Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation
The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy (MN). However, the pathogenic role of anti-PLA2R1 autoantibodies is unclear. Our aim was to evaluate the in vitro cytotoxicity of anti-PLA2R1 antibodies mediated by complement. Forty-eight patients w...
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| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2019/1324804 |
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| author | Maël Lateb Hajar Ouahmi Christine Payré Vesna Brglez Kevin Zorzi Guillaume Dolla Mohamad Zaidan Sonia Boyer-Suavet Bertrand Knebelmann Thomas Crépin Cécile Courivaud Noémie Jourde-Chiche Vincent Esnault Gérard Lambeau Barbara Seitz-Polski |
| author_facet | Maël Lateb Hajar Ouahmi Christine Payré Vesna Brglez Kevin Zorzi Guillaume Dolla Mohamad Zaidan Sonia Boyer-Suavet Bertrand Knebelmann Thomas Crépin Cécile Courivaud Noémie Jourde-Chiche Vincent Esnault Gérard Lambeau Barbara Seitz-Polski |
| author_sort | Maël Lateb |
| collection | DOAJ |
| description | The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy (MN). However, the pathogenic role of anti-PLA2R1 autoantibodies is unclear. Our aim was to evaluate the in vitro cytotoxicity of anti-PLA2R1 antibodies mediated by complement. Forty-eight patients with PLA2R1-related MN from the prospective cohort SOURIS were included. Anti-PLA2R1 titer, epitope profile, and anti-PLA2R1 IgG subclasses were characterized by ELISA. Cell cytotoxicity was evaluated by immunofluorescence in HEK293 cells overexpressing PLA2R1 incubated with patient or healthy donor sera in the presence or absence of rabbit complement or complement inhibitors. Mean cytotoxicity of anti-PLA2R1 sera for HEK293 cells overexpressing PLA2R1 was 2±2%, which increased to 24±6% after addition of rabbit complement (p<0.001) (n=48). GVB-EDTA, which inhibits all complement activation pathways, completely blocked cell cytotoxicity, whereas Mg-EGTA, which only inhibits the classical and lectin pathways, highly decreased suggesting a limited role of the alternative pathway. A higher diversity of IgG subclasses beyond IgG4 and high titer of total IgG anti-PLA2R1 were associated with increased cytotoxicity (p=0.01 and p=0.03 respectively). In a cohort of 37 patients treated with rituximab, high level of complement-mediated cytotoxicity was associated with less and delayed remission at month 6 after rituximab therapy (5/12 vs. 20/25 (p=0.03) in 8.5 months±4.4 vs. 4.8±4.0 (p=0.02)). Kaplan-Meier analysis demonstrated that high level of cytotoxicity (≥40%) (p=0.005), epitope spreading (defined by immunization beyond the immunodominant CysR domain) (p=0.002), and high titer of anti-PLA2R1 total IgG (p=0.01) were factors of poor renal prognosis. Anti-PLA2R1 antibodies containing sera can induce in vitro cytotoxicity mediated by complement activation, and the level of cytotoxicity increases with the diversity and the titer of anti-PLA2R1 IgG subclasses. These patients with high level of complement-mediated cytotoxicity could benefit from adjuvant therapy using complement inhibitor associated with rituximab to induce earlier remission and less podocyte injury. |
| format | Article |
| id | doaj-art-c591a452aa1d43698cbebe56fea1d0c0 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
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| series | Journal of Immunology Research |
| spelling | doaj-art-c591a452aa1d43698cbebe56fea1d0c02025-02-03T06:01:50ZengWileyJournal of Immunology Research2314-88612314-71562019-01-01201910.1155/2019/13248041324804Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement ActivationMaël Lateb0Hajar Ouahmi1Christine Payré2Vesna Brglez3Kevin Zorzi4Guillaume Dolla5Mohamad Zaidan6Sonia Boyer-Suavet7Bertrand Knebelmann8Thomas Crépin9Cécile Courivaud10Noémie Jourde-Chiche11Vincent Esnault12Gérard Lambeau13Barbara Seitz-Polski14Université Côte d’Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, Valbonne Sophia Antipolis, FranceService de Néphrologie-Dialyse-Transplantation, Hôpital Pasteur, CHU de Nice, Université de Nice-Sophia Antipolis, FranceUniversité Côte d’Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, Valbonne Sophia Antipolis, FranceCentre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université de