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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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Western blot analysis to detect autoantibodies to cellular constituents in sera of NZM2328 and its congenics. Cell lysate of WEHI 7.1 lymphoma cell line was used as the substrate with sera at the dilution of 1:50. On the top, sera from mice at 4–5 mo of age were used with MRL/lpr+/+(MRL) pooled sera as the positive control. Lanes 1–8, NZM.C57Lc1; lanes 9–15, NZM.C57Lc4; lanes 16–22, NZM2328. On the bottom, sera at death or at death at the age of 12 mo were used. Lanes 1–6, NZM.C57Lc1; lanes 7–13, NZM.C57Lc4; lanes 14–20, NZM2328; lanes 21–24, C57L/J.
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fig6: Western blot analysis to detect autoantibodies to cellular constituents in sera of NZM2328 and its congenics. Cell lysate of WEHI 7.1 lymphoma cell line was used as the substrate with sera at the dilution of 1:50. On the top, sera from mice at 4–5 mo of age were used with MRL/lpr+/+(MRL) pooled sera as the positive control. Lanes 1–8, NZM.C57Lc1; lanes 9–15, NZM.C57Lc4; lanes 16–22, NZM2328. On the bottom, sera at death or at death at the age of 12 mo were used. Lanes 1–6, NZM.C57Lc1; lanes 7–13, NZM.C57Lc4; lanes 14–20, NZM2328; lanes 21–24, C57L/J.

Mentions: The presence of autoantibodies against cytoplasmic constituents in sera of NZM2328 and its congenics was studied by Western blot analysis with WEHI 7.1 lymphoma cell extract as the substrate. Individual serum was used at a 1/50 dilution. By the ages of 4–5 mo, autoantibodies of multiple specificities were readily detected in NZM2328 females (Fig. 6 , top, lanes 16–22), whereas autoantibodies of limited reactivities were found in NZM.C57Lc4 (Fig. 6, top, lanes 9–15). Fewer autoantibodies were detected in the sera of NZM.C57Lc1 (Fig. 6, top, lanes 1–8). By the time the mice developed fatal glomerulonephritis, fewer circulating autoantibodies were detected in NZM2328 (Fig. 6, bottom, lanes 14–20). The sera of NZM.C57Lc4 remained limited in their autoreactivties (Fig. 6, bottom, lanes 7–13). By the age of 12 mo, sera of some of the NZM.C57Lc1 and C57L/J showed autoreactivities, whereas others remained nonautoreactive (Fig. 6, bottom, lanes 1–6 and 21–24). In Fig. 6, a MRL/lpr+/+ serum was used as the positive control to show that both top and bottom panels were developed to a similar extent in chemiluminescence.


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)

Western blot analysis to detect autoantibodies to cellular constituents in sera of NZM2328 and its congenics. Cell lysate of WEHI 7.1 lymphoma cell line was used as the substrate with sera at the dilution of 1:50. On the top, sera from mice at 4–5 mo of age were used with MRL/lpr+/+(MRL) pooled sera as the positive control. Lanes 1–8, NZM.C57Lc1; lanes 9–15, NZM.C57Lc4; lanes 16–22, NZM2328. On the bottom, sera at death or at death at the age of 12 mo were used. Lanes 1–6, NZM.C57Lc1; lanes 7–13, NZM.C57Lc4; lanes 14–20, NZM2328; lanes 21–24, C57L/J.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Western blot analysis to detect autoantibodies to cellular constituents in sera of NZM2328 and its congenics. Cell lysate of WEHI 7.1 lymphoma cell line was used as the substrate with sera at the dilution of 1:50. On the top, sera from mice at 4–5 mo of age were used with MRL/lpr+/+(MRL) pooled sera as the positive control. Lanes 1–8, NZM.C57Lc1; lanes 9–15, NZM.C57Lc4; lanes 16–22, NZM2328. On the bottom, sera at death or at death at the age of 12 mo were used. Lanes 1–6, NZM.C57Lc1; lanes 7–13, NZM.C57Lc4; lanes 14–20, NZM2328; lanes 21–24, C57L/J.
Mentions: The presence of autoantibodies against cytoplasmic constituents in sera of NZM2328 and its congenics was studied by Western blot analysis with WEHI 7.1 lymphoma cell extract as the substrate. Individual serum was used at a 1/50 dilution. By the ages of 4–5 mo, autoantibodies of multiple specificities were readily detected in NZM2328 females (Fig. 6 , top, lanes 16–22), whereas autoantibodies of limited reactivities were found in NZM.C57Lc4 (Fig. 6, top, lanes 9–15). Fewer autoantibodies were detected in the sera of NZM.C57Lc1 (Fig. 6, top, lanes 1–8). By the time the mice developed fatal glomerulonephritis, fewer circulating autoantibodies were detected in NZM2328 (Fig. 6, bottom, lanes 14–20). The sera of NZM.C57Lc4 remained limited in their autoreactivties (Fig. 6, bottom, lanes 7–13). By the age of 12 mo, sera of some of the NZM.C57Lc1 and C57L/J showed autoreactivities, whereas others remained nonautoreactive (Fig. 6, bottom, lanes 1–6 and 21–24). In Fig. 6, a MRL/lpr+/+ serum was used as the positive control to show that both top and bottom panels were developed to a similar extent in chemiluminescence.

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