A network forms around damaged bile ducts
Primary biliary cholangitis (PBC) is a chronic autoimmune disease that destroys small bile ducts inside the liver, causing cholestasis and, in some patients, fibrosis, cirrhosis and liver failure. It predominantly affects middle-aged women. The review reports an estimated global annual incidence of 1.8 cases per 100,000 people and prevalence of 18.1 per 100,000.
The authors organize recent evidence around a “peribiliary immune niche”: an interacting community of epithelial and immune cells surrounding injured ducts. Their model replaces a simpler account centered mainly on Th1 and Th17 cells. It divides disease development into three overlapping processes ( i.e. immune initiation, effector amplification and regulatory failure) that may explain why inflammation becomes chronic.
Epithelial stress may initiate disease
Biliary epithelial cells are not merely passive targets. When injured or senescent, they release inflammatory signals, attract immune cells and display molecules involved in antigen presentation and innate sensing.
During apoptosis, these cells uniquely retain the mitochondrial autoantigen PDC-E2 in apoptotic bodies. This may help explain why antimitochondrial antibodies attack bile ducts even though mitochondrial antigens occur throughout the body. Senescent epithelial cells also produce CCL2 and CX3CL1, which recruit macrophages and may spread cellular senescence. CD40 signaling and neutrophil-derived reactive oxygen species and extracellular traps result in further injury.
Dendritic cells can then present autoantigens to T cells. Recruited monocytes develop into macrophages that release inflammatory and profibrotic mediators, including IL-23 and TGF-β. Kupffer cells, the liver’s resident macrophages, can activate hepatic stellate cells and may lose part of their capacity to restrain CD8 T-cell proliferation.
Resident immune cells amplify damage
CD8 tissue-resident memory T cells can adhere to, invade and proliferate within the biliary epithelium, sustaining local cytotoxicity. Tissue-resident Th1 cells, follicular helper T cells, B cells, mucosal-associated invariant T cells, natural killer cells and NKT-like populations increase inflammatory, antibody-producing and profibrotic signals.
B cells may do more than generate antimitochondrial antibodies. Intrahepatic B cells can secrete IL-6 and interferon-γ, while one subset recruits cytotoxic CCR5-positive CD4 tissue-resident memory T cells to bile ducts. Natural killer cells have context-dependent effects: they may protect epithelial cells at lower ratios but promote T-cell activation and biliary damage when overactivated.
Meanwhile, immune restraints weaken. Regulatory T cells (Treg) are reduced or unstable and can convert toward a Th1-like state under IL-12 signaling. Double-negative T cells lose suppressive activity, while myeloid-derived suppressor-cell function may decline in patients with low gut-derived butyrate and inadequate responses to ursodeoxycholic acid (UDCA).
Treatment should follow the dominant pathway
UDCA remains first-line therapy, yet approximately 25%-50% of patients have an inadequate biochemical response. The review highlights the PPAR agonists elafibranor and seladelpar for such patients. Both improve biochemical markers, and seladelpar can reduce pruritus, but benefits for survival, transplantation and decompensation remain unconfirmed.
The paper also treats obeticholic acid as a cautionary example: its US approval was withdrawn and its European authorization revoked after safety concerns and failure of confirmatory evidence to establish clinical benefit.
Direct immune treatments remain less mature. Ustekinumab failed to significantly lower alkaline phosphatase in a phase II PBC trial. Rituximab reduced antimitochondrial antibodies and alkaline phosphatase in studies but did not improve fatigue. JAK inhibitors, engineered Treg cells, double-negative T-cell infusions, dual CD20/BAFF blockade and PD-1-targeting CAR-T cells are supported mainly by experimental or preclinical evidence.
Precision treatment remains a research goal
The authors propose combining liver biochemistry and histology with flow cytometry, single-cell sequencing and spatial transcriptomics to determine whether epithelial stress, resident T-cell activity, B-cell activation, myeloid inflammation, regulatory failure, cholestasis or fibrosis dominates in each patient.
However, this is a review rather than a new clinical trial. Much of the evidence comes from mouse models or peripheral blood, while the crucial interactions occur in liver tissue. Existing models reproduce only parts of human PBC and often fail to capture its female predominance, chronicity or advanced fibrosis. Immune-guided treatment is therefore a promising framework, not yet a validated clinical algorithm.
See the article s
Xiong J, Zhang Z, Zhang Z, et al . Immune cell remodelling and the peribiliary immune niche in primary biliary cholangitis: from initiation to chronicity. eGastroenterology 2026; 4 :e100526. doi:10.1136/egastro-2026-100526
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Immune cell remodelling and the peribiliary immune niche in primary biliary cholangitis: from initiation to chronicity