title: Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis.
abstract: Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCA-negative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Aleeza J
authors.initials: AJ
authors.lastname: Roth
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Hess
authors.forename: Mirjan M
authors.initials: MM
authors.lastname: van Timmeren
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Berg
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Poulton
authors.forename: JulieAnne
authors.initials: J
authors.lastname: McGregor
authors.forename: Madelyn
authors.initials: M
authors.lastname: Burkart
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hogan
authors.forename: Yichun
authors.initials: Y
authors.lastname: Hu
authors.forename: Witold
authors.initials: W
authors.lastname: Winnik
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Nachman
authors.forename: Coen A
authors.initials: CA
authors.lastname: Stegeman
authors.forename: John
authors.initials: J
authors.lastname: Niles
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Stephen
authors.initials: S
authors.lastname: Holdsworth
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Preston
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood / Q000276:immunology*; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology* / Q000302:isolation & purification; D016022:Case-Control Studies; D002570:Ceruloplasmin / Q000737:chemistry; D002648:Child; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000097:blood; D009195:Peroxidase / Q000737:chemistry / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D010446:Peptide Fragments; D009195:Peroxidase; D002570:Ceruloplasmin
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