Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature

Kelkka T, Kienhoefer D, Hoffmann M, Linja M, Wing K, Sareila O, Hultqvist M, Laajala E, Chen Z, Vasconcelos J, Neves E, Guedes M, Marques L, Krönke G, Helminen M, Kainulainen L, Olofsson P, Jalkanen S, Lahesmaa R, Margarida Souto-Carneiro M, Holmdahl R (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Antioxidants & Redox Signaling Mary Ann Liebert

Publisher: Mary Ann Liebert

Book Volume: 21

Pages Range: 2231-45

Journal Issue: 16

DOI: 10.1089/ars.2013.5828

Abstract

Abstract 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.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. Antioxid. Redox Signal. 21, 2231-2245.

Authors with CRIS profile

Markus Hoffmann Department of Medicine 3 – Rheumatology and Immunology Gerhard Krönke Professur für Translationale Immunologie

Involved external institutions

University of Turku / Turun yliopisto FI Finland (FI) Karolinska Institute SE Sweden (SE) Redoxis AB SE Sweden (SE) Centro Hospitalar do Porto PT Portugal (PT) Tampere University Hospital / Tampereen yliopistollinen sairaala (TAYS) FI Finland (FI) Turku University Hospital / Turun yliopistollinen keskussairaala (TYKS) FI Finland (FI) Universidade de Coimbra PT Portugal (PT)

How to cite

APA:

Kelkka, T., Kienhoefer, D., Hoffmann, M., Linja, M., Wing, K., Sareila, O.,... Holmdahl, R. (2014). Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature. Antioxidants & Redox Signaling, 21(16), 2231-45. https://doi.org/10.1089/ars.2013.5828

MLA:

Kelkka, Tiina, et al. "Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature." Antioxidants & Redox Signaling 21.16 (2014): 2231-45.

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