title: Cloning and functional expression of the murine homologue of proteinase 3: implications for the design of murine models of vasculitis.
abstract: Anti-neutrophil cytoplasmic autoantibodies recognizing conformational epitopes (c-ANCA) of proteinase 3 (PR3) from azurophil granules are a diagnostic hallmark in Wegener's granulomatosis (WG). Because a functional PR3 homologue has not been identified in rodents, it is difficult to assess immunopathological responses in rats or mice immunized with patients' derived c-ANCA or human PR3. Here we report the full length cDNA cloning and functional expression of murine PR3 in HMC-1 cells. Recombinant murine PR3 shows highly similar substrate specificities towards synthetic peptides and is inhibited by human alpha1-proteinase inhibitor like human PR3. However, neither human c-ANCA, rabbit sera nor mouse monoclonal antibodies to human PR3 recognize the murine homologue. Consequently, it is unlikely that disease observed in mice after immunization with c-ANCA or human PR3 is caused by pathogenic antibodies directed against mouse PR3. Recombinant human-mouse chimaeric variants will be a valuable new tool to localize the disease-specific immunodominant epitopes in human PR3.
authors.affiliation: Max-Planck-Institut für Psychiatrie, Abt. Neuroimmunologie, Martinsried, Germany.
authors.forename: D E
authors.initials: DE
authors.lastname: Jenne
authors.forename: L
authors.initials: L
authors.lastname: Fröhlich
authors.forename: A M
authors.initials: AM
authors.lastname: Hummel
authors.forename: U
authors.initials: U
authors.lastname: Specks
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D000918:Antibody Specificity; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008407:Mast Cells / Q000201:enzymology; D051379:Mice; D008969:Molecular Sequence Data; D053146:Myeloblastin; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014657:Vasculitis / Q000276:immunology*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D000939:Epitopes; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; D012697:Serine Endopeptidases; D053146:Myeloblastin