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¹ The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
² Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
³ Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
⁴ Department of Psychiatric Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
⁵ Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA 22908
⁶ Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908

Address correspondence to Shu Man Fu, Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia School of Medicine, Box 800412, Charlottesville, VA 22908. Phone: (434) 924-9627; Fax: (434) 924-9578; email: sf2e{at}virginia.edu

In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti–double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (NZM.C57Lc1) and NZM2328.C57L/Jc4 (NZM.C57Lc4), were generated by replacing the respective genetic intervals containing either Cgnz1 or Adnz1 with those from C57L/J, a nonlupus-prone strain. The NZM.C57Lc1 females had markedly reduced incidence of chronic glomerulonephritis and severe proteinuria. NZM.C57Lc4 females had chronic glomerulonephritis and severe proteinuria without circulating ANA, anti-dsDNA, and antinucleosome Ab. These data confirm the linkage analysis. Unexpectedly, NZM.C57Lc1 females had little anti-dsDNA and related Ab, suggesting the presence of a second locus Adnz2 on chromosome 1. The diseased NZM.C57Lc4 kidneys had immune complexes by immunofluorescence and electron microscopy. The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non–anti-dsDNA nephritogenic Ab. Thus, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of lupus nephritis. These results reaffirm that anti-dsDNA and related Ab production and chronic glomerulonephritis are under independent genetic control. These findings have significant implications in the pathogenesis of systemic lupus erythematosus.

Key Words: lupus autoantibodies • glomerulonephritis • NZM2328 • genetics

Abbreviations used in this paper: ANA, antinuclear Ab; dsDNA, double stranded DNA; EM, electron microscopic; NZM.C57Lc1, NZM2328.C57L/Jc1; NZM.C57Lc4, NZM2328.C57L/Jc4; SLE, systemic lupus erythematosus.

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