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Ankylosing spondylitis monocytes show upregulation of proteins involved in inflammation and the Ubiquitin Proteasome pathway
  1. Cynthia A. Wright (cynthiaw{at}ccmp.ox.ac.uk)
  1. Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom
    1. Mariola Edelmann
    1. Henry Wellcome Building for Molecular Physiology, University of Oxford, United Kingdom
      1. Kati diGleria
      1. Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom
        1. Simon Kollnberger
        1. Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom
          1. Holger Kramer
          1. Henry Wellcome Building for Molecular Physiology, University of Oxford, United Kingdom
            1. Simon McGowan
            1. Computational Biology Research Group, University of Oxford, United Kingdom
              1. Kirsty McHugh
              1. Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom
                1. Stephen Taylor
                1. Computational Biology Research Group, University of Oxford, United Kingdom
                  1. Benedikt M. Kessler
                  1. Henry Wellcome Building for Molecular Physiology, University of Oxford, United Kingdom
                    1. Paul Bowness
                    1. Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom

                      Abstract

                      Objectives: We wished to determine if peripheral blood monocytes from patients with Ankylosing Spondylitis (AS) differed in protein expression compared to Rheumatoid Arthritis (RA) and healthy controls (HC).

                      Methods: Monocyte protein expression was characterized by both 2D gel electrophoresis and by label-free quantitative expression profiling, using nano ultra-performance liquid chromatography coupled to ESI MSE mass spectrometry. Data sets were analysed using the Waters Expression Profiling System and Ingenuity Pathway Analysis (IPA).

                      Results: 2D gel electrophoresis showed upregulation of proteasomal constituents in AS monocytes, including the beta subunit of the proteasome activator PA28. Monocyte expression profiling and IPA showed that significant changes in protein expression within the Ubiquitin Proteasome Pathway were restricted to AS monocytes. Statistically significant differences in protein expression involving the Leukocyte Extravasation, Vascular Endothelial Growth Factor, Integrin, and Toll-like receptor signaling pathways were seen in both AS and RA monocytes compared to healthy controls. No evidence of upregulation of proteins involved in the endoplasmic reticulum stress response pathway was found in either AS or RA monocytes. Finally, the PA28 complex was shown to increase the generation of HLA-B27 antigenic epitopes by the proteasome in vitro.

                      Conclusion: Our proteomic analyses support the hypothesis that monocytes play an important role in the pathogenesis of AS and RA, and further suggest a specific role in AS for the Ubiquitin Proteasome pathway. Quantitative proteomic expression profiling constitutes a powerful new tool for rheumatology research.

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