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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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Histological, immunofluorescence, and EM studies of representative kidneys from NZM.C57Lc1 and NZM.C57Lc4 female mice. (A) Normal glomeruli (hematoxylin and eosin staining, ×200) are seen in NZM.C57Lc1. (B) In contrast, in the NZM.C57Lc4 congenic, enlarged glomeruli with mesangial proliferation, hypercellularity, obliterated capillary loops, and glomerulosclerosis are evident. (C) Immunofluorescence studies show some mesangial IgG deposits in NZM.C57Lc1, similar to the pattern seen in aged C57L/J. (D) A coarsely granular staining pattern of IgG deposits in both the mesangia and peripheral capillary walls of the glomeruli of NZM.C57Lc4. (E) Staining of the Bowman capsule and mesangia with anti-C3 Ab are seen in NZM.C57Lc1. (F) Coarsely granular staining by anti-C3 Ab throughout the glomeruli is seen in NZM.C57Lc4. (G) EM study shows normal glomeruli without electron-dense deposits in the subepithelial or subendothelial spaces (×10,000) in the kidney of NZM.C57Lc1. (H) In comparison, electron-dense deposits in both subendothelial space (arrow) and the mesangia (arrowheads) in the glomeruli of NZM.C57Lc4 are readily detected.
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fig3: Histological, immunofluorescence, and EM studies of representative kidneys from NZM.C57Lc1 and NZM.C57Lc4 female mice. (A) Normal glomeruli (hematoxylin and eosin staining, ×200) are seen in NZM.C57Lc1. (B) In contrast, in the NZM.C57Lc4 congenic, enlarged glomeruli with mesangial proliferation, hypercellularity, obliterated capillary loops, and glomerulosclerosis are evident. (C) Immunofluorescence studies show some mesangial IgG deposits in NZM.C57Lc1, similar to the pattern seen in aged C57L/J. (D) A coarsely granular staining pattern of IgG deposits in both the mesangia and peripheral capillary walls of the glomeruli of NZM.C57Lc4. (E) Staining of the Bowman capsule and mesangia with anti-C3 Ab are seen in NZM.C57Lc1. (F) Coarsely granular staining by anti-C3 Ab throughout the glomeruli is seen in NZM.C57Lc4. (G) EM study shows normal glomeruli without electron-dense deposits in the subepithelial or subendothelial spaces (×10,000) in the kidney of NZM.C57Lc1. (H) In comparison, electron-dense deposits in both subendothelial space (arrow) and the mesangia (arrowheads) in the glomeruli of NZM.C57Lc4 are readily detected.

Mentions: Histological, immunofluorescence, and EM studies of representative kidneys of the NZM2328 congenic lines are shown in Fig. 3 . The glomeruli of NZM.C57Lc1 are normal in size without cellular infiltration and similar to those seen in kidneys of C57L/J (Fig. 3 A). In contrast, the glomeruli of the NZM.C57Lc4 congenic female were enlarged with hypercellularity, mesangial proliferation, thickened capillary loops, and segmental glomerulosclerosis (Fig. 3 B). Although not shown, there were tubular atrophy and interstitial fibrosis in the diseased NZM.C57Lc4 kidneys. Immunofluorescence studies on NZM.C57Lc4 kidneys showed intense staining for IgG and C3 (Fig. 3, D and F). The thickened capillary loops were more evident with anti-IgG staining. Immunofluorescence staining of NZM.C57Lc1 kidneys showed limited staining for IgG in the mesangia and some C3 deposit in some mesangia and the Bowman capsule (Figs. 3, C and E). These limited staining patterns were often seen in aged C57L/J mice and are considered of no pathological consequences. The IgG and C3 staining patterns of NZM.C57Lc4 kidneys were suggestive of immune complex–mediated glomerulonephritis. This was confirmed by the EM study, showing electron-dense deposits in the subendothelial and subepithelial areas (Fig. 3 H). In contrast, a representative EM of NZM.C57c1 kidneys did not show such electron-dense deposits (Fig. 3 G).


