The Journal of Experimental Medicine
BioSymposia
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Published 17 March 2003. doi:10.1084/jem.20021996
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© Rockefeller University Press, 0022-1007/2003/3/777 $5.00
The Journal of Experimental Medicine, Volume 197, Number 6, 777-788

Type-I Interferon Receptor Deficiency Reduces Lupus-like Disease in NZB Mice

Marie-Laure Santiago-Raber1, Roberto Baccala1, Katarina M. Haraldsson1, Divaker Choubey2, Timothy A. Stewart3, Dwight H. Kono1 and Argyrios N. Theofilopoulos1

1 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153
3 Department of Molecular Biology, Genentech, San Francisco, CA 94080

Address correspondence to Argyrios N. Theofilopoulos, Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd/IMM3, La Jolla, CA 92037. Phone: 858-784-8135; Fax: 858-784-8361; E-mail: argyrio{at}scripps.edu

Indirect evidence suggests that type-I interferons (IFN-{alpha}/ß) 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}/ßR, the common receptor for the multiple IFN-{alpha}/ß species. Compared with littermate controls, homozygous IFN-{alpha}/ßR-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}/ßR, 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.

Key Words: autoimmunity • hemolytic anemia • ifi202 • B-1 cells • dendritic cells


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