{
  "abstract": "Introduction Systemic Sclerosis (SSc) is a rare autoimmune disease characterised by obliterative vasculopathy, fibrosis and inflammation. Almost any organ can be affected, leading to potentially life-threatening complications such as interstitial lung disease, heart failure or pulmonary arterial hypertension. The exact molecular mechanisms contributing to the manifestation of SSc are still incompletely understood, but ER-stress and UPR-activation have been demonstrated in patient-derived PBMCs. Binding immunoglobulin protein (BiP), a chaperone, is a major player that binds nascent polypeptides as they translocate into the ER and misfolded/aberrant proteins destined for degradation. Since therapy in SSc is currently oriented towards individual symptoms rather than the causes of the disease, a deeper understanding of the pathophysiology is invaluable to provide improved therapies.Material and Methods We analszed muscle tissue from six patients with SSc by immune histochemistry and unbiased proteomic profiling, and sera by ELISA and compared them to samples from five healthy controls. Confirmational studies are based on immunostaining and quantitative PCR.Results Proteomics on six SSc muscles biopsies and five healthy controls allowed quantification of 2290 proteins with 216 of them (9.43%) being significantly dysregulated. Interestingly, 14 of these proteins (BiP, CALU, CALX, G6PE, KCC2D, KCC2G, PDIA1, PDIA3, PDIA6, RCN2, SAHH2, SRPRB, TMEM43 and TRDN) were directly involved in ER-homeostasis/stress and UPR activation and 15 proteins belong to proteolysis with nine proteins involved in proteasomal function (CHIP, CUL3, OTUB1, PSA3, PSA5, PSD11, PSD12, PSMD1 and PSME1) and six in chaperone mediated autophagy and autophagosome formation (HAP28, HSP74, HSPB2, HSPB8, LAMP2 and SHLB1).Validation analyses confirmed these findings and showed up-regulation of multiple UPR-branches and chaperones. Proteomic profiling revealed clear increase of BiP in skeletal muscle tissue from SSc patients. Immunostaining studies also revealed an increase of BiP. Interestingly, BiP-deposits were not identified within the muscle fibers, but rather within the extracellular space. Notably, previous studies have shown that extracellular BiP-localization impacts immune cell function and thus immune response. Furthermore, BiP-measurement in serum samples also showed a significant increase, supporting the concept of cellular BiP-release and thus the interesting finding obtained in muscle tissue.Conclusions We here add altered protein response with strong up-regulation of UPR-mediated pathways on gene, as well as protein level in skeletal muscle of SSc patients to the pathophysiological spectrum of the disease. BiP evolves not only a promising biomarker for SSc but might also have a crucial impact on immune responses in SSc and thus expand the current understanding of the underlying disease mechanism.Abstract P.226 Figure 1Overview of the 24 proteins showing a >2fold over-expression in SSc muscle tissue compared with healthy controls",
  "authors": [
    {
      "affiliations": [
        "Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Elise Siegert Siegert"
    },
    {
      "affiliations": [
        "Leibniz Institute for Analytical Sciences - ISAS, Dortmund, Germany"
      ],
      "name": "Andreas Hentschel"
    },
    {
      "affiliations": [
        "Immanuel Krankenhaus, Berlin, Germany"
      ],
      "name": "Udo Schneider"
    },
    {
      "affiliations": [
        "Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany",
        "German Rheumatism Research Centre (DRFZ) Berlin, a Leibnitz Institute, Berlin, Germany",
        "Fraunhofer Institute for Translational Medicine and Pharmacology, Allergology and Immunology, Berlin, Germany"
      ],
      "name": "Gerhard Krönke"
    },
    {
      "affiliations": [
        "Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Werner Stenzel"
    },
    {
      "affiliations": [
        "Departement of Neuropediatrics, University of Essen, Essen, Germany"
      ],
      "name": "Andreas Roos"
    },
    {
      "affiliations": [
        "Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Corinna Preuße"
    }
  ],
  "title": "P.226 Unfolded protein response and binding immunoglobulin protein in systemic sclerosis-associated muscle disease",
  "uid": "f546c501-f5ac-5bd2-898e-050645bdaf96"
}