Characterisation and Clinical Relevance of Tertiary Lymphoid Structures in Primary Biliary Cholangitis

Background and aims: The pathological characteristics of lymphocyte infiltration in the hepatic portal tracts of patients with primary biliary cholangitis (PBC) remain unclear. Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues associated with the exacerbation of autoimmune reactions. Here, we evaluate the role of TLSs in PBC and investigate their potential therapeutic value.

Methods: We recruited 75 patients with PBC and 53 control patients with liver biopsies who were followed more than 2 years. TLSs and their maturity were identified by the amount and spatial distribution of immune cells. Bulk RNA sequencing of liver was performed in PBC patients with different TLS maturity. The sphingosine-1-phosphate receptor (S1PRs) modulator FTY720 was administered to dnTGFβRII mice to assess the role of TLSs on cholangitis.

Results: TLSs presented in 61.3% (46/75) of liver tissues from patients with PBC, including 26 patients with mature TLS (mTLS) and 20 patients with immature TLS (imTLS). The proportion of mTLS was higher in PBC compared with chronic hepatitis B and autoimmune hepatitis. PBC patients with mTLS exhibited the highest serum levels of biochemical indicators, immune globulin and proportions of liver cirrhosis. Gene sets for lymphocyte migration and chemokine signalling pathways were enriched in patients with PBC presenting with TLS. FTY720 inhibited TLS formation and relieved cholangitis and fibrosis in dnTGFβRII mice.

Conclusion: TLSs are characteristics of lymphocyte accumulation in the portal tracts of PBC, of which the maturity of TLSs correlates with the inflammation and fibrosis of PBC. Targeting TLSs formation is a potential treatment of PBC.