Ncf1-associated reduced oxidative burst promotes IL-33R+ T cell-mediated adjuvant-free arthritis in mice.
Reactive oxygen species (ROS) are important in the immune defense against invading pathogens, but they are also key molecules in the regulation of inflammatory reactions. Low levels of ROS production due to a polymorphism in the neutrophil cytosolic factor 1 (Ncf1) gene are associated with autoimmunity and arthritis severity in mouse models induced with adjuvant. We established an adjuvant-free arthritis model in which disease is induced by injection of the autoantigen collagen type II (CII) and depends on IL-5-producing T cells and eosinophils. In addition, the transgenic expression of mutated mouse CII allowed us to investigate an autoreactive immune response to an autologous Ag and by that natural tolerance mechanism. We show that a deficient ROS production, due to a spontaneous mutation in Ncf1, leads to increased autoantibody production and expansion of IL-33R-expressing T cells, impaired T cell tolerance toward tissue-specific CII, and severe arthritis in this unique model without disturbing adjuvant effects. These results demonstrate that the insufficient production of ROS promotes the breakdown of immune tolerance and development of autoimmune and adjuvant-free arthritis through an IL-5- and IL33R-dependent T cell activation pathway.
Hagenow
Kristin
K
Medical Inflammation Research, Lund University and Karolinska Institute, Stockholm, Sweden.
Gelderman
Kyra A
KA
Hultqvist
Malin
M
Merky
Patrick
P
Bäcklund
Johan
J
Frey
Oliver
O
Kamradt
Thomas
T
Holmdahl
Rikard
R
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000209:etiology* / Q000276:immunology; D024043:Collagen Type II / Q000008:administration & dosage / Q000009:adverse effects; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000378:metabolism*; D007378:Interleukins; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D016897:Respiratory Burst / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*
D024043:Collagen Type II; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D017382:Reactive Oxygen Species; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; C530318:ST2L protein, mouse; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1