Frontiers in Immunology (Oct 2022)

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

  • Roberto Littera,
  • Roberto Littera,
  • Andrea Perra,
  • Andrea Perra,
  • Michela Miglianti,
  • Ignazio S. Piras,
  • Stefano Mocci,
  • Sara Lai,
  • Maurizio Melis,
  • Teresa Zolfino,
  • Cinzia Balestrieri,
  • Maria Conti,
  • Giancarlo Serra,
  • Francesco Figorilli,
  • Davide Firinu,
  • Simona Onali,
  • Laura Matta,
  • Carmen Porcu,
  • Francesco Pes,
  • Daniela Fanni,
  • Cristina Manieli,
  • Monica Vacca,
  • Roberto Cusano,
  • Marcello Trucas,
  • Selene Cipri,
  • Stefania Tranquilli,
  • Stefania Rassu,
  • Federica Cannas,
  • Mauro Giovanni Carta,
  • Marta Anna Kowalik,
  • Erika Giuressi,
  • Gavino Faa,
  • Luchino Chessa,
  • Luchino Chessa,
  • Luchino Chessa,
  • Sabrina Giglio,
  • Sabrina Giglio,
  • Sabrina Giglio,
  • Sabrina Giglio

DOI
https://doi.org/10.3389/fimmu.2022.1007647
Journal volume & issue
Vol. 13

Abstract

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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 materialsWe 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).ResultsAnalysis 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.ConclusionThis 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.

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