Universität zu Köln

Aljabri, Abid, Vijayan, Vijith, Stankov, Metodi, Nikolin, Christoph, Figueiredo, Constanca, Blasczyk, Rainer ORCID: 0000-0003-3875-3190, Becker, Jan Ulrich ORCID: 0000-0003-2929-8085, Linkermann, Andreas ORCID: 0000-0001-6287-9725 and Immenschuh, Stephan ORCID: 0000-0003-3722-5791 (2019). HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway. Cell Death Dis., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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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-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Aljabri, Abid UNSPECIFIED UNSPECIFIED UNSPECIFIED Vijayan, Vijith UNSPECIFIED UNSPECIFIED UNSPECIFIED Stankov, Metodi UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikolin, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Figueiredo, Constanca UNSPECIFIED UNSPECIFIED UNSPECIFIED Blasczyk, Rainer UNSPECIFIED orcid.org/0000-0003-3875-3190 UNSPECIFIED Becker, Jan Ulrich UNSPECIFIED orcid.org/0000-0003-2929-8085 UNSPECIFIED Linkermann, Andreas UNSPECIFIED orcid.org/0000-0001-6287-9725 UNSPECIFIED Immenschuh, Stephan UNSPECIFIED orcid.org/0000-0003-3722-5791 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-154021
DOI:	10.1038/s41419-019-1319-5
Journal or Publication Title:	Cell Death Dis.
Volume:	10
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VIRUS NONSTRUCTURAL PROTEIN-1; ALLOGRAFT-REJECTION; HUMAN LYMPHOMA; APOPTOSIS; MITOCHONDRIA; ACTIVATION; PROLIFERATION; COMPLEMENT; MECHANISMS; METABOLISM Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15402