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Sci Transl Med. 2015 Dec 16;7(318):318ra200. doi: 10.1126/scitranslmed.aac9816.

The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection.

Author information

1
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.
2
Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Institute for Research in Immunology and Cancer (IRIC), Montréal, Québec H3T 1JA, Canada.
3
Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec G1V 4G2, Canada.
4
Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. Centre de Recherche du CHU de Québec, Québec, Québec G1V 4G2, Canada.
5
Canadian National Transplantation Research Program, Edmonton, Alberta T6G 2E1, Canada. University of Calgary, Calgary, Alberta T2N 1N4, Canada.
6
Université de Montréal, Montréal, Québec H3T 1J4, Canada.
7
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.
8
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.

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.

PMID:
26676607
DOI:
10.1126/scitranslmed.aac9816
[Indexed for MEDLINE]

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