The interleukin (IL)-12/IL-23 mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, IFN-γ, IL-12RB2, IL-23p40, IL-23p19, IL-17 and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining were detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most importantly, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance pro-fibrotic Th17 signaling and pro-inflammatory IFN-γ production that contribute to PBC pathology. In conclusion, our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention.

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Emperipolesis has been widely described in patients with autoimmune hepatitis, but the significance and the diagnostic value have not been quantitated. The goal of this study was to define the features and clinical significance of emperipolesis in autoimmune hepatitis (AIH). A retrospective histological evaluation of 101 patients with AIH and 184 controls was performed. Confocal staining for CD4, CD8, CD19, CD56, CD163, and CD11b, CK8/18 and cleaved caspase-3 was performed. Emperipolesis was observed in 65.3 % of the patients with AIH in haematoxylin and eosin (H&E)-stained slides, which was significantly higher than in patients with primary biliary cirrhosis (17.9 %), chronic hepatitis B (14.9 %), and drug-induced liver injury (25.6 %). Among AIH patients, the patients with emperipolesis had significantly higher serum (alanine aminotransferase/aspartate aminotransferase [ALT/AST]) levels. Histologically, emperipolesis was associated with more severe necroinflammatory features and more advanced fibrosis. The lymphocytes in hepatocytes were predominantly as CD8 T cells. Emperipolesis of CD8 T cells induced cleaved caspase-3 expression, and was prominent in areas apoptosis. Emperipolesis is a characteristic feature of AIH which is often seen in conjunction with interface hepatitis, plasmacytic infiltration and hepatocyte rosetting and is associated with more severe necroinflammatory and fibrotic changes. In AIH, emperipolesis is predominantly mediated by CD8 T cells, appears to induce apoptosis and may be another mechanism of autoimmune-mediated hepatocyte injury.