Nice-Sophia Antipolis, FranceCentre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université de Nice-Sophia Antipolis, FranceUniversité Côte d’Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, Valbonne Sophia Antipolis, FranceService de Néphrologie-Transplantation, Hôpital de Bicêtre, AP-HM France, Université Paris-Saclay, Villejuif, Paris, FranceCentre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université de Nice-Sophia Antipolis, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, FranceDépartement de Néphrologie, Dialyse et Transplantation, Université de Franche-Comté, Besançon, FranceDépartement de Néphrologie, Dialyse et Transplantation, Université de Franche-Comté, Besançon, FranceAix-Marseille Univ, C2VN, INSERM 1263, INRA 1260, AP-HM Hôpital de la Conception, Centre de Néphrologie et Transplantation Rénale, Marseille, FranceService de Néphrologie-Dialyse-Transplantation, Hôpital Pasteur, CHU de Nice, Université de Nice-Sophia Antipolis, FranceUniversité Côte d’Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, Valbonne Sophia Antipolis, FranceUniversité Côte d’Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, Valbonne Sophia Antipolis, FranceThe phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy (MN). However, the pathogenic role of anti-PLA2R1 autoantibodies is unclear. Our aim was to evaluate the in vitro cytotoxicity of anti-PLA2R1 antibodies mediated by complement. Forty-eight patients with PLA2R1-related MN from the prospective cohort SOURIS were included. Anti-PLA2R1 titer, epitope profile, and anti-PLA2R1 IgG subclasses were characterized by ELISA. Cell cytotoxicity was evaluated by immunofluorescence in HEK293 cells overexpressing PLA2R1 incubated with patient or healthy donor sera in the presence or absence of rabbit complement or complement inhibitors. Mean cytotoxicity of anti-PLA2R1 sera for HEK293 cells overexpressing PLA2R1 was 2±2%, which increased to 24±6% after addition of rabbit complement (p<0.001) (n=48). GVB-EDTA, which inhibits all complement activation pathways, completely blocked cell cytotoxicity, whereas Mg-EGTA, which only inhibits the classical and lectin pathways, highly decreased suggesting a limited role of the alternative pathway. A higher diversity of IgG subclasses beyond IgG4 and high titer of total IgG anti-PLA2R1 were associated with increased cytotoxicity (p=0.01 and p=0.03 respectively). In a cohort of 37 patients treated with rituximab, high level of complement-mediated cytotoxicity was associated with less and delayed remission at month 6 after rituximab therapy (5/12 vs. 20/25 (p=0.03) in 8.5 months±4.4 vs. 4.8±4.0 (p=0.02)). Kaplan-Meier analysis demonstrated that high level of cytotoxicity (≥40%) (p=0.005), epitope spreading (defined by immunization beyond the immunodominant CysR domain) (p=0.002), and high titer of anti-PLA2R1 total IgG (p=0.01) were factors of poor renal prognosis. Anti-PLA2R1 antibodies containing sera can induce in vitro cytotoxicity mediated by complement activation, and the level of cytotoxicity increases with the diversity and the titer of anti-PLA2R1 IgG subclasses. These patients with high level of complement-mediated cytotoxicity could benefit from adjuvant therapy using complement inhibitor associated with rituximab to induce earlier remission and less podocyte injury.http://dx.doi.org/10.1155/2019/1324804 |
| spellingShingle | Maël Lateb Hajar Ouahmi Christine Payré Vesna Brglez Kevin Zorzi Guillaume Dolla Mohamad Zaidan Sonia Boyer-Suavet Bertrand Knebelmann Thomas Crépin Cécile Courivaud Noémie Jourde-Chiche Vincent Esnault Gérard Lambeau Barbara Seitz-Polski Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation Journal of Immunology Research |
| title | Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation |
| title_full | Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation |
| title_fullStr | Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation |
| title_full_unstemmed | Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation |
| title_short | Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation |
| title_sort | anti pla2r1 antibodies containing sera induce in vitro cytotoxicity mediated by complement activation |
| url | http://dx.doi.org/10.1155/2019/1324804 |
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