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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

Anti-dsDNA Ab in sera and kidney eluates from NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J females at 11–12 mo. Abs to dsDNA were present in sera of NZM2328 and they were enriched in their kidney eluates. These Abs were rarely detected in the sera and the kidney eluates of the other three strains. P-values indicate significant differences of the respective strain as compared with NZM2328.
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fig7: Anti-dsDNA Ab in sera and kidney eluates from NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J females at 11–12 mo. Abs to dsDNA were present in sera of NZM2328 and they were enriched in their kidney eluates. These Abs were rarely detected in the sera and the kidney eluates of the other three strains. P-values indicate significant differences of the respective strain as compared with NZM2328.

Mentions: The lack of detectable circulating autoantibodies to dsDNA and other nuclear Ags in NZM.C57Lc4 despite the presence of immune complex–mediated nephritis is not a definitive proof that these Abs do not play a pathological role because these autoantibodies may have been fixed in the kidneys, rendering their absence in the blood. To rule out this possibility, NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J females 10–12 mo old were killed. At death, sera were collected and their kidneys were frozen in liquid nitrogen and stored for elution. Many of the NZM2328 and NZM.C57Lc4 mice have moderate to severe proteinuria. The kidneys were homogenized and acid eluates were collected and neutralized. NZM2328 and NZM.C57Lc4 kidney eluates had comparable IgG levels, whereas those of NZM.C57Lc1 and C57L/J had significantly lower levels of IgG (unpublished data). Anti-dsDNA Ab activity was expressed as units/microgram of IgG. As shown in Fig. 7 , anti-dsDNA Abs were detected in the majority of the NZM2328 sera. There was a concentration of these anti-dsDNA Abs in the NZM2328 kidneys. The enrichment of these Abs in the kidneys was ∼20-fold. As expected, few anti-dsDNA Abs were detected in the sera of NZM.C57Lc1, NZM.C57Lc4, and C57L/J. More importantly, the kidney eluates of NZM.C57Lc4 rarely had demonstrable anti-dsDNA Abs. It is of interest to note that there was little correlation of anti-dsDNA Ab concentration in the kidney eluate with serum dsDNA Ab titer in an individual mouse. In addition, the kidney eluates of NZM.C57Lc1, NZM.C57Lc4, and C57L/J did not show antinuclear reactivity on HeLa cells. There was staining for ANA with NZM2328 kidney eluates when they were used without dilution. As with sera, the sera and their paired kidney eluates were also studied regarding RF. The kidney eluates of NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J did not have detectable RF. These results support our hypothesis that ANA and RF play no significant role in the kidney disease in NZM2328 and its congenic NZM.C57Lc4.


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)

Anti-dsDNA Ab in sera and kidney eluates from NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J females at 11–12 mo. Abs to dsDNA were present in sera of NZM2328 and they were enriched in their kidney eluates. These Abs were rarely detected in the sera and the kidney eluates of the other three strains. P-values indicate significant differences of the respective strain as compared with NZM2328.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Anti-dsDNA Ab in sera and kidney eluates from NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J females at 11–12 mo. Abs to dsDNA were present in sera of NZM2328 and they were enriched in their kidney eluates. These Abs were rarely detected in the sera and the kidney eluates of the other three strains. P-values indicate significant differences of the respective strain as compared with NZM2328.
Mentions: The lack of detectable circulating autoantibodies to dsDNA and other nuclear Ags in NZM.C57Lc4 despite the presence of immune complex–mediated nephritis is not a definitive proof that these Abs do not play a pathological role because these autoantibodies may have been fixed in the kidneys, rendering their absence in the blood. To rule out this possibility, NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J females 10–12 mo old were killed. At death, sera were collected and their kidneys were frozen in liquid nitrogen and stored for elution. Many of the NZM2328 and NZM.C57Lc4 mice have moderate to severe proteinuria. The kidneys were homogenized and acid eluates were collected and neutralized. NZM2328 and NZM.C57Lc4 kidney eluates had comparable IgG levels, whereas those of NZM.C57Lc1 and C57L/J had significantly lower levels of IgG (unpublished data). Anti-dsDNA Ab activity was expressed as units/microgram of IgG. As shown in Fig. 7 , anti-dsDNA Abs were detected in the majority of the NZM2328 sera. There was a concentration of these anti-dsDNA Abs in the NZM2328 kidneys. The enrichment of these Abs in the kidneys was ∼20-fold. As expected, few anti-dsDNA Abs were detected in the sera of NZM.C57Lc1, NZM.C57Lc4, and C57L/J. More importantly, the kidney eluates of NZM.C57Lc4 rarely had demonstrable anti-dsDNA Abs. It is of interest to note that there was little correlation of anti-dsDNA Ab concentration in the kidney eluate with serum dsDNA Ab titer in an individual mouse. In addition, the kidney eluates of NZM.C57Lc1, NZM.C57Lc4, and C57L/J did not show antinuclear reactivity on HeLa cells. There was staining for ANA with NZM2328 kidney eluates when they were used without dilution. As with sera, the sera and their paired kidney eluates were also studied regarding RF. The kidney eluates of NZM2328, NZM.C57Lc1, NZM.C57Lc4, and C57L/J did not have detectable RF. These results support our hypothesis that ANA and RF play no significant role in the kidney disease in NZM2328 and its congenic NZM.C57Lc4.

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