A Comprehensive Phenotypic and Functional Immune Analysis Unravels Circulating Anti–Phospholipase A2 Receptor Antibody Secreting Cells in Membranous Nephropathy Patients
Year: 2020
Type: article
Study design: Observational Study
Abstract: Introduction Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited. Methods We analyzed 68 different B- and T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non–immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls. Lastly, we quantified the ex vivo production of phospholipase A2 receptor (PLA2R)-specific IgG by plasmablasts (measuring antibodies in culture supernatants and by the newly developed FluoroSpot assay [AutoImmun Diagnostika, Strasberg, Germany]) and assessed the circulating antibody repertoire by phage immunoprecipitation sequencing (PhIP-Seq). Results After adjusting for multiple testing, plasma cells and regulatory B cells (B REG ) were significantly higher ( P < 0.05) in MN patients compared with both control groups. The percentages of circulating plasma cells correlated with serum anti-PLA2R antibody levels ( P = 0.042) and were associated with disease activity. Ex vivo –expanded PLA2R-specific IgG-producing plasmablasts generated from circulating PLA2R-specific memory B cells (mBCs) correlated with serum anti-PLA2R IgG antibodies ( P < 0.001) in MN patients. Tumor necrosis factor-α (TNF-α) was the only significantly increased cytokine in MN patients ( P < 0.05), whereas there was no significant difference across study groups in the autoantibody and antiviral antibody repertoire. Conclusion This extensive phenotypic and functional immune characterization shows that autoreactive plasma cells are present in the circulation of MN patients, providing a new therapeutic target and a candidate biomarker of disease activity.
Source: Kidney International Reports
Authors: Chiara Cantarelli, Marta Jarque, Andrea Angeletti, Joaquin Manrique, Susan Hartzell, Timothy O’Donnell, Elliot Merritt, Uri Laserson, Laura Perin, Chiara Donadei, Lisa Anderson, Clara Fischman, Emilie Chan, Juliana Draibe, Xavier Fulladosa, Joan Torras, Leonardo V. Riella, Gaetano La Manna, Enrico Fiaccadori, Umberto Maggiore, Oriol Bestard, Paolo Cravedi
Institutions: University of Parma, Ospedale di Parma, Icahn School of Medicine at Mount Sinai, Bellvitge University Hospital, Institut d'Investigació Biomédica de Bellvitge, IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola, Complejo Hospitalario de Navarra, University of Southern California, Harvard University, Massachusetts General Hospital
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,625
Awards: G1075404386, G3043513486, G3114265307, Rol de la Alorespuesta inmunitaria de Memoria B periférica en el rechazo del Aloinjerto tras el trasplante Renal (AMBAR), G5940188725, G7185013638, G7280354385, Mecanismos y dianas terapéuticas de la respuesta Inmunológica Humoral de Memoria facilitando el rechazo del injerto en el trasplante renal, Mechanisms of complement-mediated podocyte injury in FSGS, G8322373008
OpenAlex ID: W3046348643