Exploring the Pathogenesis of Autoimmune Liver Diseases from the Heterogeneity of Target Cells

Abstract

The incidence of autoimmune liver diseases (ALDs) and research on their pathogenesis are increasing annually. However, except for autoimmune hepatitis, which responds well to immunosuppression, primary biliary cholangitis and primary sclerosing cholangitis are insensitive to immunosuppressive therapy. Besides the known effects of the environment, genetics, and immunity on ALDs, the heterogeneity of target cells provides new insights into their pathogenesis. This review started by exploring the heterogeneity in the development, structures, and functions of hepatocytes and epithelial cells of the small and large bile ducts. For example, cytokeratin (CK) 8 and CK18 are primarily expressed in hepatocytes, while CK7 and CK19 are primarily expressed in intrahepatic cholangiocytes. Additionally, emerging technologies of single-cell RNA sequencing and spatial transcriptomic are being applied to study ALDs. This review offered a new perspective on understanding the pathogenic mechanisms and potential treatment strategies for ALDs.

Keywords: Autoimmune hepatitis; Disease heterogeneity; Pathogenesis; Primary biliary cholangitis; Primary sclerosing cholangitis; Single-cell RNA sequencing.

Fig. 1. Hepatoblasts begin to differentiate under the action of FOXA and GATA.

Hepatoblasts differentiate into hepatocytes, large and small cholangiocytes. CK8, CK18, and CK19 are expressed in hepatoblasts. CK8 and CK18 are expressed in hepatocytes at week 6. CK19 is expressed in intrahepatic cholangiocytes. CK7 is expressed in intrahepatic cholangiocytes at week 20. Bcl2 is expressed in small cholangiocytes after final differentiation. P4502E1 is expressed in large cholangiocytes. CK, cytokeratin; Bcl2, B-cell lymphoma 2; HNF, hepatocyte nuclear factor.

Fig. 2. The role of hepatocytes in AIH.

1. In AIH, the expression of CYP2D6 in hepatocytes activates both Th1 and Th2 immune pathways. 2. Some inflammatory mediators induce the expression of chemokines and adhesion molecules in hepatocytes. AIH, autoimmune hepatitis; CYP2D6, Cytochrome P4502D6.