title: Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease.
abstract: The pathophysiology of glomerular lesions of membranous nephropathy (MN), including seldom-reported IgG4-related disease, is still elusive. Unlike in idiopathic MN where IgG4 prevails, in this patient IgG3 was predominant in glomerular deposits in the absence of circulating anti-phospholipase A2 receptor antibodies, suggesting a distinct pathologic process. Here we documented that IgG4 retrieved from the serum of our propositus reacted against carbonic anhydrase II (CAII) at the podocyte surface. In patient's biopsy, glomerular CAII staining increased and co-localized with subepithelial IgG4 deposits along the capillary walls. Patient's IgG4 caused a drop in cell pH followed by mitochondrial dysfunction, excessive ROS production and cytoskeletal reorganization in cultured podocytes. These events promoted mitochondrial superoxide-dismutase-2 (SOD2) externalization on the plasma membrane, becoming recognizable by complement-binding IgG3 anti-SOD2. Among patients with IgG4-related disease only sera of those with IgG4 anti-CAII antibodies caused low intracellular pH and mitochondrial alterations underlying SOD2 externalization. Circulating IgG4 anti-CAII can cause podocyte injury through processes of intracellular acidification, mitochondrial oxidative stress and neoantigen induction in patients with IgG4 related disease. The onset of MN in a subset of patients could be due to IgG4 antibodies recognizing CAII with consequent exposure of mitochondrial neoantigen in the context of multifactorial pathogenesis of disease.
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Buelli
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Perico
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Galbusera
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Abbate
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Rubina
authors.initials: R
authors.lastname: Novelli
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tentori
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rottoli
authors.affiliation: Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Sabadini
authors.affiliation: General Medical Research Center, Faculty of Medicine, Fukuoka University, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Rheumatology, University School of Medicine, Kanazawa, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawano
authors.affiliation: Department of Internal Medicine, Red Cross Hospital, Nagaoka, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Saeki
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Carlamaria
authors.initials: C
authors.lastname: Zoja
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy ; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000143:Acids / Q000378:metabolism; D000368:Aged; D015551:Autoimmunity; D024402:Carbonic Anhydrase II / Q000097:blood / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003167:Complement Activation; D003165:Complement System Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005089:Exocytosis; D005260:Female; D015433:Glomerulonephritis, Membranous / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007678:Kidney Glomerulus / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D050199:Podocytes / Q000378:metabolism / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000143:Acids; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D003165:Complement System Proteins; D013482:Superoxide Dismutase; D024402:Carbonic Anhydrase II
keywords: Carbonic anhydrase II; IgG4-related disease; Membranous nephropathy; Podocyte; Superoxide dismutase 2