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

Exosome-like vesicles containing an active 20S proteasome core contribute to autoimmunity and vascular allograft inflammation. Friendly fire from organ failure Despite advances in organ transplantation, rejection still poses a substantial risk. Autoantibodies contribute to rejection, but how these autoantibodies are generated remains unknown. Dieudé et al. found that injection of apoptotic exosome-like vesicles apoExo stimulated autoantibody production in mice, which led to increased graft rejection after transplant. The apoExo contained active 20S proteasome core complexes, and inhibition of proteasome activity decreased the immunogenicity of apoExo and graft rejection in transplanted mice. Circulating apoExo and increased anti-autoantibody titers were also observed in mouse models of ischemia-reperfusion injury, suggesting that the same organ failure that necessitates the transplant might increase the risk of rejection. Therefore, proteasome inhibitors could provide a new therapeutic avenue for graft rejection. 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.