OBJECTIVE: Studies in mice and humans have implicated type I interferon (IFN-I) in the pathogenesis of lupus. Given that the locus for IFN-I is positioned within the Sle2 murine lupus susceptibility interval on chromosome 4, we undertook this study to investigate whether differences in IFN-I levels might potentially contribute to the phenotypes ascribed to this locus. METHODS: IFN-I, anti-IFN-I, isotype control antibody, or phosphate buffered saline was administered to C57BL/6 and B6.Sle2 mice, and the serologic and cellular phenotypes were studied. In addition, B6.Sle2 mice were examined for structural and expression polymorphisms in the IFN-I gene. RESULTS: In both B6.Sle2 congenic mice and C57BL/6 control mice, antibody-mediated blockade of IFN-I augmented serum autoantibody levels and boosted B1a cell numbers. Administration of IFN-I ameliorated these 2 features previously attributed to this disease locus. Importantly, compared with B6 controls, B6.Sle2 mice had reduced levels of IFN-I in their sera and cell culture supernatants, following stimulation. Although several sequence polymorphisms were noted in the Sle2 alleles of various IFN-I genes, it was not established whether any of the noted sequence variations were causally related to the observed phenotypes. CONCLUSION: Unexpectedly, reduction of IFN-I levels reproduced the serologic and cellular phenotypes previously associated with the Sle2 lupus susceptibility interval. Placing these findings in the context of other studies, the effect of IFN-I on systemic autoimmunity appears to be far more complex than originally perceived.
OBJECTIVE: Studies in mice and humans have implicated type I interferon (IFN-I) in the pathogenesis of lupus. Given that the locus for IFN-I is positioned within the Sle2murine lupus susceptibility interval on chromosome 4, we undertook this study to investigate whether differences in IFN-I levels might potentially contribute to the phenotypes ascribed to this locus. METHODS: IFN-I, anti-IFN-I, isotype control antibody, or phosphate buffered saline was administered to C57BL/6 and B6.Sle2mice, and the serologic and cellular phenotypes were studied. In addition, B6.Sle2mice were examined for structural and expression polymorphisms in the IFN-I gene. RESULTS: In both B6.Sle2 congenic mice and C57BL/6 control mice, antibody-mediated blockade of IFN-I augmented serum autoantibody levels and boosted B1a cell numbers. Administration of IFN-I ameliorated these 2 features previously attributed to this disease locus. Importantly, compared with B6 controls, B6.Sle2mice had reduced levels of IFN-I in their sera and cell culture supernatants, following stimulation. Although several sequence polymorphisms were noted in the Sle2 alleles of various IFN-I genes, it was not established whether any of the noted sequence variations were causally related to the observed phenotypes. CONCLUSION: Unexpectedly, reduction of IFN-I levels reproduced the serologic and cellular phenotypes previously associated with the Sle2 lupus susceptibility interval. Placing these findings in the context of other studies, the effect of IFN-I on systemic autoimmunity appears to be far more complex than originally perceived.
Authors: Uma Sriram; Linda Varghese; Heather L Bennett; Neelakshi R Jog; Debra K Shivers; Yue Ning; Edward M Behrens; Roberto Caricchio; Stefania Gallucci Journal: J Immunol Date: 2012-06-01 Impact factor: 5.422
Authors: Mari L Shinohara; Linrong Lu; Jing Bu; Miriam B F Werneck; Koichi S Kobayashi; Laurie H Glimcher; Harvey Cantor Journal: Nat Immunol Date: 2006-04-09 Impact factor: 25.606
Authors: Anna-Marie Fairhurst; Chun Xie; Yuyang Fu; Andrew Wang; Christopher Boudreaux; Xin J Zhou; Ricardo Cibotti; Anthony Coyle; John E Connolly; Edward K Wakeland; Chandra Mohan Journal: J Immunol Date: 2009-10-28 Impact factor: 5.422