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Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis

Kalaaji, M.; Fenton, K. A.; Mortensen, E. S.; Olsen, R.; Sturfelt, Gunnar LU ; Alm, Per LU and Rekvig, O. P. (2007) In Kidney International 71(7). p.664-672
Abstract
Antibodies to double-stranded (dsDNA) are associated with systemic lupus erythematosus (SLE) and directly involved in human lupus nephritis. Information about their glomerular target antigens is inconsistent, and whether availability of target antigens, antibody specificity or avidity are nephritogenic parameters, is not determined. In this study, we analyzed renal tissue from anti-dsDNA antibody-positive lupus patients with nephritis by morphological and immunological assays, including immune electron microscopy (IEM) and colocalization IEM, an EM-based confocal microscopy assay. IEM demonstrated that antibody deposits were confined to electron dense structures (EDS) in glomerular membranes. These autoantibodies colocalized with... (More)
Antibodies to double-stranded (dsDNA) are associated with systemic lupus erythematosus (SLE) and directly involved in human lupus nephritis. Information about their glomerular target antigens is inconsistent, and whether availability of target antigens, antibody specificity or avidity are nephritogenic parameters, is not determined. In this study, we analyzed renal tissue from anti-dsDNA antibody-positive lupus patients with nephritis by morphological and immunological assays, including immune electron microscopy (IEM) and colocalization IEM, an EM-based confocal microscopy assay. IEM demonstrated that antibody deposits were confined to electron dense structures (EDS) in glomerular membranes. These autoantibodies colocalized with nucleosome-binding anti-dsDNA/-histone/-transcription factor antibodies. To confirm the colocalization IEM-data, we developed a colocalization terminal deoxynucleotidyltransferase (TdT) biotin-dUTP nicked end-labeled (TUNEL) IEM assay where extracellular DNA was traced by TdT-mediated introduction of biotinylated nucleotides and autoantibodies by IEM. Results consistently demonstrated that DNA colocalized with autoantibodies in glomerular membrane-associated EDS. The colocalization IEM and colocalization TUNEL IEM assays thus demonstrate that intra-glomerular membrane-associated nucleosomes are targeted by anti-dsDNA autoantibodies in human lupus nephritis. The data provide a new approach to understand basic molecular and immunological processes accounting for antibody-mediated nephritis in human SLE. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
immunology and pathology, systemic lupus erythematosus, nephritis, immune complexes, glomerulus
in
Kidney International
volume
71
issue
7
pages
664 - 672
publisher
Nature Publishing Group
external identifiers
  • wos:000245501900012
  • scopus:33947660078
ISSN
1523-1755
DOI
10.1038/sj.ki.5002133
language
English
LU publication?
yes
id
e21e3365-4746-4f45-a0d3-6cd5a83a9fad (old id 667456)
date added to LUP
2007-12-13 14:59:56
date last changed
2017-08-27 05:09:06
@article{e21e3365-4746-4f45-a0d3-6cd5a83a9fad,
  abstract     = {Antibodies to double-stranded (dsDNA) are associated with systemic lupus erythematosus (SLE) and directly involved in human lupus nephritis. Information about their glomerular target antigens is inconsistent, and whether availability of target antigens, antibody specificity or avidity are nephritogenic parameters, is not determined. In this study, we analyzed renal tissue from anti-dsDNA antibody-positive lupus patients with nephritis by morphological and immunological assays, including immune electron microscopy (IEM) and colocalization IEM, an EM-based confocal microscopy assay. IEM demonstrated that antibody deposits were confined to electron dense structures (EDS) in glomerular membranes. These autoantibodies colocalized with nucleosome-binding anti-dsDNA/-histone/-transcription factor antibodies. To confirm the colocalization IEM-data, we developed a colocalization terminal deoxynucleotidyltransferase (TdT) biotin-dUTP nicked end-labeled (TUNEL) IEM assay where extracellular DNA was traced by TdT-mediated introduction of biotinylated nucleotides and autoantibodies by IEM. Results consistently demonstrated that DNA colocalized with autoantibodies in glomerular membrane-associated EDS. The colocalization IEM and colocalization TUNEL IEM assays thus demonstrate that intra-glomerular membrane-associated nucleosomes are targeted by anti-dsDNA autoantibodies in human lupus nephritis. The data provide a new approach to understand basic molecular and immunological processes accounting for antibody-mediated nephritis in human SLE.},
  author       = {Kalaaji, M. and Fenton, K. A. and Mortensen, E. S. and Olsen, R. and Sturfelt, Gunnar and Alm, Per and Rekvig, O. P.},
  issn         = {1523-1755},
  keyword      = {immunology and pathology,systemic lupus erythematosus,nephritis,immune complexes,glomerulus},
  language     = {eng},
  number       = {7},
  pages        = {664--672},
  publisher    = {Nature Publishing Group},
  series       = {Kidney International},
  title        = {Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis},
  url          = {http://dx.doi.org/10.1038/sj.ki.5002133},
  volume       = {71},
  year         = {2007},
}