Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3
Year: 2022
Type: article
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.
Source: Arthritis & Rheumatology
DOI: 10.1002/art.42418
Authors: Marta Casal Moura, Gwen E. Thompson, Darlene A. Nelson, Lynn A. Fussner, Amber M. Hummel, Dieter E. Jenne, Daniel Emerling, Wayne Volkmuth, 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, Yuan-Ping Pang, Ulrich Specks
Institutions: Mayo Clinic, Universidade do Porto, The Ohio State University, Max Planck Institute for Biological Intelligence, University of Groningen, Cleveland Clinic, University of Michigan, University of Pennsylvania, VA Boston Healthcare System, Johns Hopkins University, Hospital for Special Surgery, Duke University, Massachusetts General Hospital, Stanford University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Mayo Clinic, Arthritis Foundation, Biogen, Biogen Idec, Mayo Foundation for Medical Education and Research, Vasculitis Foundation, Johns Hopkins University, Immune Tolerance Network, Georgia Clinical and Translational Science Alliance, Massachusetts Consortium on Pathogen Readiness, National Institutes of Health, U.S. Food and Drug Administration, Genentech, University of California, San Francisco, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources
Awards: G115515487, G1224632525, G1249096266, G1522945560, G1843845992, G18691040, G1928907602, G210009881, G2115204312, G2199907483, Institute for Clinical and Translational Research (UL1), G2673130173, Translational Research in Systemic Vasculitis, Immune tolerance network: liver transplantation, General Clinical Research Center, Development of an ANCA-Vasculitis Index of Damage (AVID), G3213106964, G3436481580, G3525393125, RANDOMIZED CLINICAL TRIAL OF ETANERCEPT IN WEGENER'S, G3721969120, G4065081385, G4184290355, G4563131724, G4715934485, G4814970433, G482277048, G488511823, General Clinical Research Center, G5488715994, G5577046437, G5671986908, G6013796670, G6078569299, G608388331, Studies in Scleroderma and Cystic Fibrosis Osteoporosis, G6239210998, Boston University Clinical and Translational Science Award (CTSA) Program UL1, G6823653762, G7603022272, G7910051277, G7929661436, Mayo Clinic Center for Translational Science Activities, G9000025438, G9000105478, G9000174125, G9000284116, G9000321406, G9000322899, G9000338350, Immune Tolerance Network, G906324947
OpenAlex ID: W4311391178