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

Abstract

This combined proteomic and histopathological study was aimed to compare tissue characteristics of immunoglobulin (Ig)G4-related sclerosing cholangitis (ISC) and primary sclerosing cholangitis (PSC) in a global, non-biased manner. Tissue proteomes and phosphorylomes of frozen large bile duct samples were analysed by a conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) 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 ISC from PSC more clearly than those of non-phosphopeptides. In the pathway analysis, ISC was found to have 11 more activated signal cascades, including three immunological pathways, all B cell- or immunoglobulin-related. On immunostaining, two immunological markers (FYN-binding protein and allograft inflammatory factor-1) up-regulated in ISC were expressed mainly in M2 macrophages, consistent with increased phagocytotic activity induced by the immunoglobulin (Ig)G-Fcγ receptor interaction. In contrast, PSC had two more activated signal pathways related to extracellular matrix (ECM) remodelling. Filamin-A involved in ECM remodelling was expressed aberrantly in injured bile ducts and associated cholangiocarcinomas in PSC, suggesting its possible roles in periductal fibrosis and carcinogenesis in PSC. This study suggested crucial roles of B cells and macrophages in ISC, and more dynamic ECM remodelling in PSC.