Blockade Effects of Anti-Interferon- (IFN-) γ Autoantibodies on IFN-γ-Regulated Antimicrobial Immunity

Abstract

The interferon- (IFN-) γ expression is elicited in response to microbial infections and activates immune surveillance by antimicrobial immune elements to induce microbial killing. Patients with adult-onset immunodeficiency who suffer from recurrent infections with microbes, particularly nontuberculous mycobacteria (NTM), commonly display genetic defects in IFN-γ signaling as well as the generation of anti-IFN-γ autoantibodies (autoAbs). Because IFN-γ is an activator of macrophage differentiation and a proinflammatory activator of innate immunity, the blockade effects of the autoAbs present in NTM patient serum on IFN-γ are hypothesized to regulate the antimicrobial function of macrophages. In the presence of patient serum, IFN-γ-induced type 1 macrophage (M1) differentiation was inhibited in PMA-stimulated human monocytic THP-1 cells. Treatment with patient serum significantly blocked the production of proinflammatory factors, including cytokines/chemokines and reactive oxygen/nitrogen species, by M1 macrophages. Importantly, IFN-γ-facilitated phagocytosis and degradation of heat-killed mycobacterium were decreased by cotreatment with patient serum. These results show the blockade activity of anti-IFN-γ autoAbs on IFN-γ-mediated antimicrobial immunity in macrophages.

Oligodeoxynucleotides containing unmethylated cytosine-guanine motifs are effective immunostimulants against pneumococcal meningitis in the immunocompetent and neutropenic host

“…Moreover, pre-conditioning with CpG ODN increased the concentration of MIP-1α in the spleen of immunocompetent and of neutropenic wild-type animals suggesting that neutrophils are not essential for MIP-1α release upon CpG ODN immunostimulation. IFN-γ, known to be a strong stimulator of the phagocytosis of bacteria by macrophages [ 54 , 55 ], unlike in experimental E. coli meningitis [ 21 ] apparently did not play a major role in this model of S. pneumoniae meningitis, since spleen concentrations in most animals were low at 24 h after infection. CpG ODN also stimulates the release of other cytokines including IL-1, IL-6, IL-18, and TNF-α.…”

Minireview: Insights into anti-interferon-γ autoantibodies

“…These include IFN-γ-driven polarization and M1 macrophages activation, the production of cytokines, chemokines and inducible nitric oxide (iNO)/nitric oxide (NO), biosynthesis and reactive oxygen species (ROS) generation, and phagocytosis and degradation efficacy. 14,15 These studies clearly demonstrate that anti-IFN-γ AAbs with neutralizing activity can impede the binding of IFN-γ to its receptor, resulting in the absence of downstream signal transduction, directly affecting immune responses against intracellular pathogens.…”

“…These autoantibodies also inhibit the downstream biological consequences of IFN-γ binding which are the up-regulation of tumor necrosis factor (TNF)-α and interleukin (IL)-12 production. 14,15 Purified anti-IFN-γ AAbs is able to block the induction of IFN-γ-inducible genes and the upregulation of HLA class II expression on peripheral blood mononuclear cells. 16 Moreover, patients that were anti-IFN-γ AAbs positive could block IFN-γ-mediated antimicrobial immunity in monocytes and macrophages.…”

Talaromyces marneffei and nontuberculous mycobacteria co-infection in HIV-negative patients

“…IFN-γ is produced principally by T lymphocytes and natural killer cells after stimulation with microbial products and interleukin (IL)-12 20 . Patients with positive AIGAs often suffer from recurrent infections, especially due to NTM 8 , 9 , 11 .…”