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IgG Glycan Hydrolysis Attenuates ANCA-Mediated Glomerulonephritis

van Timmeren, Mirjan M.; van der Veen, Betty S.; Stegeman, Coen A.; Petersen, Arjen H.; Hellmark, Thomas; Collin, Mattias LU and Heeringa, Peter (2010) In Journal of the American Society of Nephrology 21(7). p.1103-1114
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of the American Society of Nephrology
volume
21
issue
7
pages
1103 - 1114
publisher
American Society of Nephrology
external identifiers
  • wos:000280447100011
  • scopus:77954614475
ISSN
1046-6673
DOI
10.1681/ASN.2009090984
language
English
LU publication?
yes
id
3ca6cdeb-fdd1-4baa-b0f7-2b4612762cab (old id 1654365)
date added to LUP
2010-08-26 12:46:02
date last changed
2018-05-29 10:32:49
@article{3ca6cdeb-fdd1-4baa-b0f7-2b4612762cab,
  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.},
  author       = {van Timmeren, Mirjan M. and van der Veen, Betty S. and Stegeman, Coen A. and Petersen, Arjen H. and Hellmark, Thomas and Collin, Mattias and Heeringa, Peter},
  issn         = {1046-6673},
  language     = {eng},
  number       = {7},
  pages        = {1103--1114},
  publisher    = {American Society of Nephrology},
  series       = {Journal of the American Society of Nephrology},
  title        = {IgG Glycan Hydrolysis Attenuates ANCA-Mediated Glomerulonephritis},
  url          = {http://dx.doi.org/10.1681/ASN.2009090984},
  volume       = {21},
  year         = {2010},
}