Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 318, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aac9816
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Funding
- Canadian National Transplantation Research Program (CNTRP)
- Canadian Institutes of Health Research (CIHR) [MOP-15447]
- Kidney Foundation of Canada
- Canadian Cancer Society Research Institute (CCSRI) grant
- Natural Sciences and Engineering Research Council of Canada (NSERC) [311598]
- NSERC [386598]
- J.-L. Levesque Foundation
- Canadian Institutes of Health Research
- University of Montreal Nephrology Consortium
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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 naive 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.
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