期刊论文详细信息
EBioMedicine
Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease
Takako Saeki1  Mitsuhiro Kawano2  Takao Saito3  Chiara Tentori4  Ariela Benigni4  Miriam Galbusera4  Giuseppe Remuzzi4  Rubina Novelli4  Elena Gagliardini4  Daniela Rottoli4  Simona Buelli4  Mauro Abbate4  Marina Morigi4  Carlamaria Zoja4  Luca Perico4  Ettore Sabadini5 
[1] Department of Internal Medicine, Red Cross Hospital, Nagaoka, Japan;Department of Rheumatology, University School of Medicine, Kanazawa, Japan;General Medical Research Center, Faculty of Medicine, Fukuoka University, Japan;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;
关键词: IgG4-related disease;    Membranous nephropathy;    Carbonic anhydrase II;    Superoxide dismutase 2;    Podocyte;   
DOI  :  10.1016/j.ebiom.2015.03.003
来源: DOAJ
【 摘 要 】

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.

【 授权许可】

Unknown   

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