Anti-neutrophil cytoplasmic antibodies target sequential functional proteinase 3 epitopes in the sera of patients with Wegener's granulomatosis

Many patients with Wegener's granulomatosis (WG) have anti-neutrophil cytoplasmic antibodies (c-ANCA). Aside from being a diagnostic marker, these autoantibodies may play roles in disease pathogenesis. Proteinase 3 (PR3) is the primary target of c-ANCA in WG patient sera. Of 60 c-ANCA-positive...

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Bibliographic Details
Published in:	Clinical and experimental immunology Vol. 162; no. 2; pp. 262 - 270
Main Authors:	Bruner, B.F, Vista, E.S, Wynn, D.M, Harley, J.B, James, J.A
Format:	Journal Article
Language:	English
Published:	Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-11-2010 Blackwell Publishing Ltd Blackwell Oxford University Press Blackwell Science Inc
Subjects:	Adolescent Adult Aged Aged, 80 and over Algorithms Amino Acid Sequence Analytical, structural and metabolic biochemistry Antibodies, Antineutrophil Cytoplasmic - blood Antibodies, Antineutrophil Cytoplasmic - immunology Binding sites Biological and medical sciences epitope mapping Epitopes, B-Lymphocyte - chemistry Epitopes, B-Lymphocyte - immunology Female Fundamental and applied biological sciences. Psychology Granulomatosis with Polyangiitis - immunology Humans Isoelectric Point Male Medical research Medical sciences Middle Aged Models, Molecular Myeloblastin - chemistry Myeloblastin - immunology Pathogenesis Patients Peptide Fragments - chemistry Peptide Fragments - immunology PR3 Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis Surface Properties Translational Studies vasculitis Wegener's granulomatosis Young Adult Human Cartography Serine endopeptidases Antineutrophil cytoplasmic antibody Targeting Antigenic determinant Enzyme Cardiovascular disease Wegener granulomatosis Biochemistry epitope mapping Vascular disease PR3 Peptidases Vasculitis Sequential Systemic disease Hydrolases Serum Myeloblastin Wegener's granulomatosis
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Summary:	Many patients with Wegener's granulomatosis (WG) have anti-neutrophil cytoplasmic antibodies (c-ANCA). Aside from being a diagnostic marker, these autoantibodies may play roles in disease pathogenesis. Proteinase 3 (PR3) is the primary target of c-ANCA in WG patient sera. Of 60 c-ANCA-positive patients, 10 patients were selected for detailed humoral epitope analysis, contingent upon serum availability, using samples with positive levels of anti-PR3 by enzyme-linked immunosorbent assay (ELISA). Sequential epitope specificities of anti-PR3 antibodies detected by screening the maximally overlapping solid-phase octapeptides of PR3 showed seven major common antigenic targets bound by WG patient sera. These include novel and previously identified sequential PR3 epitopes bound by c-ANCA. B cell epitope prediction algorithms identified all or part of the seven defined epitopes. Several epitopes share sequence and structural proximity with functional sites, including the catalytic triad and proposed binding sites of other potential proteins [PR3 complementary peptide and soluble endothelial protein C receptor (sEPCR)]. Epitope 4 (VVLGAHNVRTQ) had the highest binding prevalence (90%) and epitope 2 (AQPHSRPYMAS) has the highest average reactivity of the antigenic regions. Epitope 4 includes the interaction site between sEPCR and PR3 which may serve as an important interaction to down-regulate inflammation. Epitopes 3, 5 and 7 are in direct proximity to amino acids that form the catalytic triad of the protein. c-ANCA targets both unique and previously known sequential PR3 peptides. This information may prove useful in understanding anti-PR3-mediated disease pathogenesis in systemic vasculitides.
Bibliography:	http://dx.doi.org/10.1111/j.1365-2249.2010.04251.x ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0009-9104 1365-2249
DOI:	10.1111/j.1365-2249.2010.04251.x