Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature.
OBJECTIVE
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 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.


METHODS
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.


CONCLUSIONS
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.
1 Medicity Research Laboratory, University of Turku , Turku, Finland .
Tiina
T
Kelkka
Deborah
D
Kienhöfer
Markus
M
Hoffmann
Marjo
M
Linja
Kajsa
K
Wing
Outi
O
Sareila
Malin
M
Hultqvist
Essi
E
Laajala
Zhi
Z
Chen
Júlia
J
Vasconcelos
Esmeralda
E
Neves
Margarida
M
Guedes
Laura
L
Marques
Gerhard
G
Krönke
Merja
M
Helminen
Leena
L
Kainulainen
Peter
P
Olofsson
Sirpa
S
Jalkanen
Riitta
R
Lahesmaa
M Margarida
MM
Souto-Carneiro
Rikard
R
Holmdahl
D000293:Adolescent; D000328:Adult; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003176:Complement C3 / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000276:immunology*; D055815:Young Adult
D003176:Complement C3; D007074:Immunoglobulin G; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016899:Interferon-beta; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1