Passive Transfer of Anti-MPO Antibodies (1)
Enhancement of glomerular injury caused by anti-glomerular basement membrane (GBM) antibodies when co-administered with anti-Myeloperoxidase (MPO) serum. Mouse models of anti-MPO GN involving passive transfer of anti-MPO antibodies were subsequently developed. Transfer of anti-MPO IgG, from MPO-immunized Mpo−/−mice, into C57BL/6 mice and Rag2−/−mice (that lack T and B lymphocytes) caused focal necrotising and crescentic pauci-immune GN, demonstrating the pathogenicity of ANCA in vivo and its role in acute glomerular injury.
Disease is usually more severe when pro-inflammatory signals, such as lipopolysaccharide (LPS), are administered around the time of antibody transfer. Administration of LPS shortly after anti-MPO antibody transfer, with subsequent elevation in tumor necrosis factor (TNF) and circulating MPO levels, was shown to result in a significantly greater proportion of glomerular crescents and glomerular necrosis.
Complement activation may be an important player. C5 deficient mice or mice treated with a neutralizing anti-C5a antibody were protected from glomerular damage after passive transfer of anti-MPO IgG. C3 depletion with Cobra Venom Factor(CVF) prevented GN after passive transfer of anti-MPO IgG or anti-MPO splenocytes, however, C3aR deficient mice are not protected. C3 is upstream in the complement cascade, its role in neutrophil activation is as a precursor for C5a generation.
In a murine model, anti-MPO antibodies were shown to bind to circulating neutrophils, altering adhesion molecules and inducing glomerular leukocyte adhesion via multiple pathways. Mechanisms of adhesion to the glomerular endothelium were affected by the dose of anti-MPO antibodies, as well as pre-treatment with LPS to modela pre-existing inflammatory state. C5a was shown to play an important role in MPO-ANCA induced neutrophil retention and activation within the glomerulus.
After activation by ANCA and localization to vulnerable vascular beds, neutrophils degranulate but they can also undergo cell death via multiple mechanisms, including neutrophil extracellular trap (NET) formation (known as NETosis). After anti-MPO antibody transfer into mice, enhanced degradation of NETs by administration of DNase I was protective against development of anti-MPO antibody GN.
The effects of factors such as environmental exposures onAAV are unclear. However, age is a risk factor for AAV development and severity. Anti-MPO antibodies were passively transferred into recipient aged mice. Aged mice developed more severe GN, with increased circulating and glomerular neutrophils and increased gene expression of pro-inflammatory cytokines. Although costly, aged mice may better model aged humans and in the future may contribute significantly to the understanding of disease pathogenesis and to studies of new treatments for AAV.