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.
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19 January 2004
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January 12 2004
Breaking Tolerance to Double Stranded DNA, Nucleosome, and Other Nuclear Antigens Is Not Required for the Pathogenesis of Lupus Glomerulonephritis
Samuel T. Waters,
Samuel T. Waters
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
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Marcia McDuffie,
Marcia McDuffie
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
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Harini Bagavant,
Harini Bagavant
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
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Umesh S. Deshmukh,
Umesh S. Deshmukh
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
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Felicia Gaskin,
Felicia Gaskin
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
4Department of Psychiatric Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
5Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA 22908
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Chao Jiang,
Chao Jiang
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
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Kenneth S.K. Tung,
Kenneth S.K. Tung
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908
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Shu Man Fu
Shu Man Fu
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
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Samuel T. Waters
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
Marcia McDuffie
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
Harini Bagavant
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
Umesh S. Deshmukh
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
Felicia Gaskin
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
4Department of Psychiatric Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
5Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA 22908
Chao Jiang
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
Kenneth S.K. Tung
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908
Shu Man Fu
1The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908
2Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908
3Department of Microbiology, 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: [email protected]
This work was presented in abstract form at the ACR 64th Annual Scientific Meeting at Philadelphia, PA in November, 2000 (Arthritis Rheum. 43:S361).
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.
Received:
September 03 2003
Accepted:
November 06 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2004
J Exp Med (2004) 199 (2): 255–264.
Article history
Received:
September 03 2003
Accepted:
November 06 2003
Citation
Samuel T. Waters, Marcia McDuffie, Harini Bagavant, Umesh S. Deshmukh, Felicia Gaskin, Chao Jiang, Kenneth S.K. Tung, Shu Man Fu; Breaking Tolerance to Double Stranded DNA, Nucleosome, and Other Nuclear Antigens Is Not Required for the Pathogenesis of Lupus Glomerulonephritis . J Exp Med 19 January 2004; 199 (2): 255–264. doi: https://doi.org/10.1084/jem.20031519
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