{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T03:04:19Z","timestamp":1777863859317,"version":"3.51.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The clinical management of autoimmune liver diseases is frequently complicated by the concomitant presentation of hepatitic and cholestatic features, an entity clinically designated as Overlap Syndrome. While the majority of patients respond to conventional combinatorial therapy involving corticosteroids and ursodeoxycholic acid, a significant subset exhibits a recalcitrant phenotype characterized by biochemical non-response and rapid fibrotic progression. The pathogenesis driving this therapeutic resistance remains incompletely defined, though emerging evidence implicates a distinct immunological architecture rather than a simple superposition of two diseases. This review delineates the multidimensional immunopathogenesis of AIH-PBC and AIH-PSC overlap syndromes with a specific focus on the interface between adaptive immunity and biliary epithelial senescence. We critically examine recent single-cell transcriptomic data that reveal specific pro-inflammatory macrophage niches and exhausted T-cell signatures unique to the overlap phenotype. Furthermore, we discuss the molecular crosstalk involving bile acid signaling and inflammatory cascades that perpetuates liver injury despite standard immunosuppression. Finally, we propose a paradigm shift towards precision medicine by evaluating the rationale for emerging biologic agents, including JAK inhibitors and B-cell depleting therapies, in the management of difficult-to-treat overlap syndromes.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1819131","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:32:27Z","timestamp":1777527147000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling immunological heterogeneity in recalcitrant AIH-PBC\/PSC overlap syndromes: from molecular crosstalk to precision therapeutics"],"prefix":"10.3389","volume":"17","author":[{"given":"Zefeng","family":"Zhang","sequence":"first","affiliation":[{"name":"Wuxi Medical College, Jiangnan University","place":["Wuxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.09.010","article-title":"Unmet clinical need in autoimmune liver diseases","volume":"62","author":"Dyson","year":"2015","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.02.013","article-title":"Support of precision medicine through risk-stratification in autoimmune liver diseases - histology, scoring systems, and non-invasive markers","volume":"17","author":"Bossen","year":"2018","journal-title":"Autoimmun Rev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"8690","DOI":"10.1038\/s41467-024-53104-9","article-title":"Single-cell RNA sequencing reveals the pro-inflammatory roles of liver-resident Th1-like cells in primary biliary cholangitis","volume":"15","author":"Jin","year":"2024","journal-title":"Nat Commun"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v31.i37.112298","article-title":"Unraveling the gut-liver axis in autoimmune liver disease overlap syndrome: a multi-omics perspective","volume":"31","author":"Akpoveta","year":"2025","journal-title":"World J Gastroenterol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3350\/cmh.2024.0821","article-title":"Hard-to-treat autoimmune hepatitis and primary biliary cholangitis: the dawn of a new era of pharmacological treatment","volume":"31","author":"Komori","year":"2025","journal-title":"Clin Mol Hepatol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/j.jhep.2008.10.001","article-title":"EASL clinical practice guidelines: autoimmune hepatitis","volume":"63","year":"2015","journal-title":"J Hepatol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.3390\/jcm9051449","article-title":"Treatment of Overlap Syndromes in Autoimmune Liver Disease: A Systematic Review and Meta-Analysis","volume":"9","author":"Freedman","year":"2020","journal-title":"J. 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