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Molecular Architecture of the Goodpasture Autoantigen in Anti-GBM Nephritis

Pedchenko, Vadim; Bondar, Olga; Fogo, Agnes B.; Vanacore, Roberto; Voziyan, Paul; Kitching, A. Richard; Wieslander, Jörgen LU ; Kashtan, Clifford; Borza, Dorin-Bogdan and Neilson, Eric G., et al. (2010) In New England Journal of Medicine 363(4). p.343-354
Abstract
BACKGROUND In Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport's post-transplantation nephritis, which is mediated by allo-antibodies against the GBM, occurs after kidney transplantation in some patients with Alport's syndrome. We compared the conformations of the antibody epitopes in Goodpasture's disease and Alport's post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis. METHODS We used an enzyme-linked immunosorbent assay to determine the specificity of circulating... (More)
BACKGROUND In Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport's post-transplantation nephritis, which is mediated by allo-antibodies against the GBM, occurs after kidney transplantation in some patients with Alport's syndrome. We compared the conformations of the antibody epitopes in Goodpasture's disease and Alport's post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis. METHODS We used an enzyme-linked immunosorbent assay to determine the specificity of circulating autoantibodies and kidney-bound antibodies to NC1 domains. Circulating antibodies were analyzed in 57 patients with Goodpasture's disease, and kidney-bound antibodies were analyzed in 14 patients with Goodpasture's disease and 2 patients with Alport's post-transplantation nephritis. The molecular architecture of key epitope regions was deduced with the use of chimeric molecules and a three-dimensional model of the alpha 345NC1 hexamer. RESULTS In patients with Goodpasture's disease, both autoantibodies to the alpha 3NC1 monomer and antibodies to the alpha 5NC1 monomer (and fewer to the alpha 4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the alpha 3NC1 and alpha 5NC1 monomers as autoantigens. High antibody titers at diagnosis of anti-GBM disease were associated with ultimate loss of renal function. The antibodies bound to distinct epitopes encompassing region Ea in the alpha 5NC1 monomer and regions E-A and Eb in the alpha 3NC1 monomer, but they did not bind to the native cross-linked alpha 345NC1 hexamer. In contrast, in patients with Alport's post-transplantation nephritis, allo-antibodies bound to the E-A region of the alpha 5NC1 subunit in the intact hexamer, and binding decreased on dissociation. CONCLUSIONS The development of Goodpasture's disease may be considered an autoimmune "conformeropathy" that involves perturbation of the quaternary structure of the alpha 345NC1 hexamer, inducing a pathogenic conformational change in the alpha 3NC1 and alpha 5NC1 subunits, which in turn elicits an autoimmune response. (Less)
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New England Journal of Medicine
volume
363
issue
4
pages
343 - 354
publisher
Massachusetts Medical Society
external identifiers
  • wos:000280139300007
  • scopus:77954823533
ISSN
0028-4793
language
English
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yes
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2fdf4816-009c-4173-a2d2-76f45802d77e (old id 1657375)
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http://www.ncbi.nlm.nih.gov/pubmed/20660402
date added to LUP
2010-09-01 09:02:58
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2018-06-24 03:17:26
@article{2fdf4816-009c-4173-a2d2-76f45802d77e,
  abstract     = {BACKGROUND In Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport's post-transplantation nephritis, which is mediated by allo-antibodies against the GBM, occurs after kidney transplantation in some patients with Alport's syndrome. We compared the conformations of the antibody epitopes in Goodpasture's disease and Alport's post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis. METHODS We used an enzyme-linked immunosorbent assay to determine the specificity of circulating autoantibodies and kidney-bound antibodies to NC1 domains. Circulating antibodies were analyzed in 57 patients with Goodpasture's disease, and kidney-bound antibodies were analyzed in 14 patients with Goodpasture's disease and 2 patients with Alport's post-transplantation nephritis. The molecular architecture of key epitope regions was deduced with the use of chimeric molecules and a three-dimensional model of the alpha 345NC1 hexamer. RESULTS In patients with Goodpasture's disease, both autoantibodies to the alpha 3NC1 monomer and antibodies to the alpha 5NC1 monomer (and fewer to the alpha 4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the alpha 3NC1 and alpha 5NC1 monomers as autoantigens. High antibody titers at diagnosis of anti-GBM disease were associated with ultimate loss of renal function. The antibodies bound to distinct epitopes encompassing region Ea in the alpha 5NC1 monomer and regions E-A and Eb in the alpha 3NC1 monomer, but they did not bind to the native cross-linked alpha 345NC1 hexamer. In contrast, in patients with Alport's post-transplantation nephritis, allo-antibodies bound to the E-A region of the alpha 5NC1 subunit in the intact hexamer, and binding decreased on dissociation. CONCLUSIONS The development of Goodpasture's disease may be considered an autoimmune "conformeropathy" that involves perturbation of the quaternary structure of the alpha 345NC1 hexamer, inducing a pathogenic conformational change in the alpha 3NC1 and alpha 5NC1 subunits, which in turn elicits an autoimmune response.},
  author       = {Pedchenko, Vadim and Bondar, Olga and Fogo, Agnes B. and Vanacore, Roberto and Voziyan, Paul and Kitching, A. Richard and Wieslander, Jörgen and Kashtan, Clifford and Borza, Dorin-Bogdan and Neilson, Eric G. and Wilson, Curtis B. and Hudson, Billy G.},
  issn         = {0028-4793},
  language     = {eng},
  number       = {4},
  pages        = {343--354},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Molecular Architecture of the Goodpasture Autoantigen in Anti-GBM Nephritis},
  volume       = {363},
  year         = {2010},
}