Remote activation of a latent epitope in an autoantigen decoded with simulated b-factors

Yuan Ping Pang, Marta Casal Moura, Gwen E. Thompson, Darlene R. Nelson, Amber M. Hummel, Dieter E. Jenne, Daniel Emerling, Wayne Volkmuth, William H. Robinson, Ulrich Specks

Research output: Contribution to journalArticle

Abstract

Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103 —offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3·ANCA interactions as new GPA treatments.

Original languageEnglish (US)
Article number2467
JournalFrontiers in immunology
Volume10
Issue numberOCT
DOIs
StatePublished - Jan 1 2019

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Keywords

  • Antigenicity
  • Antineutrophil cytoplasmic antibody
  • Autoantigen
  • Autoimmunity
  • B-factor
  • Proteinase 3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Pang, Y. P., Moura, M. C., Thompson, G. E., Nelson, D. R., Hummel, A. M., Jenne, D. E., Emerling, D., Volkmuth, W., Robinson, W. H., & Specks, U. (2019). Remote activation of a latent epitope in an autoantigen decoded with simulated b-factors. Frontiers in immunology, 10(OCT), [2467]. https://doi.org/10.3389/fimmu.2019.02467