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

Autor: Casal Moura M; Mayo Clinic and Foundation, Rochester, Minnesota, and Faculdade de Medicina da Universidade do Porto, Porto, Portugal., Thompson GE; Mayo Clinic and Foundation, Rochester, Minnesota., Nelson DR; Mayo Clinic and Foundation, Rochester, Minnesota., Fussner LA; Mayo Clinic and Foundation, Rochester, Minnesota, and the Ohio State University, Columbus, Ohio., Hummel AM; Mayo Clinic and Foundation, Rochester, Minnesota., Jenne DE; Max-Planck-Institute for Biological Intelligence, Martinsried, Germany., Emerling D; Atreca, Inc., Redwood City, California., Fervenza FC; Mayo Clinic and Foundation, Rochester, Minnesota., Kallenberg CGM; University of Groningen, Groningen, The Netherlands., Langford CA; Cleveland Clinic Foundation, Cleveland, Ohio., McCune WJ; University of Michigan, Ann Arbor., Merkel PA; University of Pennsylvania, Philadelphia., Monach PA; VA Boston Healthcare System, Rheumatology, Boston, Massachusetts., Seo P; Johns Hopkins University, Baltimore, Maryland., Spiera RF; Hospital for Special Surgery, New York., St Clair EW; Duke University, Durham, North Carolina., Ytterberg SR; Mayo Clinic and Foundation, Rochester, Minnesota., Stone JH; Massachusetts General Hospital, Boston., Robinson WH; Stanford University and VA Palo Alto, Palo Alto, California., Specks U; Mayo Clinic and Foundation, Rochester, Minnesota.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2023 May; Vol. 75 (5), pp. 748-759. Date of Electronic Publication: 2023 Mar 07.
DOI: 10.1002/art.42418
Abstrakt: 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.
(© 2022 American College of Rheumatology.)
Databáze: MEDLINE
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