{"doi":"10.1002/art.42418","title":"Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3","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. 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. 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. 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.","journal":"Arthritis & Rheumatology","year":2022,"id":288410,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":969216,"name":"Gwen Thompson","orcid":"0000-0002-3022-4035","position":1,"is_corresponding":false},{"id":969217,"name":"Darlene R. Nelson","orcid":"0000-0001-9287-1222","position":2,"is_corresponding":false},{"id":969218,"name":"Lynn A. Fussner","orcid":"0000-0003-0944-0216","position":3,"is_corresponding":false},{"id":725332,"name":"Amber M. Hummel","orcid":null,"position":4,"is_corresponding":false},{"id":969219,"name":"Dieter E. Jenne","orcid":"0000-0002-1125-9144","position":5,"is_corresponding":false},{"id":573925,"name":"Daniel Emerling","orcid":"0000-0002-8754-9201","position":6,"is_corresponding":false},{"id":242666,"name":"Fernando C. Fervenza","orcid":"0000-0002-9952-209X","position":7,"is_corresponding":false},{"id":25204,"name":"Cees G. M. Kallenberg","orcid":null,"position":8,"is_corresponding":false},{"id":251775,"name":"Carol A. Langford","orcid":"0000-0001-9498-321X","position":9,"is_corresponding":false},{"id":315994,"name":"W. Joseph McCune","orcid":null,"position":10,"is_corresponding":false},{"id":5969,"name":"Peter A. Merkel","orcid":"0000-0001-9284-7345","position":11,"is_corresponding":false},{"id":61593,"name":"Paul A. Monach","orcid":"0000-0003-4937-0515","position":12,"is_corresponding":false},{"id":328460,"name":"Philip Seo","orcid":"0000-0003-3435-6737","position":13,"is_corresponding":false},{"id":251783,"name":"Robert Spiera","orcid":"0000-0003-2911-6800","position":14,"is_corresponding":false},{"id":280488,"name":"E. William St. Clair","orcid":"0000-0003-1181-0650","position":15,"is_corresponding":false},{"id":328461,"name":"Steven R. Ytterberg","orcid":"0000-0001-5215-1263","position":16,"is_corresponding":false},{"id":25215,"name":"John H. Stone","orcid":"0000-0001-6588-9435","position":17,"is_corresponding":false},{"id":226251,"name":"William H. Robinson","orcid":"0000-0003-4385-704X","position":18,"is_corresponding":false},{"id":25214,"name":"Ulrich Specks","orcid":"0000-0002-6559-1206","position":19,"is_corresponding":false},{"id":898198,"name":"Marta Casal Moura","orcid":"0000-0001-7439-6501","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:30:14.968626Z","pmid":"36515151","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}