HLA‐G: Function, polymorphisms and pathology

Abstract

HLA‐G immune modulatory genes and molecules are presently being studied by a widespread number of research groups. In the present study, we do not aim to be exhaustive since the number of manuscripts published every year is overwhelming. Instead, our aim is pointing out facts about HLA‐G function, polymorphism and pathology that have been confirmed by several different researchers, together with exposing aspects that may have been overlooked or not sufficiently remarked in this productive field of study. On the other hand, we question whether performing mainly studies on HLA‐G and disease associations is going to give a clear answer in the future, since 40 years of study of classical HLA molecules association with disease has still given no definite answer on this issue.

HLA-G 3’UTR Polymorphisms Are Linked to Susceptibility and Survival in Spanish Gastric Adenocarcinoma Patients

“…The rs1063320 polymorphism (+3142C/G), consists of the transversion of a cytosine (C, the ancestral variant) to guanine (G) at position +3142 of the 3'UTR region, modulating the affinity of 148a, 148b and 152 miRNAs (known to either favor the direct mRNA degradation or block mRNA to protein translation) for this region (28)(29)(30). Should a C be found at position +3142, miRNAs affinity will decrease, increasing the mRNA availability and the production of HLA-G (10,11).…”

HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

“…Like the other non-classical HLA class I molecules, the HLA-G gene displays only limited polymorphism as compared to HLA-A, -B, or -C. However, an important difference with the other non-classical HLA genes is the frequent occurrence of alternative splicing of the HLA-G gene leading to seven HLA-G isoforms that can be expressed either in a membrane bound- (HLA-G1-4) or in a soluble- (HLA-G5-7) form. Soluble isoforms are the result of alternative splicing of the transmembrane region encoded by exon 5 and can form HLA-G dimers that can signal more potently than monomeric variants ( 176 , 177 ). The HLA-G1 and HLA-G5 isoform have three extracellular domains of the heavy chain and bind non-covalently to β2M.…”

“…The HLA-G1 and HLA-G5 isoform have three extracellular domains of the heavy chain and bind non-covalently to β2M. All the other isoforms express the α1 domain in combination with an α3 domain (HLA-G2 and HLA-G6), with an α2 domain (HLA-G4) or without any additional α domain (HLA-G3 and HLA-G7) ( 176 , 178 ). Another unique feature is the HLA-G promotor that has a modified regulatory enhancer A (enhA) and lacks interferon-stimulated response elements (ISRE) making it unresponsive to NFκB and IFN-ϒ ( 179 , 180 ).…”

“…HLA-G expression levels are also influenced by multiple SNPs in the promotor region, for example the -725G/T/C polymorphism in the promotor region results in higher HLA-G expression levels for -725G compared to -725C or -725T alleles ( 181 ). Given its important role in establishing and maintaining immune tolerance, HLA-G polymorphisms and levels of soluble HLA-G have been frequently determined as surrogate markers for several diseases and pathologies, and multiple studies demonstrated that high levels of membrane bound- or soluble HLA-G were associated with allograft acceptance and less occurrence of acute- or chronic graft rejection summarized in ( 175 , 176 ).…”

HLA‐G in Mayas from Yucatan: An evolutionary approach

“…Also, HLA-G proteins have been found to be tolerogenic MHC molecules. They are expressed in placental cytotrophoblast and have a role in foetal/maternal immunological tolerance (Carosella et al, 2013) and also in pathologies like spontaneous abortions, tumour immunology and transplantation autoimmunity (Arnaiz-Villena et al, 2020;Donadi et al, 2011). Polymorphism is relatively low compared to that of classical class I loci (Robinson et al, 2015).…”