IgG Glycan Hydrolysis Attenuates ANCA-Mediated Glomerulonephritis

Mirjan M. van Timmeren, Betty S. van der Veen, Coen A. Stegeman, Arjen H. Petersen, Thomas Hellmark, Mattias Collin, Peter Heeringa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

92 Citations (Scopus)

Abstract

Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MPO) and proteinase 3 (Pr3) are considered pathogenic in ANCA-associated necrotizing and crescentic glomerulonephritis (NCGN) and vasculitis. Modulation of ANCA IgG glycosylation may potentially reduce its pathogenicity by abolishing Fc receptor mediated activation of leukocytes and complement Here, we investigated whether IgG hydrolysis by the bacterial enzyme endoglycosidase S (EndoS) attenuates ANCA-mediated NCGN. In vitro, treatment of ANCA IgG with EndoS significantly attenuated ANCA-mediated neutrophil activation without affecting antigen-binding capacity. In a mouse model of antiMPO IgG/LPS-induced NCGN, we induced disease with either unmodified or EndoS-treated (deglycosylated) anti-MPO IgG. In separate experiments, we administered EndoS systemically after disease induction with unmodified anti-MPO IgG. Pretreatment of anti-MPO IgG with EndoS reduced hematuria, leukocyturia, and albuminuria and attenuated both neutrophil influx and formation of glomerular crescents After inducing disease with unmodified anti-MPO IgG, systemic treatment with EndoS reduced albuminuria and glomerular crescent formation when initiated after 3 but not 24 hours. In conclusion, IgG glycan hydrolysis by EndoS attenuates ANCA-induced neutrophil activation in vitro and prevents induction of anti-MPO IgG/LPS-mediated NCGN m vivo. Systemic treatment with EndoS early after disease induction attenuates the development of disease. Thus, modulation of IgG glycosylation is a promising strategy to interfere with ANCA-mediated inflammatory processes.

Original languageEnglish
Pages (from-to)1103-1114
Number of pages12
JournalJournal of the American Society of Nephrology
Volume21
Issue number7
DOIs
Publication statusPublished - Jul-2010

Keywords

  • ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES
  • INTERACTIONS IN-VIVO
  • SYSTEMIC VASCULITIS
  • HUMAN NEUTROPHILS
  • CRESCENTIC GLOMERULONEPHRITIS
  • WEGENERS GRANULOMATOSIS
  • STREPTOCOCCUS-PYOGENES
  • ANTIBODIES
  • FC
  • MYELOPEROXIDASE

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