title: IgG glycan hydrolysis attenuates ANCA-mediated glomerulonephritis.
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 anti-MPO 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 in 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.
authors.affiliation: Departments of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, Netherlands.
authors.forename: Mirjan M
authors.initials: MM
authors.lastname: van Timmeren
authors.forename: Betty S
authors.initials: BS
authors.lastname: van der Veen
authors.forename: Coen A
authors.initials: CA
authors.lastname: Stegeman
authors.forename: Arjen H
authors.initials: AH
authors.lastname: Petersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Hellmark
authors.forename: Mattias
authors.initials: M
authors.lastname: Collin
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000378:metabolism*; D001426:Bacterial Proteins / Q000494:pharmacology; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D006026:Glycoside Hydrolases / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007074:Immunoglobulin G / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000276:immunology; D011134:Polysaccharides / Q000378:metabolism*; D013997:Time Factors
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D011134:Polysaccharides; D009195:Peroxidase; D006026:Glycoside Hydrolases; C431325:NDOS protein, Streptococcus pyogenes
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