Four children with severe mycobacterial infections had a mutation in the gene for interferon-gamma receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor alpha by macrophages in response to interferon-gamma.
Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12-independent IFN-gamma secretion.
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.
Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-gamma-receptor (IFNgammaR1) deficiency: mutational analysis and evaluation of therapeutic options.
These results demonstrate that the granulomas in the areas of mycobacterial infection are active sites of both inflammation and fibrosis, and that the local expression of IFN-gamma by the recombinant BCG results in more efficient bacterial clearance which is accompanied by a reduction in tissue pathology.
Individuals with inherited disorders of interferon gamma (IFN-gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections.
We have found that children with complete interferon gamma (IFNgamma) receptor deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNgamma in their plasma.
Interferon-gamma mediates immunity to mycobacteria and rare mutations in the interferon-gamma receptor-1 gene (IFNGR1) result in increased susceptibility to mycobacterial infection, including TB, in affected families.
These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency).
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.
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.
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.
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).
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.
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.
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.