Impact Factor 4.716 | CiteScore 4.71
More on impact ›

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02467

Remote Activation of a Latent Epitope in an Autoantigen Decoded with Simulated B-Factors

 Yuan-Ping Pang1*,  Marta Casal Moura1, Gwen E. Thompson1, Darlene R. Nelson1, Amber M. Hummel1,  Dieter E. Jenne2,  Daniel Emerling3,  Wayne Volkmuth3, William H. Robinson4 and  Ulrich Specks1*
  • 1Mayo Clinic, United States
  • 2Max Planck Institute of Neurobiology (MPIN), Germany
  • 3Atreca, Inc, United States
  • 4Stanford University, United States

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.

Keywords: Autoimmunity, autoantigen, Antigenicity, Antineutrophil cytoplasmic antibody, Proteinase 3, b-factor

Received: 07 Aug 2019; Accepted: 03 Oct 2019.

Copyright: © 2019 Pang, Casal Moura, Thompson, Nelson, Hummel, Jenne, Emerling, Volkmuth, Robinson and Specks. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Yuan-Ping Pang, Mayo Clinic, Rochester, United States, pang@mayo.edu
Prof. Ulrich Specks, Mayo Clinic, Rochester, United States, specks.ulrich@mayo.edu