IgG glycan hydrolysis attenuates ANCA-mediated glomerulonephritis.
van Timmeren MM, van der Veen BS, Stegeman CA, Petersen AH, Hellmark T, Collin M,
Heeringa P. J Am Soc Nephrol. 2010, 21:1103.
Elimination of pathogenic IgG in autoimmune patients:
Rapidly progressive glomerulonephritis (RPGN) is acute glomerulonephritis (GN) in association with a 50% or more decrease in glomerular filtration rate within a 3-month period. If left untreated, RPGN rapidly progresses into acute renal failure and death within months. Pathologically, RPGN are immune-mediated renal diseases that are classified into: (1) anti-glomerular basement membrane (anti-GBM) disease, (2) immune complex GN, and (3) pauci-immune GN. In these diseases, (auto)antibodies as a constituent of immune complexes play a pivotal role in triggering inflammatory processes. The bound antibodies can trigger and enhance inflammation by activation of the complement cascade and/or FcγReceptor (FcγR)-bearing effector cells leading to organ damage that causes clinical pathology. Elimination of pathogenic IgG from the circulation in these autoimmune patients is pivotal for disease remission. Plasmapheresis and immunoadsorption are commonly used methods but have their limitations.
EndoS causes complete hydrolysis of circulating IgG:
The recently discovered enzyme Endoglycosidase S (EndoS) is secreted by Streptococcus pyogenes and has specific endoglycosidase activity on native IgG by hydrolyzing the conserved asparagine-linked glycans on the heavy chains of IgG. EndoS hydrolyzes all subclasses of human IgG and almost completely abolishes IgG binding to FγcRs and IgG-dependent complement activation. In vivo, administration of EndoS to mice causes complete hydrolysis of circulating IgG within hours that lasts for several days. Importantly, in vivo EndoS administration does not affect glycosylated plasma proteins other than IgG and has no detectable adverse effects. Moreover, repeated EndoS injections induce only a minimal immune response against the enzyme that does not affect its activity. Interestingly, pretreatment of pathogenic autoantibodies with EndoS abrogates disease development in mouse models of arthritis and immune thrombocytopenic purpura (ITP). Systemic injection of EndoS also rescues mice from already established ITP and inhibits pathology in lupus prone mice. All these favorable characteristics suggest that EndoS is an attractive therapeutic option for conditions driven by pathogenic IgG (auto)antibodies.
Cleavage of glycan groups inhibits development of (auto)immune-mediated diseases:
We hypothesized that cleavage of glycan groups from the Fc heavy chain of IgG by the bacterial enzyme EndoS inhibits the development of (auto)immune-mediated renal diseases. As a model for (auto)immune-mediated glomerulonephritis we employed a well described mouse model for anti-myeloperoxidase (MPO) IgG-mediated GN.
EndoS treatment of ANCA IgG:
In vitro studies demonstrated that EndoS treatment of ANCA IgG significantly attenuated ANCA-mediated neutrophil activation without affecting antigen binding capacity. More specifically, ANCA IgG mediated neutrophil oxygen radical production and degranulation of lactoferrin and elastase were diminished to a large extent upon ANCA IgG treatemt with.EndoS. In vivo, EndoS pretreatment of anti-MPO IgG reduced hematuria, leukocyturia, and albuminuria in the mouse model of anti-MPO IgG-induced GN. Early glomerular neutrophil influx was diminished and glomerular crescent formation was markedly attenuated. Furthermore, systemic treatment with EndoS after 3h reduced albuminuria and glomerular crescent formation, while EndoS treatment after 24h did not attenuate disease parameters.
Conclusion:
These results suggest that modulation of IgG glycosylation by EndoS is a promising strategy to interfere with the early ANCA-mediated inflammatory processes.