The role of HLA-G in primary biliary cholangitis and response to therapy

Michela Miglianti^1*STEFANO MOCCI^2,3*Roberto Littera^4,5*Serra Giancarlo⁶Balestieri Cinzia⁶Conti Maria⁶Pes Francesco⁶Deidda Silvia⁷Lorrai Michela²Mereu Caterina²Murgia Michela²Sanna Celeste²Alessia Mascia⁸Sedda Francesca⁸Duś-Ilnicka Irena⁹Carta Mauro¹Lai Sara⁴Giuressi Erika⁴Selene Cipri¹⁰Maurizio Melis⁵Zolfino Teresa¹¹Sabrina Giglio^2,3,4*Andrea Perra^5,8*Luchino Chessa^1,6

• ¹Department of Medical Sciences and Public Health, Faculty of Medicine and Surgery, University of Cagliari, Cagliari, Sardinia, Italy
• ²Medical Genetics Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy., Cagliari, Italy
• ³Centre for Research University Services (CeSAR, Centro Servizi di Ateneo per la Ricerca), University of Cagliari, Monserrato, Italy
• ⁴Medical Genetics Unit, R. Binaghi Hospital, Local Public Health and Social Care Unit (ASSL) of Cagliari, Cagliari, Sardinia, Italy
• ⁵Associazione per l’Avanzamento della Ricerca per i Trapianti (AART), Cagliari, Sardinia, Italy
• ⁶Liver Unit, Department of Internal Medicine, University Hospital of Cagliari, Cagliari, Sardinia, Italy
• ⁷Pneumology Unit, R. Binaghi Hospital, ASSL Cagliari, Cagliari, Sardinia, Italy
• ⁸Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Sardinia, Italy
• ⁹Department of Oral Pathology, Wroclaw Medical University, Wrocław, Silesian, Poland
• ¹⁰Department of Oncohematology, Cell Therapy, Gene Therapies and Hematopoietic Transplantation, Bambino Gesù Children's Hospital (IRCCS), Rome, Lazio, Italy
• ¹¹Gastroenterology Unit, ARNAS Brotzu, Cagliari, Italy

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. 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, HLA-G alleles, and 3'UTR haplotypes were analyzed alongside clinical data, including therapy response to ursodeoxycholic acid.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 HLA-G*01:01:01:08/UTR-1 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= 2.6×10 -9 ). 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 UTR-1 carriers, sHLA-G levels were particularly reduced in PBC patients. The HLA-G*01:01:01:08/UTR-1 haplotype correlated with the lowest sHLA-G levels and poorer therapy response (60% vs 24.1%, P = 0.0001). These findings suggest HLA-G variants, especially HLA-G*01:01:01:08/UTR-1, as potential biomarkers for PBC prognosis and treatment outcomes.