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Breaking tolerance to double stranded DNA, nucleosome, and other nuclear antigens is not required for the pathogenesis of lupus glomerulonephritis.

Waters ST, McDuffie M, Bagavant H, Deshmukh US, Gaskin F, Jiang C, Tung KS, Fu SM - J. Exp. Med. (2004)

Bottom Line: These data confirm the linkage analysis.The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non-anti-dsDNA nephritogenic Ab.These findings have significant implications in the pathogenesis of systemic lupus erythematosus.

View Article: PubMed Central - PubMed

Affiliation: The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

ABSTRACT
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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Marked reduction of circulating anti-dsDNA, antinuclear, and antinucleosome Ab in NZM.C57Lc1 and NZM.C57Lc4 congenic lines in comparison with NZM2328. Staining of HeLa cell nuclei by DAPI are seen in A, C, and E. The right side of the figure shows the presence of ANA in the serum of NZM2328 (B) but not in the sera of NZM.C57Lc1 (D) and NZM.C57Lc4 (F). Although not shown, the majority of the sera from C57L/J were not positive for ANA. On the bottom, frequencies of the presence of anti-dsDNA, antinuclear, and antihistone/DNA Ab in these strains are summarized.
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fig4: Marked reduction of circulating anti-dsDNA, antinuclear, and antinucleosome Ab in NZM.C57Lc1 and NZM.C57Lc4 congenic lines in comparison with NZM2328. Staining of HeLa cell nuclei by DAPI are seen in A, C, and E. The right side of the figure shows the presence of ANA in the serum of NZM2328 (B) but not in the sera of NZM.C57Lc1 (D) and NZM.C57Lc4 (F). Although not shown, the majority of the sera from C57L/J were not positive for ANA. On the bottom, frequencies of the presence of anti-dsDNA, antinuclear, and antihistone/DNA Ab in these strains are summarized.

Mentions: Sera from the terminal bleeds of female NZM2328 and its two congenic lines were analyzed for ANA, anti-dsDNA, and antinucleosome Ab. As shown in the top of Fig. 4 , ANAs were readily detected in the sera of NZM2328 and not in those of NZM.C57Lc1 and NZM.C57Lc4. The quantitative data of this study are summarized in the bottom of Fig. 4. At 1/50 dilution, 19.2% (5/26) of NZM.C57Lc1 sera and 4.5% (1/22) of NZM.C57Lc4 sera were positive for ANAs. 12% of the C57L/J sera at 12 mo of age were positive for ANAs. For comparison, 53.3% (24/45) of NZM2328 sera were positive for ANAs. Thus, there were marked reductions of ANAs in both NZM congenics. Similar marked reductions in circulating anti-dsDNA and antinucleosome (histone–DNA complexes) Abs were also detected in these two congenics. It is important to note that the incidences of these three autoantibodies were not significantly different from those in the nonlupus–prone strain C57L/J. In addition, the serum IgG concentrations of C57L/J, NZM2328, and its two congenics were similar.


Breaking tolerance to double stranded DNA, nucleosome, and other nuclear antigens is not required for the pathogenesis of lupus glomerulonephritis.

Waters ST, McDuffie M, Bagavant H, Deshmukh US, Gaskin F, Jiang C, Tung KS, Fu SM - J. Exp. Med. (2004)

Marked reduction of circulating anti-dsDNA, antinuclear, and antinucleosome Ab in NZM.C57Lc1 and NZM.C57Lc4 congenic lines in comparison with NZM2328. Staining of HeLa cell nuclei by DAPI are seen in A, C, and E. The right side of the figure shows the presence of ANA in the serum of NZM2328 (B) but not in the sera of NZM.C57Lc1 (D) and NZM.C57Lc4 (F). Although not shown, the majority of the sera from C57L/J were not positive for ANA. On the bottom, frequencies of the presence of anti-dsDNA, antinuclear, and antihistone/DNA Ab in these strains are summarized.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211766&req=5

fig4: Marked reduction of circulating anti-dsDNA, antinuclear, and antinucleosome Ab in NZM.C57Lc1 and NZM.C57Lc4 congenic lines in comparison with NZM2328. Staining of HeLa cell nuclei by DAPI are seen in A, C, and E. The right side of the figure shows the presence of ANA in the serum of NZM2328 (B) but not in the sera of NZM.C57Lc1 (D) and NZM.C57Lc4 (F). Although not shown, the majority of the sera from C57L/J were not positive for ANA. On the bottom, frequencies of the presence of anti-dsDNA, antinuclear, and antihistone/DNA Ab in these strains are summarized.
Mentions: Sera from the terminal bleeds of female NZM2328 and its two congenic lines were analyzed for ANA, anti-dsDNA, and antinucleosome Ab. As shown in the top of Fig. 4 , ANAs were readily detected in the sera of NZM2328 and not in those of NZM.C57Lc1 and NZM.C57Lc4. The quantitative data of this study are summarized in the bottom of Fig. 4. At 1/50 dilution, 19.2% (5/26) of NZM.C57Lc1 sera and 4.5% (1/22) of NZM.C57Lc4 sera were positive for ANAs. 12% of the C57L/J sera at 12 mo of age were positive for ANAs. For comparison, 53.3% (24/45) of NZM2328 sera were positive for ANAs. Thus, there were marked reductions of ANAs in both NZM congenics. Similar marked reductions in circulating anti-dsDNA and antinucleosome (histone–DNA complexes) Abs were also detected in these two congenics. It is important to note that the incidences of these three autoantibodies were not significantly different from those in the nonlupus–prone strain C57L/J. In addition, the serum IgG concentrations of C57L/J, NZM2328, and its two congenics were similar.

Bottom Line: These data confirm the linkage analysis.The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non-anti-dsDNA nephritogenic Ab.These findings have significant implications in the pathogenesis of systemic lupus erythematosus.

View Article: PubMed Central - PubMed

Affiliation: The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus