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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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Development of severe proteinuria in females of NZM2328 and NZM.C57Lc4 but not in those of NZM.C57Lc1. (A) Incidence of severe proteinuria in each strain of mice. (B) Kinetics of proteinuria development.
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fig2: Development of severe proteinuria in females of NZM2328 and NZM.C57Lc4 but not in those of NZM.C57Lc1. (A) Incidence of severe proteinuria in each strain of mice. (B) Kinetics of proteinuria development.

Mentions: Cohorts of NZM.C57Lc1 and NZM.C57Lc4 females were observed for the development of severe proteinuria and acute and chronic glomerulonephritis. As shown in Fig. 2 A, 70% (24/34) of NZM.C57Lc4 female mice developed severe proteinuria and only 3 of the 41 NZM.C57Lc1 females (7.3%) had severe proteinuria by 12 mo of age. The incidence of severe proteinuria for NZM.C57Lc4 was similar to that of parental stain NZM2328. The incidence of severe proteinuria in NZM.C57Lc1 female mice was markedly reduced. The kinetics of proteinuria development was similar between NZM2328 and its congenic NZM.C57Lc4. There was a delay of 4 mo in the development of severe proteinuria in the three NZM.C57Lc1 mice.


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)

Development of severe proteinuria in females of NZM2328 and NZM.C57Lc4 but not in those of NZM.C57Lc1. (A) Incidence of severe proteinuria in each strain of mice. (B) Kinetics of proteinuria development.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Development of severe proteinuria in females of NZM2328 and NZM.C57Lc4 but not in those of NZM.C57Lc1. (A) Incidence of severe proteinuria in each strain of mice. (B) Kinetics of proteinuria development.
Mentions: Cohorts of NZM.C57Lc1 and NZM.C57Lc4 females were observed for the development of severe proteinuria and acute and chronic glomerulonephritis. As shown in Fig. 2 A, 70% (24/34) of NZM.C57Lc4 female mice developed severe proteinuria and only 3 of the 41 NZM.C57Lc1 females (7.3%) had severe proteinuria by 12 mo of age. The incidence of severe proteinuria for NZM.C57Lc4 was similar to that of parental stain NZM2328. The incidence of severe proteinuria in NZM.C57Lc1 female mice was markedly reduced. The kinetics of proteinuria development was similar between NZM2328 and its congenic NZM.C57Lc4. There was a delay of 4 mo in the development of severe proteinuria in the three NZM.C57Lc1 mice.

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