Remote Activation of a Latent Epitope in an Autoantigen Decoded With Simulated B-Factors. Frontiers in immunology Pang, Y., Casal Moura, M., Thompson, G. E., Nelson, D. R., Hummel, A. M., Jenne, D. E., Emerling, D., Volkmuth, W., Robinson, W. H., Specks, U. 2019; 10: 2467

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.

View details for DOI 10.3389/fimmu.2019.02467

View details for PubMedID 31708920