Frontiers in Immunology (Oct 2019)

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

DOI
https://doi.org/10.3389/fimmu.2019.02467
Journal volume & issue
Vol. 10

Abstract

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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.

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