Evidence for charge-based mimicry in anti dsDNA antibody generation.

Francesco Scolari, Federica Bui, Barbara Trezzi, Giacomo Emmi, Ilaria Cavazzana, Valentina Binda, Paride Fenaroli, Isabella Pisani, Carlomaurizio Montecucco, Domenico Santoro, Simone Negrini, Stefano Volpi, Marta Mosca, Angela Tincani, Enrico Verrina, Franco Franceschini, Angelo Ravelli, Pier Luigi Meroni, Gian Marco Ghiggeri, Federico Pratesi, Giovanni Candiano, Marco Prunotto, Andrea Angeletti, Xhuliana Kajana, Gabriella Moroni, Renato Alberto Sinico, Micaela Fredi, Augusto Vaglio, Lorenzo Cavagna, Maurizio Bruschi, Paola Migliorini, Francesco Locatelli, Giulia Pazzola, Giampaola Pesce, Marcello Bagnasco, Angelo Manfredi, Giuseppe Alvise Ramirez, Pasquale Esposito

Journal: Journal of autoimmunity 2022;132():102900

PMID: 36087539

Full Text on Elsevier Science View on PubMed

Abstract

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.

Address: Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Department of Biomedical Sciences, Humanitas University and IRCCS Humanitas Research Hospital, Milan, Italy.; Department of Medicine and Surgery, University of Milan, Bicocca, Italy.; Rheumatology and Clinical Immunology, ASST Spedali Civili and University of Brescia, Italy.; Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, And Nephrology and Dialysis Unit, Meyer Children's Hospital, Florence, Italy.; Division of Rheumatology, University and IRCCS Policlinico S. Matteo, Pavia, Italy.; Clinical Immunology Unit, Department of Internal Medicine, University of Pisa, Italy.; Nephrology and Dialysis, Arciospedale Santa Maria Nuova, Reggio Emilia, Italy.; Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genoa, Italy.; Unit of Internal Medicine and Immunology, IRCCS Ospedale San Raffaele, Milan, Italy.; Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.; Department of Internal Medicine, University of Genoa, Italy.; Division of Nephrology, University of Genoa and Policlinico San Martino, Genoa, Italy.; Lupus Clinic Department of Biomedicine, University of Florence, University Hospital Careggi, Florence, Italy.; Nephrology Unit, University Hospital, University of Parma, Parma, Italy.; Nephrology and Dialysis Unit, University of Messina and G Martino Hospital, Messina, Italy.; Division of Nephrology and Dialysis, University of Brescia and Ospedale di Montichiari, Brescia, Italy.; Division of Pediatric Rheumatology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Rheumatologu Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.; Experimental Laboratory of Immunological and Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address: [email protected].; Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy. Electronic address: [email protected].

DOI: 10.1016/j.jaut.2022.102900

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MeSH Terms: Humans, Antibodies, Antinuclear, Lupus Nephritis, Lupus Erythematosus, Systemic, Autoantibodies, Immunoglobulin G, Annexin A1, DNA