A global proteomic study identifies distinct pathological features of IgG4‐related and primary sclerosing cholangitis

<jats:sec><jats:title>Aims</jats:title><jats:p>This combined proteomic and histopathological study was aimed to compare tissue characteristics of immunoglobulin (Ig)G4‐related sclerosing cholangitis (<jats:styled-content style="fixed-case">ISC</jats:styled-content>) and primary sclerosing cholangitis (<jats:styled-content style="fixed-case">PSC</jats:styled-content>) in a global, non‐biased manner.</jats:p></jats:sec><jats:sec><jats:title>Methods and results</jats:title><jats:p>Tissue proteomes and phosphorylomes of frozen large bile duct samples were analysed by a conventional liquid chromatography‐tandem mass spectrometry (<jats:styled-content style="fixed-case">LC</jats:styled-content>‐<jats:styled-content style="fixed-case">MS</jats:styled-content>/<jats:styled-content style="fixed-case">MS</jats:styled-content>) protocol and additional phosphopeptide enrichment methods. The proteomic examination identified 23 373 peptides and 4870 proteins, including 4801 phosphopeptides and 1121 phosphoproteins. The expression profiles of phosphopeptides discriminated <jats:styled-content style="fixed-case">ISC</jats:styled-content> from <jats:styled-content style="fixed-case">PSC</jats:styled-content> more clearly than those of non‐phosphopeptides. In the pathway analysis, <jats:styled-content style="fixed-case">ISC</jats:styled-content> was found to have 11 more activated signal cascades, including three immunological pathways, all B cell‐ or immunoglobulin‐related. On immunostaining, two immunological markers (<jats:styled-content style="fixed-case">FYN</jats:styled-content>‐binding protein and allograft inflammatory factor‐1) up‐regulated in <jats:styled-content style="fixed-case">ISC</jats:styled-content> were expressed mainly in M2 macrophages, consistent with increased phagocytotic activity induced by the immunoglobulin (Ig)G‐Fcγ receptor interaction. In contrast, <jats:styled-content style="fixed-case">PSC</jats:styled-content> had two more activated signal pathways related to extracellular matrix (<jats:styled-content style="fixed-case">ECM</jats:styled-content>) remodelling. Filamin‐A involved in <jats:styled-content style="fixed-case">ECM</jats:styled-content> remodelling was expressed aberrantly in injured bile ducts and associated cholangiocarcinomas in <jats:styled-content style="fixed-case">PSC</jats:styled-content>, suggesting its possible roles in periductal fibrosis and carcinogenesis in <jats:styled-content style="fixed-case">PSC</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This study suggested crucial roles of B cells and macrophages in <jats:styled-content style="fixed-case">ISC</jats:styled-content>, and more dynamic <jats:styled-content style="fixed-case">ECM</jats:styled-content> remodelling in <jats:styled-content style="fixed-case">PSC</jats:styled-content>.</jats:p></jats:sec>