Myeloperoxidase in vascular disease and autoimmunity Public Deposited

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  • March 21, 2019
  • Astern, Joshua Michael
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • This dissertation defines mechanisms whereby myeloperoxidase (MPO) can mediate vascular damage when released into the vessel, and explores the pathogenesis of an autoimmune disease targeting MPO. The most abundant neutrophil granule protein, MPO generates powerful oxidants that contribute to innate host defense. However, these same oxidants cause host injury; the release of MPO into the vessel correlates with the impairment of vasoregulatory processes and cellular injury. Herein, we report that cytokeratin 1, an endothelial protein, mediates MPO binding and internalization. Cytokeratin 1 also functions as a scaffolding protein for the vasoregulatory plasma kallikrein-kinin system. This system produces bradykinin, a potent inducer of endothelial nitric oxide synthesis. Our investigations revealed that MPO bound and co-localized with high molecular weight kininogen on endothelial cells, and this interaction interfered with bradykinin cleavage by plasma kallikrein. Further, MPO oxidized and inactivated both kininogen and kallikrein, thus preventing bradykinin release. This work identified cytokeratin 1 as a facilitator of MPO-mediated responses, and provided a new paradigm by which MPO affects vasoregulatory processes during inflammation. One disease characterized by excess intravascular neutrophil degranulation is antineutrophil cytoplasmic autoantibody (ANCA)-mediated vasculitis. One major ANCA specificity is for MPO (MPO-ANCA). The origin of these pathogenic autoantibodies is unknown, though our group previously published studies implicating proteins complementary in sequence to autoantigens as the inciting elements of autoimmune disease in patients with proteinase 3-specific ANCA. In chapter 2, we demonstrated the presence of anti-complementary MPO antibodies in patients; this implied that the development of MPO-specific antibodies was a result of an anti-idiotypic response against the anti-complementary protein antibody, and in this way normal tolerogenic mechanisms were bypassed. For this dissertation, we tested the hypothesis that complementary proteins could cause disease in an MPO-ANCA mouse model. While results were not as we predicted, the work revealed the importance of identifying a pathogenic epitope. An epitope mapping study was carried out using a mass spectrometry-based technique, a tool that may generate powerful data for us in the near future. While the human data suggests a role for complementary proteins in MPO-ANCA disease, proving causation in an animal model remains an elusive goal.
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  • In Copyright
  • Preston, Gloria A.
  • Falk, Ronald J.
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  • University of North Carolina at Chapel Hill
  • Open access

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