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Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis

Roth, A. J., Ooi, J. D., Hess, J. J., van Timmeren, M. M., Berg, E. A., Poulton, C. E., McGregor, J., Burkart, M., Hogan, S. L., Hu, Y., Winnik, W., Nachman, P. H., Stegeman, C. A., Niles, J., Heeringa, P., Kitching, A. R., Holdsworth, S., Jennette, J. C., Preston, G. A. & Falk, R. J., Apr-2013, In : The Journal of Clinical Investigation. 123, 4, p. 1773-1783 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Aleeza J. Roth
  • Joshua D. Ooi
  • Jacob J. Hess
  • Mirjan M. van Timmeren
  • Elisabeth A. Berg
  • Caroline E. Poulton
  • JulieAnne McGregor
  • Madelyn Burkart
  • Susan L. Hogan
  • Yichun Hu
  • Witold Winnik
  • Patrick H. Nachman
  • Coen A. Stegeman
  • John Niles
  • Peter Heeringa
  • A. Richard Kitching
  • Stephen Holdsworth
  • J. Charles Jennette
  • Gloria A. Preston
  • Ronald J. Falk

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.

Original languageEnglish
Pages (from-to)1773-1783
Number of pages11
JournalThe Journal of Clinical Investigation
Volume123
Issue number4
Publication statusPublished - Apr-2013

    Keywords

  • ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES, SMALL-VESSEL VASCULITIS, MPO-ANCA, MICROSCOPIC POLYANGIITIS, WEGENERS-GRANULOMATOSIS, NATURAL AUTOANTIBODIES, BASEMENT-MEMBRANE, MYELOPEROXIDASE, GLOMERULONEPHRITIS, CERULOPLASMIN

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