Ameliorated course of glucose-6-phosphate isomerase (G6PI)-induced arthritis in IFN-γ receptor knockout mice exposes an arthritis-promoting role of IFN-γ.
The absence of IFN-γ signaling leads to an increased inflammatory response in many murine models of autoimmune diseases induced by a CFA-assisted immunization schedule. We investigated the role of endogenous IFN-γ in arthritis induced by immunization with glucose-6-phosphate isomerase (G6PI) in CFA in DBA/1 mice. Surprisingly, and in contrast to our previous findings in collagen-induced arthritis (CIA), G6PI-induced arthritis was found to be reduced in IFN-γ receptor-deficient (IFN-γR KO) mice, demonstrating a proinflammatory role for IFN-γ in this model. Milder disease in IFN-γR KO mice was associated with less vigorous innate and adaptive immune responses early (day 9) after immunization: less proliferation of myeloid cells in the spleen, less osteoclast formation, less G6PI-reactive Th cells (as measured by ex vivo stimulation and flow cytometry and by in vivo skin reactivity to G6PI) and lower G6PI-specific immunoglobulin serum levels. Surprisingly, on day 21, despite continued milder disease in IFN-γR KO mice, their Th cell responses were no longer diminished but augmented as compared to wild-type mice, and their numbers of immature myeloid splenocytes were also more increased. These data reveal that IFN-γ signaling is critical for the induction of the early immune responses which trigger G6PI-induced arthritis. The strikingly different clinical consequences of absent IFN-γ signaling in G6PI-induced arthritis compared with the very similarly induced CIA emphasize that the role of a single cytokine in experimentally induced arthritis depends critically on the very nature of the inciting (auto)antigen and in particular on the kinetics of the disease manifestation elicited by the antigen.
Institute of Immunology, Jena University Hospital, Jena, Germany.
Oliver
O
Frey
Tania
T
Mitera
Hilde
H
Kelchtermans
Evelien
E
Schurgers
Thomas
T
Kamradt
Patrick
P
Matthys
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D005956:Glucose-6-Phosphate Isomerase / Q000008:administration & dosage / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000096743:Interferon gamma Receptor
D005956:Glucose-6-Phosphate Isomerase; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor