PATHOLOGICAL CHARACTERISTICS AND ROLE OF PLASMA CELLS IN REFRACTORY PRIMARY BILIARY CHOLANGITIS: IMPLICATIONS FOR TARGETED THERAPY

Background: Approximately 40% of primary biliary cholangitis (PBC) patients exhibit poor response to ursodeoxycholic acid (UDCA) and prognosis, referred to as refractory PBC. There is an urgent need to explore new treatment approaches for this patient population. Previous studies have suggested that autoantibodies secreted by plasma cells play a promoting role in the progression of PBC, suggesting that depleting plasma cells may be key to treating refractory PBC.
Aims: We aimed to evaluate the pathological characteristics of refractory PBC, analyze the correlation between plasma cell infiltration and disease severity. Furthermore, we explored the role of plasma cells in PBC by depleting plasma cells in mice to find new therapeutic targets for refractory PBC.
Methods: Liver biopsies was underwent in 32 PBC patients to evaluate the pathological characteristics of refractory PBC and analyze the correlation between plasma cell infiltration and disease severity. We obtained data from public databases and analyzed the infiltration of immune cells in the livers of UDCA-responsive and non-responsive PBC patients from public databases using CIBERSORT deconvolution method. Furthermore, we depleted plasma cells in mice by using the proteasome inhibitor bortezomib (BTZ) in dnTGF-βRII mice and evaluated the therapeutic effects of plasma cell depletion in PBC through assessing serum biochemical and immunological indicators, liver pathology, expression of inflammatory factors in the liver, and infiltration of immune cells.
Results: Compared with UDCA responders, refractory PBC patients showed significant lymphocyte cluster formation in the periportal area, with some lymphocyte clusters exhibiting germinal centers. Plasma cells were observed in a crown-like arrangement around bile ducts, with occasional penetration into the bile duct epithelium. The number of infiltrating plasma cells positively correlated with periportal and bile duct inflammation, as well as serum globulin (GLB) levels. In addition, refractory PBC patients exhibited significantly increased plasma cell infiltration in the liver, which was consistent with the results of bioinformatics analysis from public databases. Depletion of plasma cells in dnTGF-βRII mice using BTZ intervention resulted in a reduction in plasma cell infiltration in the liver and peripheral lymph nodes. Compared to the vehicle-treated group, the BTZ-treated mice showed decreased levels of total bilirubin and GLB in serum, decreased expression of Interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the liver, and improvement in periportal and bile duct inflammation based on histopathology.
Conclusion: Plasma cells play an important role in refractory PBC. Depletion of plasma cells can ameliorate bile duct inflammation in a mouse model of PBC, which provides a novel therapeutic strategy for refractory PBC.