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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-10-01
• Series: Frontiers in Immunology
• Subjects: autoimmunity; autoantigen; antigenicity; antineutrophil cytoplasmic antibody; Proteinase 3; B-factor
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2019.02467/full

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.