title: Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
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 alloantibodies 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 alpha345NC1 hexamer.
  
  
  RESULTS
  In patients with Goodpasture's disease, both autoantibodies to the alpha3NC1 monomer and antibodies to the alpha5NC1 monomer (and fewer to the alpha4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the alpha3NC1 and alpha5NC1 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 E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer. In contrast, in patients with Alport's post-transplantation nephritis, alloantibodies bound to the E(A) region of the alpha5NC1 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 alpha345NC1 hexamer, inducing a pathogenic conformational change in the alpha3NC1 and alpha5NC1 subunits, which in turn elicits an autoimmune response. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
authors.affiliation: Center for Matrix Biology, Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Vadim
authors.initials: V
authors.lastname: Pedchenko
authors.forename: Olga
authors.initials: O
authors.lastname: Bondar
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Roberto
authors.initials: R
authors.lastname: Vanacore
authors.forename: Paul
authors.initials: P
authors.lastname: Voziyan
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Jörgen
authors.initials: J
authors.lastname: Wieslander
authors.forename: Clifford
authors.initials: C
authors.lastname: Kashtan
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
authors.forename: Eric G
authors.initials: EG
authors.lastname: Neilson
authors.forename: Curtis B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Billy G
authors.initials: BG
authors.lastname: Hudson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D000906:Antibodies / Q000097:blood / Q000737:chemistry; D001323:Autoantibodies / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000097:blood / Q000737:chemistry; D001666:Binding Sites, Antibody; D024141:Collagen Type IV / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D005260:Female; D050533:Glomerular Basement Membrane / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000737:chemistry / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009393:Nephritis / Q000276:immunology; D009394:Nephritis, Hereditary / Q000276:immunology* / Q000601:surgery; D011183:Postoperative Complications / Q000276:immunology; D011487:Protein Conformation; D020033:Protein Isoforms; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes; D007518:Isoantibodies; D020033:Protein Isoforms; C051951:antiglomerular basement membrane antibody