Immunomodulatory checkpoint receptor hvem is associated with disease progression in primary biliary cholangitis

Background and Aims

The roles of immunomodulatory pathways such as the checkpoint receptor network in the pathogenesis and treatment responses in primary biliary cholangitis (PBC) are not well understood. The aim of the current investigation was to understand the role of soluble checkpoint receptors (sol-CRs) in the pathogenesis of PBC and their utility as biomarkers of response to ursodeoxycholic acid (UDC) and progression to advanced cirrhosis.

Method

Plasma samples from 64 PBC patients were compared to 10 healthy controls (HC). PBC subgroups were 24 UDC responders (UDCR) according to the Paris criteria, 18 UDC non-responders (UDCNR), 22 end-stage PBC prior to liver transplantation (ESPBC). Luminex multiplex ELISA was used to quantify concentrations of 14 sol-CRs.

Results

PBC patients were predominantly female (n=62, 97%) with a mean age of 55 years. ESPBC had significantly higher liver prognostic scores compared to UDCR and UDCNR, whilst there was no difference between the latter two. Soluble HVEM was the only sol-CR to be upregulated in UDCR compared to HC (p=0.023). Soluble HVEM remained elevated in all PBC subgroups compared to HC and its significance increased in ESPBC (p<0.0001). Soluble HVEM was also positively associated with the presence of other autoimmune diseases in UDCR (p=0.001). There was a progressive increase in the expression of several sol-CRs, particularly soluble CD80, LAG3 and CD137, as the disease phenotype progressed from UDCR to ESPBC. Soluble PDL1 remained undetectable in the majority of patients.

Conclusion

Soluble HVEM is associated with progressive disease in PBC patients. This molecule is associated with modulation of T-cell functionality and warrants further exploration as a biomarker to stratify patients and as a novel therapeutic target in PBC.