'Classic' anti-neutrophil cytoplasmic autoantibodies (cANCA), 'Wegener's autoantigen' and their immunopathogenic role in Wegener's granulomatosis.
Wegener's autoantigen (WA), a 29 kD multifunctional protein, is the principal target antigen of autoantibodies associated with Wegener's granulomatosis (WG). WA was first identified as proteinase 3 (PR3), which is now known to be identical with myeloblastin and AGP7. Like other lysosomal proteins, WA/PR3 displays enzymatic activity, differentiation factor activity for myeloid precursor cells, and antimicrobial functions. Neutrophilic polymorphonuclear leukocytes (PMN) and a subpopulation of monocytes contain high levels of WA/PR3 in their myeloperoxidase-positive granules. The autoantibodies from WG sera produce a finely granular, centrally accentuated fluorescence pattern on PMN and monocytes and have been designated 'classic' pattern antineutrophil cytoplasmic autoantibodies (cANCA). However, PMN/monocyte activation (in vitro/ex vivo) is associated with the translocation of WA/PR3 on the cytoplasm membrane. WA/PR3 is accessible to the WG-associated autoantibody: cANCA stimulate cytokine-preactivated PMN to produce oxygen radicals and to degranulate. Furthermore, cANCA interfere with the biological functions of WA/PR3 (e.g. inhibition of elastinolytic activity). Hence, cANCA represents not only the best seromarker for WG so far available, but several lines of evidence indicate that the autoantibodies against WA/PR3 play a major role in the pathogenesis of this enigmatic disease.
Medical University in Lübeck, Department of Clinical Rheumatology, and Rhemaklinik Bad Bramstedt, Germany.
W L
WL
Gross
E
E
Csernok
B K
BK
Flesch
D000595:Amino Acid Sequence; D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D001483:Base Sequence; D003593:Cytoplasm / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D014890:Granulomatosis with Polyangiitis / Q000175:diagnosis / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D053146:Myeloblastin; D009504:Neutrophils / Q000276:immunology* / Q000648:ultrastructure; D009195:Peroxidase / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology* / Q000378:metabolism; D014657:Vasculitis / Q000145:classification / Q000175:diagnosis
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D001324:Autoantigens; D009195:Peroxidase; D012697:Serine Endopeptidases; D053146:Myeloblastin