title: Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice.
abstract: Indirect evidence suggests that type-I interferons (IFN-alpha/beta) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the alpha-chain of IFN-alpha/betaR, the common receptor for the multiple IFN-alpha/beta species. Compared with littermate controls, homozygous IFN-alpha/betaR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-alpha/betaR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Santiago-Raber
authors.forename: Roberto
authors.initials: R
authors.lastname: Baccala
authors.forename: Katarina M
authors.initials: KM
authors.lastname: Haraldsson
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Stewart
authors.forename: Dwight H
authors.initials: DH
authors.lastname: Kono
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
mesh_terms: D000818:Animals; D000921:Antibody-Producing Cells / Q000378:metabolism; D004247:DNA / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000628:therapy; D016131:Lymphocyte Subsets; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate
chemical_list: D007136:Immunoglobulins; D016898:Interferon-alpha; D008565:Membrane Proteins; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D004247:DNA