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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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Related in: MedlinePlus

Lack of RF in sera of NZM2328 and its congenics. Human IgG was used as the substrate in A and C to detect anti-IgG activities. Mouse sera were used at a dilution of 1:50 for A and 1:250 for C. Rabbit IgG was used as the substrate in B and D with mouse sera diluted at 1:50 and 1:250, respectively. A pool of MRL/lpr+/+sera was used as a positive control showing readily detectable RF in this strain of mice.
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fig5: Lack of RF in sera of NZM2328 and its congenics. Human IgG was used as the substrate in A and C to detect anti-IgG activities. Mouse sera were used at a dilution of 1:50 for A and 1:250 for C. Rabbit IgG was used as the substrate in B and D with mouse sera diluted at 1:50 and 1:250, respectively. A pool of MRL/lpr+/+sera was used as a positive control showing readily detectable RF in this strain of mice.

Mentions: The sera from NZM2328, NZM.-C57Lc1, and NZM.C57Lc4 females were screened for RF. As shown in Fig. 5 , there were little anti-IgG Ab activities in the sera of NZM2328 and its congenic lines. The lack of RF in C57L/J was also demonstrated. In contrast, RF activities were readily demonstrated in sera from MRL/lpr+/+females. These results were obtained with either rabbit IgG or human IgG as the substrate and with sera either at 1/50 or 1/250 dilutions.


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)

Lack of RF in sera of NZM2328 and its congenics. Human IgG was used as the substrate in A and C to detect anti-IgG activities. Mouse sera were used at a dilution of 1:50 for A and 1:250 for C. Rabbit IgG was used as the substrate in B and D with mouse sera diluted at 1:50 and 1:250, respectively. A pool of MRL/lpr+/+sera was used as a positive control showing readily detectable RF in this strain of mice.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Lack of RF in sera of NZM2328 and its congenics. Human IgG was used as the substrate in A and C to detect anti-IgG activities. Mouse sera were used at a dilution of 1:50 for A and 1:250 for C. Rabbit IgG was used as the substrate in B and D with mouse sera diluted at 1:50 and 1:250, respectively. A pool of MRL/lpr+/+sera was used as a positive control showing readily detectable RF in this strain of mice.
Mentions: The sera from NZM2328, NZM.-C57Lc1, and NZM.C57Lc4 females were screened for RF. As shown in Fig. 5 , there were little anti-IgG Ab activities in the sera of NZM2328 and its congenic lines. The lack of RF in C57L/J was also demonstrated. In contrast, RF activities were readily demonstrated in sera from MRL/lpr+/+females. These results were obtained with either rabbit IgG or human IgG as the substrate and with sera either at 1/50 or 1/250 dilutions.

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