AUTHOR=Miglianti Michela , Mocci Stefano , Littera Roberto , Serra Giancarlo , Balestieri Cinzia , Conti Maria , Pes Francesco , Deidda Silvia , Lorrai Michela , Mereu Caterina , Murgia Michela , Sanna Celeste , Mascia Alessia , Sedda Francesca , Duś-Ilnicka Irena , Cipri Selene , Carta Mauro Giovanni , Lai Sara , Giuressi Erika , Melis Maurizio , Zolfino Teresa , Giglio Sabrina , Perra Andrea , Chessa Luchino 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1585535

DOI=10.3389/fimmu.2025.1585535

ISSN=1664-3224

ABSTRACT=IntroductionPrimary 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.MethodsA 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.ResultsThe 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).DiscussionThese findings suggest HLA-G variants, especially HLA-G*01:01:01:08/UTR-1, as potential biomarkers for PBC prognosis and treatment outcomes.