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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

NZM.C57Lc1 and NZM.C57Lc4 congenic lines were derived by replacing the genetic intervals in NZM2328 with those from C57L/J (hatched bars). The genetic intervals with SLE susceptibility genes in NZM2328 delineated by informative microsatellite markers are shown (open bars). Chromosome intervals are not drawn to scale.
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fig1: NZM.C57Lc1 and NZM.C57Lc4 congenic lines were derived by replacing the genetic intervals in NZM2328 with those from C57L/J (hatched bars). The genetic intervals with SLE susceptibility genes in NZM2328 delineated by informative microsatellite markers are shown (open bars). Chromosome intervals are not drawn to scale.

Mentions: A microsatellite marker-assisted protocol was used to facilitate the generation of both NZM.C57Lc1 and NZM.C57Lc4. A panel of 91 informative markers was used for the selection of the breeding pairs. As shown in Fig. 1 , the C57L/J alleles were maintained throughout the genomic interval flanked by D1Mit15 (87.9 cM) and D1Mit155 (112.0 cM) for the derivation of NZM.C57Lc1 and D4Mit91 (15.6 cM) and D4Mit72 (59.9 cM) for NZM.C57Lc4. Each of these genetic intervals contains the 95% confidence interval for the loci linked to acute and chronic glomerulonephritis (Agnz1 and Cgnz1) on chromosome 1 and to ANA and anti-dsDNA Ab production (Adnz1) on chromosome 4.


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)

NZM.C57Lc1 and NZM.C57Lc4 congenic lines were derived by replacing the genetic intervals in NZM2328 with those from C57L/J (hatched bars). The genetic intervals with SLE susceptibility genes in NZM2328 delineated by informative microsatellite markers are shown (open bars). Chromosome intervals are not drawn to scale.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: NZM.C57Lc1 and NZM.C57Lc4 congenic lines were derived by replacing the genetic intervals in NZM2328 with those from C57L/J (hatched bars). The genetic intervals with SLE susceptibility genes in NZM2328 delineated by informative microsatellite markers are shown (open bars). Chromosome intervals are not drawn to scale.
Mentions: A microsatellite marker-assisted protocol was used to facilitate the generation of both NZM.C57Lc1 and NZM.C57Lc4. A panel of 91 informative markers was used for the selection of the breeding pairs. As shown in Fig. 1 , the C57L/J alleles were maintained throughout the genomic interval flanked by D1Mit15 (87.9 cM) and D1Mit155 (112.0 cM) for the derivation of NZM.C57Lc1 and D4Mit91 (15.6 cM) and D4Mit72 (59.9 cM) for NZM.C57Lc4. Each of these genetic intervals contains the 95% confidence interval for the loci linked to acute and chronic glomerulonephritis (Agnz1 and Cgnz1) on chromosome 1 and to ANA and anti-dsDNA Ab production (Adnz1) on chromosome 4.

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