title: Quaternary epitopes of α345(IV) collagen initiate Alport post-transplant anti-GBM nephritis.
abstract: Alport post-transplant nephritis (APTN) is an aggressive form of anti-glomerular basement membrane disease that targets the allograft in transplanted patients with X-linked Alport syndrome. Alloantibodies develop against the NC1 domain of α5(IV) collagen, which occurs in normal kidneys, including renal allografts, forming distinct α345(IV) and α1256(IV) networks. Here, we studied the roles of these networks as antigens inciting alloimmunity and as targets of nephritogenic alloantibodies in APTN. We found that patients with APTN, but not those without nephritis, produce two kinds of alloantibodies against allogeneic collagen IV. Some alloantibodies targeted alloepitopes within α5NC1 monomers, shared by α345NC1 and α1256NC1 hexamers. Other alloantibodies specifically targeted alloepitopes that depended on the quaternary structure of α345NC1 hexamers. In Col4a5-null mice, immunization with native forms of allogeneic collagen IV exclusively elicited antibodies to quaternary α345NC1 alloepitopes, whereas alloimmunogens lacking native quaternary structure elicited antibodies to shared α5NC1 alloepitopes. These results imply that quaternary epitopes within α345NC1 hexamers may initiate alloimmune responses after transplant in X-linked Alport patients. Thus, α345NC1 hexamers are the culprit alloantigen and primary target of all alloantibodies mediating APTN, whereas α1256NC1 hexamers become secondary targets of anti-α5NC1 alloantibodies. Reliable detection of alloantibodies by immunoassays using α345NC1 hexamers may improve outcomes by facilitating early, accurate diagnosis.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Florina
authors.initials: F
authors.lastname: Olaru
authors.forename: Wentian
authors.initials: W
authors.lastname: Luo
authors.forename: Xu-Ping
authors.initials: XP
authors.lastname: Wang
authors.forename: Linna
authors.initials: L
authors.lastname: Ge
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Hertz
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Kashtan
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sado
authors.forename: Yoav
authors.initials: Y
authors.lastname: Segal
authors.forename: Billy G
authors.initials: BG
authors.lastname: Hudson
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001485:Basement Membrane / Q000276:immunology; D002417:Cattle; D024141:Collagen Type IV / Q000737:chemistry / Q000276:immunology*; D018604:Epitope Mapping; D000882:Haplorhini; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007518:Isoantibodies / Q000097:blood / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009394:Nephritis, Hereditary / Q000276:immunology* / Q000601:surgery*; D011183:Postoperative Complications / Q000276:immunology; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D020836:Protein Structure, Quaternary; D014184:Transplantation, Homologous
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D007074:Immunoglobulin G; D007518:Isoantibodies; C057112:type IV collagen alpha3 chain