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

TITLE=Remote Activation of a Latent Epitope in an Autoantigen Decoded With Simulated B-Factors

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02467

DOI=10.3389/fimmu.2019.02467

ISSN=1664-3224

ABSTRACT=<p>Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val<sup>103</sup> possessing a Ser195Ala mutation relative to wild-type PR3-Val<sup>103</sup>—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-Val<sup>103</sup>, a triple mutant of iPR3-Val<sup>103</sup>, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val<sup>103</sup> was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val<sup>103</sup> 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.</p>