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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Primary biliary cholangitis (PBC) is a rare autoimmune liver disease involving bile duct damage and fibrosis. This study explores the role of HLA-G, an immunomodulatory molecule crucial for immune tolerance, in PBC pathogenesis and treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A cohort of 166 PBC patients from Sardinia was compared to 180 healthy controls and 205 autoimmune hepatitis type 1 (AIH-1) patients. Plasma soluble HLA-G (sHLA-G) levels, <jats:italic>HLA-G<\/jats:italic> alleles, and <jats:italic>3\u2019UTR<\/jats:italic> haplotypes were analyzed alongside clinical data, including therapy response to ursodeoxycholic acid.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The UTR-1 haplotype was significantly more frequent in PBC patients than in controls (48.2% vs 34.3%, Pc= 0.0018). The extended haplotype <jats:italic>HLA-G*01:01:01:08\/UTR-1<\/jats:italic> was also strongly associated with PBC (23.2% vs 12.5% in controls, Pc = 0.008; 23.2% vs 6.6% in AIH-1, Pc= 2.6\u00d710<jats:sub>-9<\/jats:sub>). PBC patients exhibited lower sHLA-G levels compared to controls and AIH-1 (9.1 U\/mL vs 24.03 U\/mL and 13.9 U\/mL, respectively). Among <jats:italic>UTR-1<\/jats:italic> carriers, sHLA-G levels were particularly reduced in PBC patients. The <jats:italic>HLA-G*01:01:01:08\/UTR-1<\/jats:italic> haplotype correlated with the lowest sHLA-G levels and poorer therapy response (60% vs 24.1%, P = 0.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest HLA-G variants, especially <jats:italic>HLA-G*01:01:01:08\/UTR-1<\/jats:italic>, as potential biomarkers for PBC prognosis and treatment outcomes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1585535","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T05:21:45Z","timestamp":1753766505000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The role of HLA-G in primary biliary cholangitis and response to 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