Alternative Complement Pathway Induction by Anca

This Correspondence relates to "Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies" (Am J Pathol 2007, 170:52–64). This Correspondence relates to "Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies" (Am J Pathol 2007, 170:52–64). Last year J.C. Jennette and collaborators1Xiao H Schreiber A Heeringa P Falk RJ Jennette JC Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.Am J Pathol. 2007; 170: 52-64Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar published an excellent paper in The American Journal of Pathology, demonstrating that anti-neutrophil cytoplasmic antibodies (ANCA) induce disease via complement amplification in a mouse model for ANCA-induced glomerulonephritis and vasculitis. The data imply that these autoantibodies do not generate a regular immune complex that would have induced classical pathway complement activation. Instead, by binding to neutrophils, these autoantibodies induce the release of factors capable of stimulating complement amplification. The authors could not address the nature of these factors but list a few components that might be involved, such as the release of properdin, which could bind apoptotic cells, attract C3b, and generate an amplifying C3 convertase, as shown recently.2Xu W Berger SP Trouw LA de Boer HC Schlagwein N Mutsaers C Daha MR van Kooten C Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation.J Immunol. 2008; 180: 7613-7621PubMed Google Scholar However, as indicated, neutrophils also release proteases, among which elastase,2Xu W Berger SP Trouw LA de Boer HC Schlagwein N Mutsaers C Daha MR van Kooten C Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation.J Immunol. 2008; 180: 7613-7621PubMed Google Scholar cathepsin G,3Baici A Knöpfel M Fehr K Cleavage of the four human IgG subclasses with cathepsin G.Scand J Immunol. 1982; 16: 487-498Crossref PubMed Scopus (20) Google Scholar and PR34Dolman KM Jager A Sonnenberg A von dem Borne AE Goldschmeding R Proteolysis of classic anti-neutrophil cytoplasmic autoantibodies (C-ANCA) by neutrophil proteinase 3.Clin Exp Immunol. 1995; 101: 8-12Crossref PubMed Scopus (18) Google Scholar are known to generate F(ab′)2-like fragments from IgG molecules. F(ab′)2-containing immune complexes have been known for many years to stimulate complement amplification together with a serum factor.5Reid KB Complement fixation by the F(ab′)2-fragment of pepsin-treated rabbit antibody.Immunology. 1971; 20: 649-658PubMed Google Scholar My group has recently identified this factor as anti-hinge natural antibodies, which together with F(ab′)2-containing immune complexes generate rigidified, secondary immune complexes that capture dimeric C3b, a potent precursor of the amplifying C3 convertase in human plasma.6Fumia S Goede JS Fischler M Luginbühl A Frick S Fodor P Lutz HU Human F(ab′)2-containing immune complexes together with anti-hinge natural antibodies stimulate complement amplification in vitro and in vivo.Mol Immunol. 2008; 45: 2951-2961Crossref PubMed Scopus (28) Google Scholar It is, however, unlikely that this very same mechanism may operate in mice, since mice lack IgG anti-hinge natural antibodies.7Yano S Kaku S Suzuki K Terazaki C Sakayori T Kawasaki T Kawamura K Sugita Y Hoshino K Masuho Y Natural antibodies against the immunoglobulin F(ab′)2 fragment cause elimination of antigens recognized by the F(ab′)2 from the circulation.Eur J Immunol. 1995; 25: 3128-3133Crossref PubMed Scopus (17) Google Scholar On the other hand, it is possible that certain anti-idiotypic antibodies exert a similar effect in mice as ANCA-induced glomerular damage is significantly higher when splenocytes rather than the IgG fraction from MPO-immunized Mpo−/− mice are injected.1Xiao H Schreiber A Heeringa P Falk RJ Jennette JC Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.Am J Pathol. 2007; 170: 52-64Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 8Xiao H Heeringa P Hu P Liu Z Zhao M Aratani Y Maeda N Falk RJ Jennette JC Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.J Clin Invest. 2002; 110: 955-963Crossref PubMed Scopus (1019) Google Scholar I encourage researchers in this field to elucidate the actual mechanism of how ANCA antibodies mediate complement amplification in mice, so that we may gain better insight into how the mouse model differs from the events presumably operating in humans.