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

Autor: Marta Casal, Moura, Gwen E, Thompson, Darlene R, Nelson, Lynn A, Fussner, Amber M, Hummel, Dieter E, Jenne, Daniel, Emerling, Fernando C, Fervenza, Cees G M, Kallenberg, Carol A, Langford, W Joseph, McCune, Peter A, Merkel, Paul A, Monach, Philip, Seo, Robert F, Spiera, E William, St Clair, Steven R, Ytterberg, John H, Stone, William H, Robinson, Ulrich, Specks
Rok vydání: 2023
Předmět:
Zdroj: Arthritis & Rheumatology. 75:748-759
ISSN: 2326-5205
2326-5191
DOI: 10.1002/art.42418
Popis: Proteinase 3 (PR3) is the major antigen for anti-neutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3 anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) recognize different epitopes on PR3. We aimed to study the effect of mutations on PR3 antigenicity.The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing three point mutations in Epitope 15 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen the differential PR3-ANCA binding. A patient-derived monoclonal ANCA (moANCA518) that selectively binds to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 was used as a gauge of remote epitope activation. Selective binding was determined by inhibition experiments.Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with 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.The preferential binding of PR3-ANCAs from patients like 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 MCPR-2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding of variable performance characteristics of immunoassays and design of potential novel treatment approaches. This article is protected by copyright. All rights reserved.
Databáze: OpenAIRE
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