Back to Search
Start Over
HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway
- Source :
- Cell Death & Disease, Web of Science, Cell Death and Disease, Vol 10, Iss 3, Pp 1-15 (2019)
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group UK, 2019.
-
Abstract
- 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-γ-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.
- Subjects :
- 0301 basic medicine
Graft Rejection
Cancer Research
Programmed cell death
Stress fiber
Necroptosis
Immunology
Apoptosis
Human leukocyte antigen
030230 surgery
Article
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Interferon-gamma
Necrosis
0302 clinical medicine
Human Umbilical Vein Endothelial Cells
Humans
lcsh:QH573-671
Cytochalasin D
Membrane Potential, Mitochondrial
biology
lcsh:Cytology
Histocompatibility Antigens Class II
Antibodies, Monoclonal
Endothelial Cells
Cell Biology
Actin cytoskeleton
Cell biology
Actin Cytoskeleton
030104 developmental biology
chemistry
biology.protein
Antibody
Lysosomes
Reactive Oxygen Species
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 10
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....a87dfe38da9651cd20e66f567d406ad1