Etiopathogenesis of Primary Sclerosing Cholangitis

Abstract

The etiopathogenesis of primary sclerosing cholangitis (PSC) remains undefined. Immunopathogenetic mechanisms appear to be involved, based on human leukocyte antigen complex susceptibility associations, existence of multiple autoantibodies, and presence of inflammatory bowel disease in > 75% of patients. PSC may represent an autoimmune disease with atypical features or an immune-mediated inflammatory disease, similar to inflammatory bowel disease itself. Immunogenetic susceptibility is closely linked to ligands for innate immune cells and capacity for sustained production of proinflammatory cytokines. Immunopathogenesis involves a multistep process initiated by the activation of cholangiocyte by bacterial pathogen-associated molecular patterns (stimuli of innate immunity) and proinflammatory cytokines in conjunction with aberrant expression of gut-specific chemokines and endothelial cell adhesion molecules in the liver. After recruitment of gut-primed memory T cells into the portal tracts and peribiliary space, additional mechanisms produce focal, fibrous, obliterative lesions. Progressive periductal fibrosis, chronic inflammation, and ischemic atrophy of biliary epithelia result in ductopenia, cholestasis, and obstructive strictures, culminating in secondary biliary cirrhosis.

Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease

“…To support and expand these findings, mRNA was isolated from control and SGVHD livers and analyzed by real-time PCR for T H 17 and T H 1 cytokines and inflammatory mediators that are associated with mucosal/liver inflammation. In the SGVHD liver, there was a significant increase in mRNA for IFN-␥ (P ϭ 0.0009) as previously published in this model (19) and as demonstrated clinically (42). Since T H 17 cells have been shown to be elevated in IBD (20,27) and in the SGVHD liver (Fig.…”

“…ϩ T cells (42). Initial studies demonstrated that SGVHD-mediated colon inflammation could be mediated by T H 17 or T H 1 immune responses Fig.…”

Autoantibodies in primary sclerosing cholangitis

“…These notions suggest that additional pathogenetic factors may exist (e.g. bile acid toxicity [18] ), and to what extent and at what disease stage autoimmune mechanisms contribute to the bile duct damage observed in PSC is not known.…”

Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

“…Many antibodies have been detected in PSC patients with varying prevalences, including antinuclear antibodies (24-53%), smooth muscle antibodies (13-20%), anti-perinuclear cytoplasmic antibody ( 65-88%) (Mulder et al, 1993;Bansi et al, 1996;Terjung & Spengler, 2005;Terjung et al, 2000). However, in contrast to other autoimmune diseases, PSC is more frequently encountered in male subjects, and it does not respond to immunosuppressive therapy (O'Mahony & Vierling, 2006). One hypothesis that aims to explain the increased incidence of PSC in IBD patients postulates that the transportation of bacterial endotoxins from the inflamed colonic mucosa to the liver via the portal circulation stimulates the Kupffer cells (Fausa et al, 1991;Aoki et al, 2005).…”