CD11c + T ‐Bet + B Cell Expansion Reveals a Distinct Pathogenic Signature in Autoimmune Liver Diseases

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ABSTRACT Background and Aims Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are distinct autoimmune liver diseases (AILDs) that differ in pathogenesis and response to therapy. Moreover, some patients exhibit features of both, known as AIH/PBC overlap. Although AILDs are traditionally considered T cell‐driven, B cells have emerged as key contributors to disease progression. In this study, we investigated CD11c + T‐bet + B cells, implicated in different autoimmune diseases and never explored in AILDs. Methods Circulating peripheral blood mononuclear cells (PBMC) were isolated from whole blood obtained from patients with AIH ( n = 15), PBC ( n = 8), AIH/PBC overlap syndrome ( n = 11), and healthy donors (HD, n = 12). B and T cell subsets were analysed by conventional and spectral flow‐cytometry. Clinical and laboratory parameters were recorded at the time of sample collection, and serum IL‐21, sCD40L, and BAFF levels were measured by ELISA and by flow cytometry. Results Total CD19 + B‐cell frequencies were comparable across groups. However, the canonical atypical B‐cell subset defined as CD11c + T‐bet + CD21 − was significantly expanded in AIH and AIH/PBC patients but not in PBC. Phenotypic characterisation showed that these cells were enriched in double‐negative and naïve‐like B‐cell subsets and displayed the expected chemokine receptor profile of atypical B cells, with higher CXCR3 and lower CXCR5 expression compared with conventional B cells. Circulating follicular helper T cells (cTfh) were increased in AIH and AIH/PBC and correlated with the overall T‐bet + B‐cell compartment. Serum IL‐21 levels were higher in patients with AILDs, particularly in treatment non‐responders. Conclusions Expansion of atypical CD11c + T‐bet + B cells, together with increased cTfh frequencies, hallmarks AIH and AIH/PBC. These findings support disease‐specific B‐cell alterations and distinct immune signatures in AIH and AIH/PBC compared with PBC, highlighting potential therapeutic implications for targeting pathogenic B cell subsets in AIH.

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