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

Area of Science:

• Hepatology
• Immunology
• Pathology

Background:

• The role of lymphocyte infiltration in primary biliary cholangitis (PBC) hepatic portal tracts is not fully understood.
• Tertiary lymphoid structures (TLSs), ectopic lymphoid tissues, are implicated in autoimmune disease exacerbation.

Purpose of the Study:

• To evaluate the role of TLSs in PBC pathogenesis.
• To investigate the therapeutic potential of targeting TLSs in PBC.

Main Methods:

• Analysis of liver biopsies from 75 PBC patients and 53 controls.
• Identification and maturity assessment of TLSs based on immune cell distribution.
• Bulk RNA sequencing in PBC patients with varying TLS maturity.
• In vivo study using FTY720 (a sphingosine-1-phosphate receptor modulator) in mice to assess TLSs' role in cholangitis.

Main Results:

• TLSs were present in 61.3% of PBC liver tissues, with mature TLS (mTLS) observed in 26 patients.
• mTLS was more prevalent in PBC compared to other liver diseases and correlated with higher biochemical indicators, immunoglobulin levels, and liver cirrhosis.
• Enrichment of lymphocyte migration and chemokine signaling pathways was noted in PBC patients with TLS.
• FTY720 treatment reduced TLS formation and ameliorated cholangitis and fibrosis in a mouse model.

Conclusions:

• TLSs characterize lymphocyte accumulation in PBC portal tracts, with maturity correlating to inflammation and fibrosis.
• Targeting TLS formation presents a potential therapeutic avenue for PBC.