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Reactive Oxygen Species Deficiency Induces Autoimmunity with Type 1 Interferon Signature

2014; Mary Ann Liebert, Inc.; Volume: 21; Issue: 16 Linguagem: Inglês

10.1089/ars.2013.5828

1557-7716

Tiina Kelkka, Deborah Kienhöfer, Markus Hoffmann, Marjo Linja, Kajsa Wing, Outi Sareila, Malin Hultqvist, Essi Laajala, Zhi Chen, Júlia Vasconcelos, Esmeralda Neves, Margarida Guedes, Lino Marques, Gerhard Krönke, Merja Helminen, Leena Kainulainen, Peter Olofsson, Sirpa Jalkanen, Riitta Lahesmaa, Margarida Souto‐Carneiro, Rikard Holmdahl,

Immune Response and Inflammation

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation.A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin.Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans.We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.