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Proteome-scale autoantibody profiling in PSC: Associations with clinical phenotypes and evidence for neuroendocrine
Martin Cornillet1, Aiva Lundberg Båve1,2, Dan Sun1
1Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
Background & Aims:
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with heterogeneous phenotypes and progression. Autoimmune traits, such as the presence of autoantibodies, are suspected to drive its heterogeneity.
Methods:
We performed a proteome-scale autoantibody screen of IgG and IgA isotypes using >42,100 protein fragments. This was followed by a validation of 1,153 selected autoantibodies, in serum samples from 466 patients with PSC in a longitudinal setting using the SUPRIM cohort and 214 controls.
Results:
We identified autoantibodies associated with clinical phenotypes, biochemical and clinical severity, comorbidities, and disease progression (e.g. alkaline phosphatase and albumin level p <e-10, presence of hepatobiliary malignancies p <0.001, seroconversion before transplantation p <0.001). Rather than a single universal autoantibody marker, small patient subgroups were positive for various autoantibodies with variable specificity. Global analysis of autoantigen targets revealed an overrepresentation of proteins normally expressed in immune-privileged sites, including the brain, testis, and retina. When interrogating tissue-specific autoantigen co-expression linked to expression and splicing quantitative trait loci of PSC risk variants, the thyroid emerged as an additional relevant tissue. We also detected increased autoantibody diversity associated with PSC duration and end-stage disease, already observable several years before liver transplantation. Multiomics analysis across body compartments confirmed neuroendocrine dysregulation in PSC. Our results are provided as a resource for further studies.
Conclusions:
Overall, our data support the cryptic antigen and epitope-drifting autoimmune theories and indicate that neuroendocrine dysregulation may contribute to PSC pathogenesis.
Impact And Implications:
From a proteome-scale profiling of the SUPRIM cohort, we provide a short list of autoantibodies associated with clinical phenotypes and progression, along with the peptide sequences used to capture them. We identify across multiple datasets neuroendocrine deregulations in primary sclerosing cholangitis and provide a short list of related key plasma proteins. These data and technical details should facilitate validation studies, investigations of related pathophysiological mechanisms and development of low-cost tools for diagnostic or prognostic purposes.
