PMID- 26137589
OWN - NLM
STAT- MEDLINE
DCOM- 20160809
LR  - 20220330
IS  - 2352-3964 (Print)
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 2
IP  - 5
DP  - 2015 May
TI  - Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related 
      Disease.
PG  - 456-66
LID - 10.1016/j.ebiom.2015.03.003 [doi]
AB  - 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.
FAU - Buelli, Simona
AU  - Buelli S
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Perico, Luca
AU  - Perico L
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Galbusera, Miriam
AU  - Galbusera M
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Abbate, Mauro
AU  - Abbate M
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Morigi, Marina
AU  - Morigi M
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Novelli, Rubina
AU  - Novelli R
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Gagliardini, Elena
AU  - Gagliardini E
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Tentori, Chiara
AU  - Tentori C
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Rottoli, Daniela
AU  - Rottoli D
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Sabadini, Ettore
AU  - Sabadini E
AD  - Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, 
      Bergamo, Italy.
FAU - Saito, Takao
AU  - Saito T
AD  - General Medical Research Center, Faculty of Medicine, Fukuoka University, Japan.
FAU - Kawano, Mitsuhiro
AU  - Kawano M
AD  - Department of Rheumatology, University School of Medicine, Kanazawa, Japan.
FAU - Saeki, Takako
AU  - Saeki T
AD  - Department of Internal Medicine, Red Cross Hospital, Nagaoka, Japan.
FAU - Zoja, Carlamaria
AU  - Zoja C
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
FAU - Remuzzi, Giuseppe
AU  - Remuzzi G
AD  - 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.
FAU - Benigni, Ariela
AU  - Benigni A
AD  - IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria 
      Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150306
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Acids)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Reactive Oxygen Species)
RN  - 9007-36-7 (Complement System Proteins)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 4.2.1.- (Carbonic Anhydrase II)
SB  - IM
CIN - EBioMedicine. 2015 May;2(5):374-5. PMID: 26137581
MH  - Acids/metabolism
MH  - Aged
MH  - *Autoimmunity
MH  - Carbonic Anhydrase II/blood/metabolism
MH  - Cell Membrane/metabolism
MH  - Cells, Cultured
MH  - Complement Activation
MH  - Complement System Proteins/metabolism
MH  - Cytoskeleton/metabolism
MH  - Exocytosis
MH  - Female
MH  - Glomerulonephritis, Membranous/blood/*immunology/pathology
MH  - Humans
MH  - Immunoglobulin G/*immunology
MH  - Kidney Glomerulus/pathology/ultrastructure
MH  - Male
MH  - Middle Aged
MH  - Mitochondria/*metabolism/ultrastructure
MH  - Podocytes/metabolism/ultrastructure
MH  - Reactive Oxygen Species/metabolism
MH  - Superoxide Dismutase/metabolism
PMC - PMC4485911
OTO - NOTNLM
OT  - Carbonic anhydrase II
OT  - IgG4-related disease
OT  - Membranous nephropathy
OT  - Podocyte
OT  - Superoxide dismutase 2
EDAT- 2015/07/03 06:00
MHDA- 2015/07/03 06:01
PMCR- 2015/03/06
CRDT- 2015/07/03 06:00
PHST- 2014/12/03 00:00 [received]
PHST- 2015/03/04 00:00 [revised]
PHST- 2015/03/05 00:00 [accepted]
PHST- 2015/07/03 06:00 [entrez]
PHST- 2015/07/03 06:00 [pubmed]
PHST- 2015/07/03 06:01 [medline]
PHST- 2015/03/06 00:00 [pmc-release]
AID - S2352-3964(15)00066-3 [pii]
AID - 10.1016/j.ebiom.2015.03.003 [doi]
PST - epublish
SO  - EBioMedicine. 2015 Mar 6;2(5):456-66. doi: 10.1016/j.ebiom.2015.03.003. 
      eCollection 2015 May.