PMID- 30850581
OWN - NLM
STAT- MEDLINE
DCOM- 20200520
LR  - 20200520
IS  - 2041-4889 (Electronic)
VI  - 10
IP  - 3
DP  - 2019 Mar 8
TI  - HLA class II antibodies induce necrotic cell death in human endothelial cells via 
      a lysosomal membrane permeabilization-mediated pathway.
PG  - 235
LID - 10.1038/s41419-019-1319-5 [doi]
LID - 235
AB  - Antibody-mediated rejection (AMR) is the major cause of allograft loss after 
      solid organ transplantation. Circulating donor-specific antibodies against human 
      leukocyte antigen (HLA), in particular HLA class II antibodies are critical for 
      the pathogenesis of AMR via interactions with endothelial cells (ECs). To 
      investigate the effects of HLA class II antibody ligation to the graft 
      endothelium, a model of HLA-DR antibody-dependent stimulation was utilized in 
      primary human ECs. Antibody ligation of HLA class II molecules in 
      interferon-gamma-treated ECs caused necrotic cell death without complement via a 
      pathway that was independent of apoptosis and necroptosis. HLA-DR-mediated cell 
      death was blocked by specific neutralization of antibody ligation with 
      recombinant HLA class II protein and by lentiviral knockdown of HLA-DR in ECs. 
      Importantly, HLA class II-mediated cytotoxicity was also induced by relevant 
      native allele-specific antibodies from human allosera. Necrosis of ECs in 
      response to HLA-DR ligation was mediated via hyperactivation of lysosomes, 
      lysosomal membrane permeabilization (LMP), and release of cathepsins. Notably, 
      LMP was caused by reorganization of the actin cytoskeleton. This was indicated by 
      the finding that LMP and actin stress fiber formation by HLA-DR antibodies were 
      both downregulated by the actin polymerization inhibitor cytochalasin D and 
      inhibition of Rho GTPases, respectively. Finally, HLA-DR-dependent actin stress 
      fiber formation and LMP led to mitochondrial stress, which was revealed by 
      decreased mitochondrial membrane potential and generation of reactive oxygen 
      species in ECs. Taken together, ligation of HLA class II antibodies to ECs 
      induces necrotic cell death independent of apoptosis and necroptosis via a 
      LMP-mediated pathway. These findings may enable novel therapeutic approaches for 
      the treatment of AMR in solid organ transplantation.
FAU - Aljabri, Abid
AU  - Aljabri A
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
AD  - King Saud Medical City, Riyadh, Saudi Arabia.
FAU - Vijayan, Vijith
AU  - Vijayan V
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
FAU - Stankov, Metodi
AU  - Stankov M
AD  - Department for Clinical Immunology and Rheumatology, Hannover Medical School, 
      Hannover, Germany.
FAU - Nikolin, Christoph
AU  - Nikolin C
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
FAU - Figueiredo, Constanca
AU  - Figueiredo C
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
FAU - Blasczyk, Rainer
AU  - Blasczyk R
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
FAU - Becker, Jan Ulrich
AU  - Becker JU
AD  - Institute of Pathology, University Cologne, Cologne, Germany.
FAU - Linkermann, Andreas
AU  - Linkermann A
AUID- ORCID: 0000-0001-6287-9725
AD  - Department of Internal Medicine III, Division of Nephrology, University Carl 
      Gustav Carus, Dresden, Germany.
FAU - Immenschuh, Stephan
AU  - Immenschuh S
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany. 
      immenschuh.stephan@mh-hannover.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190308
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Reactive Oxygen Species)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Actin Cytoskeleton/metabolism
MH  - Antibodies, Monoclonal/*toxicity
MH  - Apoptosis/drug effects
MH  - Endothelial Cells/*drug effects/*immunology/metabolism
MH  - Graft Rejection
MH  - Histocompatibility Antigens Class II/*immunology
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Interferon-gamma/pharmacology
MH  - Lysosomes/*drug effects/enzymology/immunology
MH  - Membrane Potential, Mitochondrial/drug effects/immunology
MH  - Necrosis/*immunology
MH  - Reactive Oxygen Species/immunology/metabolism
PMC - PMC6408495
COIS- The authors declare no competing interests.
EDAT- 2019/03/10 06:00
MHDA- 2020/05/21 06:00
PMCR- 2019/03/08
CRDT- 2019/03/10 06:00
PHST- 2018/09/12 00:00 [received]
PHST- 2018/12/06 00:00 [accepted]
PHST- 2018/11/30 00:00 [revised]
PHST- 2019/03/10 06:00 [entrez]
PHST- 2019/03/10 06:00 [pubmed]
PHST- 2020/05/21 06:00 [medline]
PHST- 2019/03/08 00:00 [pmc-release]
AID - 10.1038/s41419-019-1319-5 [pii]
AID - 1319 [pii]
AID - 10.1038/s41419-019-1319-5 [doi]
PST - epublish
SO  - Cell Death Dis. 2019 Mar 8;10(3):235. doi: 10.1038/s41419-019-1319-5.