Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice

ML Santiago-Raber, R Baccala… - The Journal of …, 2003 - rupress.org
ML Santiago-Raber, R Baccala, KM Haraldsson, D Choubey, TA Stewart, DH Kono…
The Journal of experimental medicine, 2003rupress.org
Indirect evidence suggests that type-I interferons (IFN-α/β) 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 α-chain of IFN-α/βR, the common receptor for the
multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-deleted
NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis,
hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions …
Indirect evidence suggests that type-I interferons (IFN-α/β) 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 α-chain of IFN-α/βR, the common receptor for the multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-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-α/βR, 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.
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