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

J Exp Med. 2003 Mar 17;197(6):777-88. doi: 10.1084/jem.20021996.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibody-Producing Cells / metabolism
  • DNA / immunology
  • Dendritic Cells / physiology
  • Female
  • Humans
  • Immunoglobulins / metabolism
  • Interferon-alpha / metabolism
  • Interferon-beta / metabolism
  • Kidney / cytology
  • Kidney / metabolism
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / therapy
  • Lymphocyte Subsets
  • Membrane Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NZB
  • Mice, Knockout
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism*
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism
  • Survival Rate

Substances

  • Immunoglobulins
  • Interferon-alpha
  • Membrane Proteins
  • Receptors, Interferon
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • DNA