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Abstract: TH-PO553

Autoantibodies Against Laminin-521 Are Pathogenic in Anti-Glomerular Basement Membrane Disease

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Kuang, Huang, Peking University First Hospital Department of Nephrology, Beijing, Beijing, China
  • Shen, Congrong, Peking University First Hospital Department of Nephrology, Beijing, Beijing, China
  • Jia, Xiao Yu, Peking University First Hospital Department of Nephrology, Beijing, Beijing, China
  • Cui, Zhao, Peking University First Hospital Department of Nephrology, Beijing, Beijing, China
  • Zhao, Ming-Hui, Peking University First Hospital Department of Nephrology, Beijing, Beijing, China
Background

We previously demonstrated that laminin-521 is a novel autoantigen within the GBM and that antibodies to laminin-521 are present in about one-third of patients. However, definitive evidence for a pathogenic role of these antibodies has been lacking.

Methods

In this study, a rare case of atypical anti-GBM disease whose serum was negative for anti-a3(IV)NC1 antibody prompted us to investigate the possible presence of autoantibodies binding to laminin-521. Additionally, WKY rats were immunized with recombinant human laminin-521 to test the pathogenicity of antibodies to laminin-521 in vivo. Disease control and negative control rats were immunized with recombinant human α3(IV)NC1 and phosphate-buffered saline, respectively.

Results

The patient was diagnosed with a kidney biopsy. Circulating autoantibodies reactive exclusively to laminin-521 were confirmed in this patient. Immunoblot results reveal circulating IgG from this patient binds α5 and γ1 chains. A decrease in antibody levels was observed and was associated with improved clinical presentation after plasmapheresis. In rats immunized with laminin-521, but not in negative controls, severe proteinuria, crescentic glomerulonephritis, IgG deposits, complement activation, and infiltration of T cells and macrophages were observed. Lung hemorrhage occurred in 75.0% (6/8) of rats. Besides, sera and kidney elutes from laminin-521 immunization rats demonstrated a high level of IgG binding to laminin-521 but not to human α3(IV)NC1, while the opposite was observed in human α3(IV)NC1-immunized rats.

Conclusion

Patient data and animal studies imply a causative role of autoantibodies against laminin-521 in the development of anti-GBM disease and aid in the understanding of its etiology.