Possible Role of the HMGB1 and RAGE inflammatory pathway in primary sclerosing cholangitis

Question: Damage-associated molecular patterns (DAMP) and pattern recognition receptors might play a role in the pathogenesis of primary sclerosing cholangitis (PSC). The receptor for advanced glycation end products (RAGE) and its ligand High Mobility Group Box Protein 1 (HMGB1), a nuclear protein with proinflammatory properties, are part of this endogenous system. This study aims to analyze the influence of the HMGB1 and RAGE inflammatory pathway in PSC. Methods: Serum and bile samples, clinical baseline data and laboratory findings of 69 PSC patients were collected retrospectively from a PSC study database. In addition, bile samples from 32 controls were collected. HMGB1 levels in bile and serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) and bile acid concentration was measured with fluorescence spectroscopy. From the same study database, 324 PSC patients were analyzed for the RAGE G82SSNP by PCR. Results: ELISA analysis showed significantly higher biliary HMGB1 concentrations in PSC patients (n = 69, median 124.1 ng/ml) than in the control group (n = 32, median 6.85 ng/ml, p < 0.001). There was no correlation between biliary HMGB1 and bile acid concentration (p = 0.216), but bile acid levels were significantly lower in PSC patients (p = 0.002). Within the PSC cohort, there were no significant correlations between biliary HMGB1 levels and cholestasis parameters and further subgroup analysis showed no significant difference in biliary HMGB1 levels in age, sex, presence of inflammatory bowel disease or dominant stenosis. Evaluation of survival revealed no significant influence of biliary HMGB1 concentrations. Median serum HMGB1 (n = 22, median 2.4 ng/ml) was significantly lower than median biliary HMGB1 of the concomitant bile samples (n = 22, median 151 ng/ml, p = 0.001). Analysis of the G82SSNP RAGE SNP in PSC patients showed 8 patients with heterozygote mutant alleles (8/324, 2.5%). Patients carrying the gain-of-function mutation had more often dominant stenosis of the large bile ducts (100.0% vs. 61.3%; p = 0.04). Evaluation of survival showed significant reduced survival in the mutant allele group (p < 0.001). Conclusion: The study shows significantly increased levels of HMGB1 in the bile of PSC patients in contrast to low concentrations in the control group. The PSC patients with the mutant allele RAGE SNP, associated with a gain of function, show significant lower survival. Although there is no evidence of HMGB1 as a marker for disease activity or survival, the findings of this study strongly associate biliary HMGB1 with presence of PSC and a gain of function within the HMGB1 and RAGE pathway with reduced survival.