Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener's Granulomatosis

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2010
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Kuhl, Angelika
Korkmaz, Brice
Utecht, Bert
Schönermarck, Ulf
Specks, Ulrich
Jenne, Dieter E.
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Journal of Immunology. American Association of Immunologists. 2010, 185(1), pp. 387-399. ISSN 0022-1767. eISSN 1550-6606. Available under: doi: 10.4049/jimmunol.0903887
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Anti-neutrophil cytoplasmic Abs (cANCAs) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener’s granulomatosis (WG). Although the three-dimensional structure of PR3 is known, binding sites of mAbs and cANCAs have not been mapped to date. Competitive binding and biosensor experiments suggested the existence of four nonoverlapping areas on the PR3 surface. In this paper, we present an approach to identify these discontinuous surface regions that cannot be mimicked by linear peptides. The very few surface substitutions found in closely related PR3 homologs from primates, which were further varied by the construction of functional human-gibbon hybrids, resulted in the differential loss of three Ab binding sites, two of which were mapped to the N-terminal β-barrel and one to the linker segment connecting the N- and C-terminal barrels of PR3. The sera from WG patients differed in their binding to gibbon PR3 and the gibbon-human PR3 hybrid, and could be divided into two groups with similar or significantly reduced binding to gibbon PR3. Binding of almost all sera to PR3–α1-protease inhibitor (α1–PI) complexes was even more reduced and often absent, indicating that major antigenic determinants overlap with the active site surface on PR3 that associates with α1-PI. Similarly, the mouse mAbs CLB12.8 and 6A6 also did not react with gibbon PR3 and PR3–α1-PI complexes. Our data strongly suggest that cANCAs from WG patients at least in part recognize similar surface structures as do mouse mAbs and compete with the binding of α1-PI to PR3.

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ISO 690KUHL, Angelika, Brice KORKMAZ, Bert UTECHT, Andrea KNIEPERT, Ulf SCHÖNERMARCK, Ulrich SPECKS, Dieter E. JENNE, 2010. Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener's Granulomatosis. In: Journal of Immunology. American Association of Immunologists. 2010, 185(1), pp. 387-399. ISSN 0022-1767. eISSN 1550-6606. Available under: doi: 10.4049/jimmunol.0903887
BibTex
@article{Kuhl2010-07-01Mappi-52708,
  year={2010},
  doi={10.4049/jimmunol.0903887},
  title={Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener's Granulomatosis},
  number={1},
  volume={185},
  issn={0022-1767},
  journal={Journal of Immunology},
  pages={387--399},
  author={Kuhl, Angelika and Korkmaz, Brice and Utecht, Bert and Kniepert, Andrea and Schönermarck, Ulf and Specks, Ulrich and Jenne, Dieter E.}
}
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