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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

Interactive model for the pathogenesis of SLE. Pathway I, autoantibody production and activation of effector T cells and pathway II, activation of susceptibility genes and end organ damage, can be initiated independently while they interact at different levels as indicated by pathways III and IV. The interactions between these pathways lead to end organ damage.
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fig9: Interactive model for the pathogenesis of SLE. Pathway I, autoantibody production and activation of effector T cells and pathway II, activation of susceptibility genes and end organ damage, can be initiated independently while they interact at different levels as indicated by pathways III and IV. The interactions between these pathways lead to end organ damage.

Mentions: The findings reported here have significant implications on our thinking of the pathogenesis of SLE. An alternative and a less anti-dsDNA– and antinucleosome Ab–centric model for the pathogenesis of SLE is put forth and depicted in Fig. 9 . In this model, autoantibody production and autoreactive T cell generation (Fig. 9, pathway I) and activation of genes leading to end organ damage (Fig. 9, pathway II) are independent events. Activation of the autoimmune response is either as a result of genetic predisposition or environmental factors such as chemical exposure and infections. Genes controlling end organ susceptibility exert their influence on the targeted end organs by causing differential expression of genes and/or increased apoptosis in target organs, which may lead to overexpression of organ-specific Ag. The initiation of these two pathways might be independent of each other. This is supported by both clinical and experimental data. Clinically, many patients with significant titers of ANA do not have symptoms and signs of SLE. Specifically, they do not have end organ damage. In experimental models such as NZM2328, male mice have significant elevations of ANA and anti-dsDNA Ab without chronic glomerulonephritis. The recent work by Jacob et al. (34), shows that Stat4-deficient NZM2328 developed accelerated nephritis and increased mortality with lower titers of anti-DNA Ab. In contrast, Stat6-deficient NZM2328 mice had a significant reduction of nephritis despite the presence of high levels of anti-DNA Ab.


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)

Interactive model for the pathogenesis of SLE. Pathway I, autoantibody production and activation of effector T cells and pathway II, activation of susceptibility genes and end organ damage, can be initiated independently while they interact at different levels as indicated by pathways III and IV. The interactions between these pathways lead to end organ damage.
© Copyright Policy
Related In: Results  -  Collection

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

fig9: Interactive model for the pathogenesis of SLE. Pathway I, autoantibody production and activation of effector T cells and pathway II, activation of susceptibility genes and end organ damage, can be initiated independently while they interact at different levels as indicated by pathways III and IV. The interactions between these pathways lead to end organ damage.
Mentions: The findings reported here have significant implications on our thinking of the pathogenesis of SLE. An alternative and a less anti-dsDNA– and antinucleosome Ab–centric model for the pathogenesis of SLE is put forth and depicted in Fig. 9 . In this model, autoantibody production and autoreactive T cell generation (Fig. 9, pathway I) and activation of genes leading to end organ damage (Fig. 9, pathway II) are independent events. Activation of the autoimmune response is either as a result of genetic predisposition or environmental factors such as chemical exposure and infections. Genes controlling end organ susceptibility exert their influence on the targeted end organs by causing differential expression of genes and/or increased apoptosis in target organs, which may lead to overexpression of organ-specific Ag. The initiation of these two pathways might be independent of each other. This is supported by both clinical and experimental data. Clinically, many patients with significant titers of ANA do not have symptoms and signs of SLE. Specifically, they do not have end organ damage. In experimental models such as NZM2328, male mice have significant elevations of ANA and anti-dsDNA Ab without chronic glomerulonephritis. The recent work by Jacob et al. (34), shows that Stat4-deficient NZM2328 developed accelerated nephritis and increased mortality with lower titers of anti-DNA Ab. In contrast, Stat6-deficient NZM2328 mice had a significant reduction of nephritis despite the presence of high levels of anti-DNA Ab.

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