Rat anti Mouse IFNGR1 monoclonal antibody, clone 281022

IL-12/23-interferon-gamma circuit enhances reactive oxygen species (ROS) synthesis in macrophage to attack intracellular pathogens such as mycobacteria and salmonella. Defective ROS in patients with chronic granulomatous disease (CGD) have increased susceptibility to these pathogens. However, patients with defective IL-12/23-interferon-gamma circuit rather than CGD are not recognized in Taiwan, endemic for tuberculosis and salmonella. The purpose of this study was to identify Taiwanese patients with defective IL-12/23-IFN-gamma circuit. In a long-term molecular study of primary immunodeficiency diseases (PIDD), the tentative CGD patients presenting with Bacille Calmette-Guerin (BCG)-induced infection, refractory atypical mycobacterial cutaneous granuloma and osteomyelitis, recurrent salmonella sepsis, and pneumatocele were studied for the IL-12/23-IFN-gamma circuit. ROS was first measured to exclude CGD. Candidate genes of IL12RB1, IFNRG1, IL12p40, IFNRG2, signal transducer and activator of transcription-1, and NF-kappa B essential modulator and their encoding protein expressions were analyzed. Of the 175 Taiwanese PIDD patients during a 28-year period, three patients from two unrelated families were identified with the hotspot INFRG1 deletion mutation (818del4) and had CGD features, presenting as cutaneous granuloma, and multiple osteomyelitis infected by non-tuberculosis mycobacteria, Mycobacteria avium complex and Mycobacterium scrofulaceum. Another with mis-sense IL12RB1 mutation (Arg211Pro) was noted as recurrent Salmonella enteritidis D sepsis and pneumatocele. Patients with defective IL-12/23-IFN-gamma circuit may resemble or overlap CGD manifestations of refractory cutaneous atypical mycobacterial granuloma and salmonella pneumatocele.

Imaging biomarkers for immune activation may be valuable for early-stage detection, therapeutic testing, and research on neurodegenerative conditions. In the present study, we determined whether diffusion magnetic resonance imaging-derived free water signal is a sensitive marker for neuroinflammatory effects of interferon-gamma (Ifn-gamma). Neonatal wild-type mice were injected in the cerebral ventricles with recombinant adeno-associated viruses expressing the inflammatory cytokine Ifn-gamma. Groups of mice expressing Ifn-gamma and age-matched controls were imaged at 1, 5 and 8 months. Mice deficient in Ifngr1(-/-) and Stat1(-/-) were scanned at 5 months as controls for the signaling cascades activated by Ifn-gamma. The results indicate that Ifn-gamma affected fractional anisotropy (FA), mean diffusivity (MD), and free water (FW) in white matter structures, midline cortical areas, and medial thalamic areas. In these structures, FA and MD decreased progressively from 1 to 8 months of age, while FW increased significantly. The observed reductions in FA and MD and increased FW with elevated brain Ifn-gamma was not observed in Ifngr1(-/-) or Stat1(-/-) mice. These results suggest that the observed microstructure changes involve the Ifn-gr1 and Stat1 signaling. Interestingly, increases in FW were observed in midbrain of Ifngr1(-/-) mice, which suggests alternative Ifn-gamma signaling in midbrain. Although initial evidence is offered in relation to the sensitivity of the FW signal to neurodegenerative and/or inflammatory patterns specific to Ifn-gamma, further research is needed to determine applicability and specificity across animal models of neuroinflammatory and degenerative disorders.