The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis

• Published in: Frontiers in immunology Vol. 13; p. 1007647
• Main Authors: Littera, Roberto, Perra, Andrea, Miglianti, Michela, Piras, Ignazio S., Mocci, Stefano, Lai, Sara, Melis, Maurizio, Zolfino, Teresa, Balestrieri, Cinzia, Conti, Maria, Serra, Giancarlo, Figorilli, Francesco, Firinu, Davide, Onali, Simona, Matta, Laura, Porcu, Carmen, Pes, Francesco, Fanni, Daniela, Manieli, Cristina, Vacca, Monica, Cusano, Roberto, Trucas, Marcello, Cipri, Selene, Tranquilli, Stefania, Rassu, Stefania, Cannas, Federica, Carta, Mauro Giovanni, Kowalik, Marta Anna, Giuressi, Erika, Faa, Gavino, Chessa, Luchino, Giglio, Sabrina
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 12.10.2022
• Subjects: HLA-G alleles; human leukocyte antigen; Immunology; plasma cell; Sardinian population; soluble HLA-G; type 1 autoimmune hepatitis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.1007647

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH). Method and materials We analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy). Results Analysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls ( D’ = 0.92 vs D’ = 0.50 respectively; P = 1.3x10 -8 ). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 – 17.4) U/mL vs 21.3 (16.5 – 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 – 44.8) U/mL vs 8.8 (6.1 – 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies. Conclusion This study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1.