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

Abstract

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.

The correlation between soluble human leukocyte antigen (sHLA‐G) levels and +3010 polymorphism

“…The alternative splicing of 92bDel transcript is caused by the +3010/C allele (rs1710, allele C), which is found in most 14 bp + haplotypes that include UTR‐2, ‐5 and ‐7 (Carosella et al., 2015). Accordingly, HLA‐G lineages express 92bDel transcripts differently, whereas the 3010/C allele causes alternative splicing to create shorter and more stable transcripts (Castelli et al., 2023).…”

“…The HLA‐G gene is located within the major histocompatibility complex on the short arm of chromosome 6 at position 6p21.2–21.3. It comprises seven introns and eight exons and encodes the HLA‐G molecule's heavy chain (Littera et al., 2022). Interestingly, exons 7 and 8 are not subject to protein translation, because of a stop codon in exon 6 (Castelli et al., 2011).…”

Non-Classical HLA Class 1b and Hepatocellular Carcinoma

“…Indeed, it has been found that increased ILT2 expression engaging HLA-G contributes to the dysfunction of CD56dimCD16+NK cells [ 117 ] and that a tumor-expressing HLA-G promotes the accumulation and suppressive activities of immune cells such as Treg and mast cells, as well as converting NK cells, T-cells and macrophages toward a pro-tumor phenotype [ 118 ]. Moreover, sHLA-G, which is associated with the UTR1 HLA-G haplotype, was found tolerogenic, and thus reduces the inflammation also associated with a better clinical course in type 1 autoimmune hepatitis [ 119 ], as well as in liver transplantation through the immunosuppressive properties of HLA-G (reviewed in [ 35 ]). Of note, a recent study demonstrated NKG2A/CD94 to be an additional receptor for HLA-G that moreover was able to distinguish amino acid differences in the HLA-G heavy chain.…”