Membrane-bound and soluble immune checkpoints are abundant in ascitic fluid from patients with decompensated cirrhosis

Background Immune checkpoint receptors (ICRs) regulate immune responses by balancing the stimulatory and inhibitory signals delivered to immune cells by antigen-presenting cells. Evidence suggests that membrane-bound and soluble ICRs are dysregulated in liver disease, particularly in alcoholic hepatitis. We hypothesized that membrane-bound and soluble ICRs are compartmentalized and aberrantly regulated in patients with acute liver failure (ACLF) and spontaneous bacterial peritonitis (SBP).

Methods Paired ascitic fluid (AF) and blood samples from 80 patients with decompensated cirrhosis were analyzed for T cell-bound and soluble ICRs by flow cytometry, ELISA, and Luminex technology. Patients were stratified according to the presence of SBP (n=30) or ACLF (n=40).

Result Compared with serum levels, AF was a soluble ICR-rich compartment for all receptors measured, with sTIM-3 being the most abundant. Membrane-bound PD-1 and LAG-3 were significantly more abundantly expressed in peritoneal CD3+T cells than in circulating T cells. SBP did not significantly affect the levels or expression of soluble or membrane-bound ICR, except for increased membrane-bound CTLA-4 expression during SBP in both blood and AF. Serum levels of sTIM-3 were increased during ACLF compared with acute decompensation without ACLF, whereas membrane-bound ICRs remained stable during ACLF. Serum levels of sTIM-3 and sLAG-3 correlated with liver dysfunction and systemic inflammation.

Conclusion Patients with end-stage liver disease have significantly higher ICRs in AD compared with blood, which may contribute to their systemic and local immune homeostasis. Targeting the balance between membrane-bound and soluble ICR in the peritoneal cavity could contribute to the control of SBP.

Publication History

Article published online:
18 January 2023