title: The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection.
abstract: Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. However, mechanisms of immunization to apoptotic components remain largely uncharacterized. We used large-scale proteomics, with validation by electron microscopy and biochemical methods, to compare the protein profiles of apoptotic bodies and apoptotic exosome-like vesicles, smaller extracellular vesicles released by endothelial cells downstream of caspase-3 activation. We identified apoptotic exosome-like vesicles as a central trigger for production of anti-perlecan antibodies and acceleration of rejection. Unlike apoptotic bodies, apoptotic exosome-like vesicles triggered the production of anti-perlecan antibodies in naïve mice and enhanced anti-perlecan antibody production and allograft inflammation in mice transplanted with an MHC (major histocompatibility complex)-incompatible aortic graft. The 20S proteasome core was active within apoptotic exosome-like vesicles and controlled their immunogenic activity. Finally, we showed that proteasome activity in circulating exosome-like vesicles increased after vascular injury in mice. These findings open new avenues for predicting and controlling maladaptive humoral responses to apoptotic cell components that enhance the risk of rejection after transplantation.
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Dieudé
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Institute for Research in Immunology and Cancer (IRIC), Montréal, Québec H3T 1JA, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Bell
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Turgeon
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Deborah
authors.initials: D
authors.lastname: Beillevaire
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Pomerleau
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Katia
authors.initials: K
authors.lastname: Hamelin
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Shijie
authors.initials: S
authors.lastname: Qi
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada.
authors.forename: Chanel
authors.initials: C
authors.lastname: Béland
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada.
authors.forename: Wahiba
authors.initials: W
authors.lastname: Dhahri
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cailhier
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Centre de Recherche du CHU de Québec, Québec, Québec G1V 4G2, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rousseau
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Centre de Recherche du CHU de Québec, Québec, Québec G1V 4G2, Canada.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Duchez
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Centre de Recherche du CHU de Québec, Québec, Québec G1V 4G2, Canada.
authors.forename: Tania
authors.initials: T
authors.lastname: Lévesque
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Lau
authors.affiliation: Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Rondeau
authors.affiliation: Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Gingras
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Danie
authors.initials: D
authors.lastname: Muruve
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Rivard
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Héloise
authors.initials: H
authors.lastname: Cardinal
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Institute for Research in Immunology and Cancer (IRIC), Montréal, Québec H3T 1JA, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
authors.affiliation: Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Desjardins
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Centre de Recherche du CHU de Québec, Québec, Québec G1V 4G2, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Boilard
authors.affiliation: Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Institute for Research in Immunology and Cancer (IRIC), Montréal, Québec H3T 1JA, Canada. marie-josee.hebert.chum@ssss.gouv.qc.ca pierre.thibault@umontreal.ca.
authors.forename: Pierre
authors.initials: P
authors.lastname: Thibault
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada. Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. marie-josee.hebert.chum@ssss.gouv.qc.ca pierre.thibault@umontreal.ca.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Hébert
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D064591:Allografts; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055354:Exosomes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006801:Humans; D056724:Immunity, Humoral; D007511:Ischemia / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D051381:Rats; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D019812:Heparan Sulfate Proteoglycans; D010446:Peptide Fragments; C071927:perlecan; D046988:Proteasome Endopeptidase Complex