Laminin-521 is a novel target of autoantibodies associated with lung hemorrhage in anti-gbm disease

Abstract

Background Antiglomerular basement membrane (anti-GBM) disease is characterized byGNand often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within a345(IV) collagen-a major component of the glomerular and alveolar basementmembranes. 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 IgGautoantibodies binding to laminin-521were found in about one third of patientswith 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%, P50.005). Antilaminin-521autoantibodieswerepredominantly of IgG1 andIgG4 subclasses andsignificantly associated with lung hemorrhage (P50.005), hemoptysis (P50.008), and smoking (P50.01), although not with proteinuria or serum creatinine at diagnosis. Conclusions Besides a345(IV) collagen, laminin-521 is anothermajor 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.