dependent signaling.
Also briefly summarized are updates on newly described leukocyte adhesion defects and on inherited susceptibility to mycobacterial infection due to defects in interleukin (IL)-12 and interferon-gamma pathways.
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.