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Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease

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 A(2) r...

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Autores principales: Buelli, Simona, Perico, Luca, Galbusera, Miriam, Abbate, Mauro, Morigi, Marina, Novelli, Rubina, Gagliardini, Elena, Tentori, Chiara, Rottoli, Daniela, Sabadini, Ettore, Saito, Takao, Kawano, Mitsuhiro, Saeki, Takako, Zoja, Carlamaria, Remuzzi, Giuseppe, Benigni, Ariela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485911/
https://www.ncbi.nlm.nih.gov/pubmed/26137589
http://dx.doi.org/10.1016/j.ebiom.2015.03.003
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author Buelli, Simona
Perico, Luca
Galbusera, Miriam
Abbate, Mauro
Morigi, Marina
Novelli, Rubina
Gagliardini, Elena
Tentori, Chiara
Rottoli, Daniela
Sabadini, Ettore
Saito, Takao
Kawano, Mitsuhiro
Saeki, Takako
Zoja, Carlamaria
Remuzzi, Giuseppe
Benigni, Ariela
author_facet Buelli, Simona
Perico, Luca
Galbusera, Miriam
Abbate, Mauro
Morigi, Marina
Novelli, Rubina
Gagliardini, Elena
Tentori, Chiara
Rottoli, Daniela
Sabadini, Ettore
Saito, Takao
Kawano, Mitsuhiro
Saeki, Takako
Zoja, Carlamaria
Remuzzi, Giuseppe
Benigni, Ariela
author_sort Buelli, Simona
collection PubMed
description 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 A(2) 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.
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spelling pubmed-44859112015-07-01 Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease Buelli, Simona Perico, Luca Galbusera, Miriam Abbate, Mauro Morigi, Marina Novelli, Rubina Gagliardini, Elena Tentori, Chiara Rottoli, Daniela Sabadini, Ettore Saito, Takao Kawano, Mitsuhiro Saeki, Takako Zoja, Carlamaria Remuzzi, Giuseppe Benigni, Ariela EBioMedicine Original Article 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 A(2) 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. Elsevier 2015-03-06 /pmc/articles/PMC4485911/ /pubmed/26137589 http://dx.doi.org/10.1016/j.ebiom.2015.03.003 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Buelli, Simona
Perico, Luca
Galbusera, Miriam
Abbate, Mauro
Morigi, Marina
Novelli, Rubina
Gagliardini, Elena
Tentori, Chiara
Rottoli, Daniela
Sabadini, Ettore
Saito, Takao
Kawano, Mitsuhiro
Saeki, Takako
Zoja, Carlamaria
Remuzzi, Giuseppe
Benigni, Ariela
Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease
title Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease
title_full Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease
title_fullStr Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease
title_full_unstemmed Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease
title_short Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease
title_sort mitochondrial-dependent autoimmunity in membranous nephropathy of igg4-related disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485911/
https://www.ncbi.nlm.nih.gov/pubmed/26137589
http://dx.doi.org/10.1016/j.ebiom.2015.03.003
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