Enrichment and Clinical Relevance of FcRL5⁺CD27⁺ B Cells in Autoimmune Hepatitis

Background: Dysregulation of B cells has been implicated in the development of autoimmune hepatitis (AIH), yet identification of potentially pathogenic subpopulations remains elusive. Fc receptor-like 5 (FcRL5), a B cell surface marker, represents a potential identifier of pathogenic subsets. This study aimed to investigate the function and immunophenotypic profile of FcRL5⁺B cells in AIH and evaluates their therapeutic targetability. Methods: Immunohistochemistry was performed on liver biopsies from AIH, nonalcoholic steatohepatitis (NASH), chronic hepatitis B (CHB), and healthy controls. Flow cytometry was conducted on liver grafts from AIH patients, healthy donor livers, and peripheral blood samples. FcRL5⁺CD27⁺ B cells were induced in vitro using CpG and IL-15 stimulation. Phenotypic analysis was performed by flow cytometry, and RNA sequencing was conducted on total B cells after induction. STAT3 and STAT5 inhibitors were added at the start of induction to evaluate their effects on cell expansion. Results: FcRL5⁺ cells were significantly enriched in the livers of AIH patients, predominantly within the CD19⁺CD27⁺ memory B cell compartment. These cells exhibited a pro-inflammatory phenotype, characterized by high expression of CXCR3 and CD11c, along with robust secretion of GM-CSF. Longitudinal analysis revealed a marked decrease in intrahepatic FcRL5⁺ cell frequency following clinical remission in AIH patients. RNA sequencing and functional assays indicated that the JAK-STAT pathway regulates the proliferation and function of FcRL5⁺CD27⁺ B cells, with STAT3 and STAT5 phosphorylation playing critical roles. Conclusion: This study highlights the importance of FcRL5⁺CD27⁺ memory B cells in the pathogenesis of autoimmune hepatitis and identifies them as promising targets for therapeutic intervention.