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)

Histological, immunofluorescence, and EM studies of representative kidneys from NZM.C57Lc1 and NZM.C57Lc4 female mice. (A) Normal glomeruli (hematoxylin and eosin staining, ×200) are seen in NZM.C57Lc1. (B) In contrast, in the NZM.C57Lc4 congenic, enlarged glomeruli with mesangial proliferation, hypercellularity, obliterated capillary loops, and glomerulosclerosis are evident. (C) Immunofluorescence studies show some mesangial IgG deposits in NZM.C57Lc1, similar to the pattern seen in aged C57L/J. (D) A coarsely granular staining pattern of IgG deposits in both the mesangia and peripheral capillary walls of the glomeruli of NZM.C57Lc4. (E) Staining of the Bowman capsule and mesangia with anti-C3 Ab are seen in NZM.C57Lc1. (F) Coarsely granular staining by anti-C3 Ab throughout the glomeruli is seen in NZM.C57Lc4. (G) EM study shows normal glomeruli without electron-dense deposits in the subepithelial or subendothelial spaces (×10,000) in the kidney of NZM.C57Lc1. (H) In comparison, electron-dense deposits in both subendothelial space (arrow) and the mesangia (arrowheads) in the glomeruli of NZM.C57Lc4 are readily detected.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211766&req=5

fig3: Histological, immunofluorescence, and EM studies of representative kidneys from NZM.C57Lc1 and NZM.C57Lc4 female mice. (A) Normal glomeruli (hematoxylin and eosin staining, ×200) are seen in NZM.C57Lc1. (B) In contrast, in the NZM.C57Lc4 congenic, enlarged glomeruli with mesangial proliferation, hypercellularity, obliterated capillary loops, and glomerulosclerosis are evident. (C) Immunofluorescence studies show some mesangial IgG deposits in NZM.C57Lc1, similar to the pattern seen in aged C57L/J. (D) A coarsely granular staining pattern of IgG deposits in both the mesangia and peripheral capillary walls of the glomeruli of NZM.C57Lc4. (E) Staining of the Bowman capsule and mesangia with anti-C3 Ab are seen in NZM.C57Lc1. (F) Coarsely granular staining by anti-C3 Ab throughout the glomeruli is seen in NZM.C57Lc4. (G) EM study shows normal glomeruli without electron-dense deposits in the subepithelial or subendothelial spaces (×10,000) in the kidney of NZM.C57Lc1. (H) In comparison, electron-dense deposits in both subendothelial space (arrow) and the mesangia (arrowheads) in the glomeruli of NZM.C57Lc4 are readily detected.
Mentions: Histological, immunofluorescence, and EM studies of representative kidneys of the NZM2328 congenic lines are shown in Fig. 3 . The glomeruli of NZM.C57Lc1 are normal in size without cellular infiltration and similar to those seen in kidneys of C57L/J (Fig. 3 A). In contrast, the glomeruli of the NZM.C57Lc4 congenic female were enlarged with hypercellularity, mesangial proliferation, thickened capillary loops, and segmental glomerulosclerosis (Fig. 3 B). Although not shown, there were tubular atrophy and interstitial fibrosis in the diseased NZM.C57Lc4 kidneys. Immunofluorescence studies on NZM.C57Lc4 kidneys showed intense staining for IgG and C3 (Fig. 3, D and F). The thickened capillary loops were more evident with anti-IgG staining. Immunofluorescence staining of NZM.C57Lc1 kidneys showed limited staining for IgG in the mesangia and some C3 deposit in some mesangia and the Bowman capsule (Figs. 3, C and E). These limited staining patterns were often seen in aged C57L/J mice and are considered of no pathological consequences. The IgG and C3 staining patterns of NZM.C57Lc4 kidneys were suggestive of immune complex–mediated glomerulonephritis. This was confirmed by the EM study, showing electron-dense deposits in the subendothelial and subepithelial areas (Fig. 3 H). In contrast, a representative EM of NZM.C57c1 kidneys did not show such electron-dense deposits (Fig. 3 G).

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