The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection
Article [Accepted Manuscript]
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Science translational medicine ; vol. 7, no. 318.Publisher(s)
American Association for the Advancement of ScienceAuthor(s)
Abstract(s)
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.
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