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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

Abs eluted from nephritic kidneys of NZM2328 and NZM.C57Lc4 mice are reactive with proteins within the kidney and liver extracts. Proteins in the kidney (left) and liver (right) extracts were separated on a 12% SDS-PAGE, transferred to nitrocellulose paper, and used for analyzing the reactivity of Abs eluted from the nephritic kidneys of NZM2328 (lanes 2 and 3) and NZM.C57Lc4 (lanes 4 and 5) mice. Each lane is equivalent to 60 μg total protein. Abs were used at a concentration of 30 (lanes 2 and 4) and 10 μg/ml (lanes 3 and 5). Lane 1 in both panels represents reactivity of the goat anti–mouse IgG–horseradish peroxidase conjugate with the extracts. Numbers on the left represent molecular weights in kilodaltons.
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fig8: Abs eluted from nephritic kidneys of NZM2328 and NZM.C57Lc4 mice are reactive with proteins within the kidney and liver extracts. Proteins in the kidney (left) and liver (right) extracts were separated on a 12% SDS-PAGE, transferred to nitrocellulose paper, and used for analyzing the reactivity of Abs eluted from the nephritic kidneys of NZM2328 (lanes 2 and 3) and NZM.C57Lc4 (lanes 4 and 5) mice. Each lane is equivalent to 60 μg total protein. Abs were used at a concentration of 30 (lanes 2 and 4) and 10 μg/ml (lanes 3 and 5). Lane 1 in both panels represents reactivity of the goat anti–mouse IgG–horseradish peroxidase conjugate with the extracts. Numbers on the left represent molecular weights in kilodaltons.

Mentions: Kidney and liver from 8-wk-old NZM2328 were perfused with cold PBS. Extracts of them were used as substrates for Western blot analysis. Kidney eluates from NZM2328 and NZM.C57Lc4 were used at either 30 or 10 μg/ml for assaying Ab activity to these extracts. The results are summarized in Fig. 8 . Both eluates from NZM2328 and NZM.C57Lc4 kidneys stained several bands in the region between molecular weights of 25 and 40 kD in the kidney extract. The eluate from NZM2328 also had activities against proteins of higher molecular weights. Although the bands were not distinct, proteins of a lower molecular weight of <21 kD were also reactive with the NZM2328 eluate. It appears that the reactive Ags are also present in the liver extract. Similar results were obtained in another experiment.


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)

Abs eluted from nephritic kidneys of NZM2328 and NZM.C57Lc4 mice are reactive with proteins within the kidney and liver extracts. Proteins in the kidney (left) and liver (right) extracts were separated on a 12% SDS-PAGE, transferred to nitrocellulose paper, and used for analyzing the reactivity of Abs eluted from the nephritic kidneys of NZM2328 (lanes 2 and 3) and NZM.C57Lc4 (lanes 4 and 5) mice. Each lane is equivalent to 60 μg total protein. Abs were used at a concentration of 30 (lanes 2 and 4) and 10 μg/ml (lanes 3 and 5). Lane 1 in both panels represents reactivity of the goat anti–mouse IgG–horseradish peroxidase conjugate with the extracts. Numbers on the left represent molecular weights in kilodaltons.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Abs eluted from nephritic kidneys of NZM2328 and NZM.C57Lc4 mice are reactive with proteins within the kidney and liver extracts. Proteins in the kidney (left) and liver (right) extracts were separated on a 12% SDS-PAGE, transferred to nitrocellulose paper, and used for analyzing the reactivity of Abs eluted from the nephritic kidneys of NZM2328 (lanes 2 and 3) and NZM.C57Lc4 (lanes 4 and 5) mice. Each lane is equivalent to 60 μg total protein. Abs were used at a concentration of 30 (lanes 2 and 4) and 10 μg/ml (lanes 3 and 5). Lane 1 in both panels represents reactivity of the goat anti–mouse IgG–horseradish peroxidase conjugate with the extracts. Numbers on the left represent molecular weights in kilodaltons.
Mentions: Kidney and liver from 8-wk-old NZM2328 were perfused with cold PBS. Extracts of them were used as substrates for Western blot analysis. Kidney eluates from NZM2328 and NZM.C57Lc4 were used at either 30 or 10 μg/ml for assaying Ab activity to these extracts. The results are summarized in Fig. 8 . Both eluates from NZM2328 and NZM.C57Lc4 kidneys stained several bands in the region between molecular weights of 25 and 40 kD in the kidney extract. The eluate from NZM2328 also had activities against proteins of higher molecular weights. Although the bands were not distinct, proteins of a lower molecular weight of <21 kD were also reactive with the NZM2328 eluate. It appears that the reactive Ags are also present in the liver extract. Similar results were obtained in another experiment.

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