IFN-α confers resistance of systemic lupus erythematosus nephritis to therapy in NZB/W F1 mice

Zheng Liu, Ramalingam Bethunaickan, Weiqing Huang, Meera Ramanujam, Michael P. Madaio, Anne Davidson

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Abstract

The critical role of IFN-α in the pathogenesis of human systemic lupus erythematosus has been highlighted in recent years. Exposure of young lupus-prone NZB/W F1 mice to IFN-α in vivo leads to an accelerated lupus phenotype that is dependent on T cells and is associated with elevated serum levels of BAFF, IL-6, and TNF-α, increased splenic expression of IL-6 and IL-21, formation of large germinal centers, and the generation of large numbers of short-lived plasma cells that produce IgG2a and IgG3 autoantibodies. In this study, we show that both IgG2a and IgG3 autoantibodies are pathogenic in IFN-α - accelerated lupus, and their production can be dissociated by using low-dose CTLA4-Ig. Only high-dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody production and significantly delays death from lupus nephritis. In contrast, BAFF/APRIL blockade has no effect on germinal centers or the production of IgG anti-dsDNA Abs but, if given at the time of IFN-α challenge, delays the progression of lupus by attenuating systemic and renal inflammation. Temporary remission of nephritis induced by combination therapy with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal centers and depletion of shortlived plasma cells, but relapse occurs more rapidly than in conventional NZB/W F1 mice. This study demonstrates that IFN-α renders NZB/W F1 relatively resistant to therapeutic intervention and suggests that the IFN signature should be considered when randomizing patients into groups and analyzing the results of human clinical trials in systemic lupus erythematosus.

Original languageEnglish (US)
Pages (from-to)1506-1513
Number of pages8
JournalJournal of Immunology
Volume187
Issue number3
DOIs
StatePublished - Aug 1 2011

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Liu, Z., Bethunaickan, R., Huang, W., Ramanujam, M., Madaio, M. P., & Davidson, A. (2011). IFN-α confers resistance of systemic lupus erythematosus nephritis to therapy in NZB/W F1 mice. Journal of Immunology, 187(3), 1506-1513. https://doi.org/10.4049/jimmunol.1004142