Abstract
HLA-G molecule has well-recognized tolerogenic properties, and the encoding gene shows lower frequency of polymorphism at the coding region but higher variability at regulatory 5’ and 3’ untranslated (3’UTR) regions. At least three 3’UTR polymorphic sites have been associated with HLA-G mRNA regulation, including the 14 base pair (14bp) Insertion/Deletion, +3142C-G and +3187A-G. We studied the association of polymorphic sites at 3’UTR (sequencing analysis, encompassing the 14bp Ins-Del/+3003T-C/+3010C-G/+3027C-A/+3035C-T/+3142C-G/+3187A-G/+3196C-G polymorphic sites) with plasma soluble HLA-G levels (sHLA-G, detected by ELISA) in 187 French and 153 Brazilian healthy individuals. Allele and genotype frequencies were closely similar in both populations; however, Brazilians showed a higher HLA-G 3’UTR haplotype diversity. Considering sHLA-G levels in both populations altogether, individuals presenting 14bp Del/Del showed higher levels compared to 14bpIns/Ins genotype (P <0.05); those presenting +3010C/G showed higher levels compared to the +3010C-C genotype (P< 0.05); those presenting +3027C-C showed higher levels than the +3027A-A genotype (P< 0.05); and those bearing +3035C-C showed higher levels compared to the +3035C-T (P < 0.01) and +3035T-T (P < 0.05) genotypes. The analyses of 3’UTR haplotypes showed that UTR-1 (DelTGCCCGC) was associated with higher expression of sHLA-G, whereas UTR-5 (InsTCCTGAC) and UTR-7 (InsTCATGAC) with lower expression and other UTRs (UTR-2/3/4/6) exhibited intermediate levels. Since the differential expression of HLA-G may be beneficial or harmful depending on the underlying condition, the identification of individuals genetically programmed to differentially express HLA-G may help on defining novel strategies to control the immune response against the underlying disorder.
Highlights
HLA-G is a nonclassical class Ib molecule, first identified on fetal extravillous cytotrophoblast cells, placental macrophages, and mesenchymal chronic villi [1], which has been primarily associated with maternal-fetal tolerance [2]
Since the HLA-G gene has a limited polymorphism at the coding region, relatively few distinct molecules are coded, which present little amino acid variability in protein regions responsible for molecule dimerization and interaction with inhibitory receptors [31]
The regulatory regions of the gene have a crucial role in determining the magnitude of gene and protein expression, and polymorphic sites observed along the gene regulatory regions, including the 5’untranslated regulatory region (URR) and 3’ untranslated (3’UTR), are potential candidates
Summary
HLA-G is a nonclassical class Ib molecule, first identified on fetal extravillous cytotrophoblast cells, placental macrophages, and mesenchymal chronic villi [1], which has been primarily associated with maternal-fetal tolerance [2]. The expression of HLA-G1 has been exclusively linked to inhibitory function. Diverse studies have shown that HLA-G1 expression on tumor cells inhibits immune effector cell function through interaction with inhibitory leukocyte receptors. At least two major HLA-G leukocyte receptors have been identified, including immunoglobulin-like transcript-2 (ILT2, designated as CD85j or LILRB1) and ILT4 (CD85d/LILRB2). The expression of the additional HLA-G receptor KIR2DL4 is mainly restricted to a CD56bright subset of NK cells, which constitute a minority of peripheral NK cells, but a majority of uterine NK cells [9]
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