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Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3.

Authors :
Casal Moura M
Thompson GE
Nelson DR
Fussner LA
Hummel AM
Jenne DE
Emerling D
Fervenza FC
Kallenberg CGM
Langford CA
McCune WJ
Merkel PA
Monach PA
Seo P
Spiera RF
St Clair EW
Ytterberg SR
Stone JH
Robinson WH
Specks U
Source :
Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2023 May; Vol. 75 (5), pp. 748-759. Date of Electronic Publication: 2023 Mar 07.
Publication Year :
2023

Abstract

Objective: Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3-targeting ANCAs (PR3-ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity.<br />Methods: The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen for differential PR3-ANCA binding. A patient-derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation-free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments.<br />Results: Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared to iPR3. This differential binding of PR3-ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518.<br />Conclusion: The preferential binding of PR3-ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches.<br /> (© 2022 American College of Rheumatology.)

Details

Language :
English
ISSN :
2326-5205
Volume :
75
Issue :
5
Database :
MEDLINE
Journal :
Arthritis & rheumatology (Hoboken, N.J.)
Publication Type :
Academic Journal
Accession number :
36515151
Full Text :
https://doi.org/10.1002/art.42418