The immunobiology of primary sclerosing cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease histologically characterized by the presence of intrahepatic and/or extrahepatic biliary duct concentric, obliterative fibrosis, eventually leading to cirrhosis. Approximately 75% of patients with PSC have inflammatory bowel disease. The male predominance of PSC, the lack of a defined, pathogenic autoantigen, and the potential role of the innate immune system suggest that it may be due to dysregulation of immunity rather than a classic autoimmune disease. However, PSC is associated with several classic autoimmune diseases, and the strongest genetic link to PSC identified to date is with the human leukocyte antigen DRB01*03 haplotype. The precise immunopathogenesis of PSC is largely unknown but likely involves activation of the innate immune system by bacterial components delivered to the liver via the portal vein. Induction of adhesion molecules and chemokines leads to the recruitment of intestinal lymphocytes. Bile duct injury results from the sustained inflammation and production of inflammatory cytokines. Biliary strictures may cause further damage as a result of bile stasis and recurrent secondary bacterial cholangitis. Currently, there is no effective therapy for PSC and developing a rational therapeutic strategy demands a better understanding of the disease.

Fig. 1

Proposed mechanism for the immunopathogenesis of primary sclerosing cholangitis. Prior to the development of PSC, intestinal lymphocytes are activated in gut-associated lymph tissue and primed by dendritic cells to express α4β7 and CCR9 which result in the homing of these cells to MAdCAM-1 and CCL25, respectively. Normally, the expression of MAdCAM-1 and CCL25 is restricted to the gut, but in PSC, MADCAM-1 is found on portal vein endothelium and CCL25 on periportal sinusoidal endothelium. Although it has yet to be defined where lymphocytes enter the liver (portal venules, sinusoids, or post-sinusoidal capillaries), the expression of MAdCAM-1 and CCL25 leads to the recruitment of CD44+ α4β7+ CCR9+ memory cells from the gut. The mechanisms leading to the expression of MAdCAM-1 and CCL25 in the liver are unknown but the latter appears to be PSC-specific. In addition, the recurrence of PSC after liver transplantation suggests that this is not an aberrant property inherent in the PSC liver. Induction of MAdCAM-1 and CCL25 may be in response to pathogen-associated molecular patterns (PAMPs) that enter the liver from the gut via the portal vein or sinusoids and bind Toll-like receptors (TLRs) on macrophages (Kuppfer cells, KC) and dendritic cells. Activation of these cells leads to the secretion of inflammatory cytokines which have been shown to induce MAdCAM-1 expression on hepatic endothelial cells. The reported enrichment of αEβ7 lymphocytes in the PSC has been suggested to result from a transition of α4β7+ to αEβ7+ induced by transforming growth factor-β (TGF-β). The localization of lymphocytes to the biliary epithelium is poorly understood. Biliary epithelial cells (BEC) can express a variety of cytokines and chemokines as well as MHC class I and II, CD44, and TLRs. LPS, a potent TLR-4 ligand, induces CCL28 production by BEC leading to the recruitment of α4β1+ CCR10+ regulatory T cells (Treg). However, this phenomenon is seen in a variety of inflammatory liver diseases and is not specific for PSC. We should also note that while TLRs are present on BEC, they are localized to the apical membrane and likely only have contact with PAMPs in the case of ascending cholangitis. Anti-BEC antibodies have been detected in PSC patients and stimulate the production of several cytokines by BEC that could lead to localized recruitment of inflammatory cells