title: Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production.
abstract: Chronic granulomatous disease (CGD) is a primary immunodeficiency defined by mutations in the NADPH oxidase complex leading to reduced superoxide production, increased susceptibility to infection, chronic inflammation, and recurring abscess and granuloma formation. Here, we found that CGD mice were hyperresponsive to abscess-inducing T-cell-dependent carbohydrate antigens (glycoantigens) due to a ten-fold increase in NO production within APCs, which is known to be necessary for glycoantigen presentation on MHC class II. CGD mice exhibited increased Th1 pro-inflammatory T-cell responses in vitro and in vivo, characterized by more severe abscess pathology. This phenotype was also seen in WT animals following adoptive transfer of neutrophil-depleted APCs from CGD animals, demonstrating that this phenotype was independent of neutrophil and T-cell defects. Finally, pharmacological attenuation of NO production to WT levels in vivo reduced abscess incidence and severity in CGD without overt increases in inflammation or the ability to clear infection, suggesting a potential new treatment option for early stage CGD-associated infections.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Colleen J
authors.initials: CJ
authors.lastname: Lewis
authors.forename: Brian A
authors.initials: BA
authors.lastname: Cobb
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000235:genetics; D019264:Adoptive Transfer; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D006099:Granuloma; D006105:Granulomatous Disease, Chronic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D000578:Amidines; D001596:Benzylamines; D006023:Glycoproteins; D008562:Membrane Glycoproteins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases