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Abstract: FR-PO582

Reduced ANCA-Sialylation Increases Anti-Myeloperoxidase-Induced Necrotizing Crescentic Glomerulonephritis in a Mouse Model

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Lodka, Dörte, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Rousselle, Anthony, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Lucke, Sylvia, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Ebert, Maximilian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Schneider, Udo, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Kettritz, Ralph, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Schreiber, Adrian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

The glycosylation of IgG and especially of autoantibodies is an important regulator of antibody functionality. It has already been described that IgG glycosylation affects the binding ability to Fc receptors. It is also known that the glycosylation pattern of ANCA is altered during active AAV. However, only a few studies showed a direct relationship between glycosylation patterns and cellular functionality in AAV-relevant processes. We tested the hypothesis that B cells from active AAV patients are hypoglycosylated and that hypoglycosylated ANCA trigger stronger neutrophil activation in vitro and more severe MPO-ANCA induced NCGN.

Methods

The glycosylation status of B cells from patients compared to healthy controls was analyzed by flow cytometry. IgG from patients with active AAV were sialylated and desialylated in vitro. These modified antibodies were used in neutrophil stimulation assays to investigate the influence of sialylation status on ROS production, NETs induction and IL-1b secretion. Anti-MPO NCGN was induced in WT mice by passive IgG-transfer from MPO-immunized mice. The administered IgG originated from either MPO-/- (normal IgG) or MPO-/-/St6gal1-/--mice (hyposialylated IgG). Histological evaluation of renal sections as well as flow cytometric analyses of blood and kidney cells were performed.

Results

B cells from active patients showed about a third reduced levels of sialic acid, terminal galactose and fucose compared to healthy controls. In vitro sialylation of IgG from active patients resulted in about 64%, 70% and 55% decreased ROS production, NETs formation and IL-1b secretion, respectively. Finally, mice receiving hyposialylated IgG from MPO-/-/St6gal1-/--mice showed worsened NCGN compared to mice receiving IgG from MPO-/--mice, as evidenced by an increased proportion of crescentic (20.9% vs. 8.4%) and necrotic (10.7% vs. 4.27%) glomeruli.

Conclusion

Glycosylation, especially sialylation of IgG, affects the severity of AAV disease. Increased IgG-sialylation had a protective effect as shown by reduced ROS production, NETs formation and IL-1b secretion in vitro. Conversely, sialic acid deficiency aggravated MPO-ANCA induced vasculitis in a murine disease model.

Funding

  • Government Support – Non-U.S.