C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies

Ellen Toyonaga, Wataru Nishie, Kentaro Izumi, Ken Natsuga, Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Yoshiaki Hirako, Daisuke Sawamura, Wataru Fujimoto, Hiroshi Shimizu

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Transmembrane collagen XVII (COL17) is a hemidesmosomal component of basal keratinocytes that can be targeted by autoantibodies in autoimmune blistering disorders, including linear IgA dermatosis (LAD). COL17 can be physiologically cleaved within the juxtamembranous extracellular NC16A domain, and LAD autoantibodies preferentially react with the processed ectodomains, indicating that the processing induces neoepitopes. However, the details of how neoepitopes develop have not been elucidated. In this study, we show that C-terminal processing of COL17 also plays a role in inducing neoepitopes for LAD autoantibodies. First, the mAb hC17-ect15 targeting the 15th collagenous domain of COL17 was produced, which showed characteristics similar to LAD autoantibodies. The mAbs preferentially reacted with C-terminally deleted (up to 682 amino acids) recombinant COL17, suggesting that C-terminal processing shows neoepitopes on the 15th collagenous domain. The LAD autoantibodies also react with C-terminal deleted COL17. Therefore, neoepitopes for LAD autoantibodies also develop after C-terminal processing. Finally, the passive transfer of the mAb hC17-ect15 into human COL17-expressing transgenic mice failed to induce blistering disease, suggesting that neoepitope-targeting antibodies are not always pathogenic. In summary, this study shows that C-terminal processing induces dynamic structural changes and neoepitopes for LAD autoantibodies on COL17.

Original languageEnglish
Pages (from-to)2552-2559
Number of pages8
JournalJournal of Investigative Dermatology
Volume137
Issue number12
DOIs
Publication statusPublished - 2017 Dec

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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    Toyonaga, E., Nishie, W., Izumi, K., Natsuga, K., Ujiie, H., Iwata, H., Yamagami, J., Hirako, Y., Sawamura, D., Fujimoto, W., & Shimizu, H. (2017). C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies. Journal of Investigative Dermatology, 137(12), 2552-2559. https://doi.org/10.1016/j.jid.2017.07.831