Cong-Rong Shen1, Xiao-Yu Jia1, Wentian Luo2, Florina Olaru2, Zhao Cui1, Ming-Hui Zhao1,3, Dorin-Bogdan Borza4. 1. Renal Division, Institute of Nephrology, Peking University First Hospital, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China. 2. Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee. 3. Peking-Tsinghua Center for Life Sciences, Beijing, China. 4. Department of Microbiology, Immunology and Physiology, Meharry Medical College, Nashville, Tennessee dborza@mmc.edu.
Abstract
BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within α345(IV) collagen-a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known. METHODS: A retrospective study of circulating autoantibodies from 101 patients with anti-GBM/Goodpasture's disease and 85 controls used a solid-phase immunoassay to measure IgG binding to human recombinant laminin-521 with native-like structure and activity. RESULTS: Circulating IgG autoantibodies binding to laminin-521 were found in about one third of patients with anti-GBM antibody GN, but were not detected in healthy controls or in patients with other glomerular diseases. Autoreactivity toward laminin-521 was significantly more common in patients with anti-GBM GN and lung hemorrhage, compared with those with kidney-limited disease (51.5% versus 23.5%, P=0.005). Antilaminin-521 autoantibodies were predominantly of IgG1 and IgG4 subclasses and significantly associated with lung hemorrhage (P=0.005), hemoptysis (P=0.008), and smoking (P=0.01), although not with proteinuria or serum creatinine at diagnosis. CONCLUSIONS: Besides α345(IV) collagen, laminin-521 is another major autoantigen targeted in anti-GBM disease. Autoantibodies to laminin-521 may have the potential to promote lung injury in anti-GBM disease by increasing the total amount of IgG bound to the alveolar basement membranes.
BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within α345(IV) collagen-a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known. METHODS: A retrospective study of circulating autoantibodies from 101 patients with anti-GBM/Goodpasture's disease and 85 controls used a solid-phase immunoassay to measure IgG binding to human recombinant laminin-521 with native-like structure and activity. RESULTS: Circulating IgG autoantibodies binding to laminin-521 were found in about one third of patients with anti-GBM antibody GN, but were not detected in healthy controls or in patients with other glomerular diseases. Autoreactivity toward laminin-521 was significantly more common in patients with anti-GBM GN and lung hemorrhage, compared with those with kidney-limited disease (51.5% versus 23.5%, P=0.005). Antilaminin-521 autoantibodies were predominantly of IgG1 and IgG4 subclasses and significantly associated with lung hemorrhage (P=0.005), hemoptysis (P=0.008), and smoking (P=0.01), although not with proteinuria or serum creatinine at diagnosis. CONCLUSIONS: Besides α345(IV) collagen, laminin-521 is another major autoantigen targeted in anti-GBM disease. Autoantibodies to laminin-521 may have the potential to promote lung injury in anti-GBM disease by increasing the total amount of IgG bound to the alveolar basement membranes.
Authors: Vadim Pedchenko; Olga Bondar; Agnes B Fogo; Roberto Vanacore; Paul Voziyan; A Richard Kitching; Jörgen Wieslander; Clifford Kashtan; Dorin-Bogdan Borza; Eric G Neilson; Curtis B Wilson; Billy G Hudson Journal: N Engl J Med Date: 2010-07-22 Impact factor: 91.245
Authors: Michael A Fox; Joshua R Sanes; Dorin-Bogdan Borza; Veraragavan P Eswarakumar; Reinhard Fässler; Billy G Hudson; Simon W M John; Yoshifumi Ninomiya; Vadim Pedchenko; Samuel L Pfaff; Michelle N Rheault; Yoshikazu Sado; Yoav Segal; Michael J Werle; Hisashi Umemori Journal: Cell Date: 2007-04-06 Impact factor: 41.582
Authors: R A Pierce; G L Griffin; M S Mudd; M A Moxley; W J Longmore; J R Sanes; J H Miner; R M Senior Journal: Am J Respir Cell Mol Biol Date: 1998-08 Impact factor: 6.914
Authors: Dale R Abrahamson; Brooke M Steenhard; Larysa Stroganova; Adrian Zelenchuk; Patricia L St John; Margaret G Petroff; Manuel Patarroyo; Dorin Bogdan Borza Journal: Kidney Int Date: 2019-07-10 Impact factor: 10.612
Authors: Sophie Ohlsson; Hans Herlitz; Sigrid Lundberg; Daina Selga; Johan Mölne; Jörgen Wieslander; Mårten Segelmark Journal: Am J Kidney Dis Date: 2013-11-01 Impact factor: 8.860