Perlecan Is a Novel Target of Autoantibodies in Anti-glomerular Basement Membrane Disease

Background: Anti-glomerular basement membrane (anti-GBM) disease is an autoimmune kidney disease in which autoantibodies are directed against GBM components. Type IV collagen and laminin α5β2γ1 (LM521) within GBM are two major target antigens in anti-GBM disease. Perlecan is a type of heparan sulfate proteoglycan, ubiquitously expressed in basement membranes, and a target of antibodies implicated in allograft rejection. The present study aimed to investigate whether perlecan could be recognized by anti-GBM antibodies, and further analyzed the properties and clinical associations of anti-perlecan antibodies. Methods: A total of 108 patients diagnosed with anti-GBM disease between January 2000 to December 2018 were included in the study. Additionally, one hundred patients with various active glomerular diseases were utilized as disease controls, along with 20 health controls. IgG antibodies against perlecan were detected by enzyme-linked immunosorbent assay and immunoblot. Results: Circulating IgG antibodies against perlecan were detected in 18.5% (10/108) of the anti-GBM patients, but not in healthy controls or any other disease controls. Anti-perlecan IgG antibodies were predominantly of IgG3 subclass. Patients with anti-perlecan autoantibodies had a higher prevalence of lung hemorrhage than those without (55.0% vs 26.1%, P = 0.012). A “triple-positive” subgroup in anti-GBM disease was identified, who had circulating autoantibodies simultaneously against type IV collagen, laminin 521, and perlecan. This subgroup had the highest prevalence of lung hemorrhage (66.7%, 10/15) and incidence of end-stage kidney disease events (93.3%, 14/15), indicating a more aggressive immune-mediated tissue injury among these patients. Conclusion: Perlecan was identified as another novel target in anti-GBM disease and expanded the repertoire of target antigens of anti-GBM antibodies. The discovery of autoantibodies against perlecan identified a triple-positive subgroup with more severe clinical phenotype among patients with anti-GBM disease. The pathogenic role of autoimmunity against perlecan and the pathophysiology of the co-presence of three autoantibodies merit further investigation in future.