期刊
ANTIOXIDANTS & REDOX SIGNALING
卷 21, 期 16, 页码 2231-2245出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2013.5828
关键词
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资金
- Academy, Sigrid Juselius Foundation
- Swedish Research Council
- Academy of Finland Center of Excellence in Molecular Systems Immunology and Physiology Research [250114]
- European Community [Health-F2-2011-278611, HEALTH-F2-2008-223404, LSHM-CT-2005-018661]
- IMI program BeTheCure
- Nordic Center of Excellence in Disease Genetics
- Marie Curie grant [PERG-GA-2008-239422-BNOX]
- ELAN-program of the University clinic Erlangen
- Staedler Stiftung
- Austrian Science Fund (FWF) [J3102-B13]
- Austrian Science Fund (FWF) [J 3102] Funding Source: researchfish
- Austrian Science Fund (FWF) [J3102] Funding Source: Austrian Science Fund (FWF)
Aims: 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. Results: 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 naive 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. Innovation: 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. Conclusion: 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.
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