HLA-G Genotype/Expression/Disease Association Studies: Success, Hurdles, and Perspectives

Abstract

The non-classical HLA-G is a well-known immune-modulatory molecule. In physiological condition, HLA-G surface expression is restricted to the maternal-fetal interface and to immune-privileged adult tissues, whereas soluble forms of HLA-G are detectable in various body fluids. HLA-G can be de novo expressed in pathological conditions including tumors, chronic infections, or after allogeneic transplantation. HLA-G exerts positive effects modulating innate and adaptive immune responses and promoting tolerance, or detrimental effects inducing immune escape mechanisms. HLA-G locus, in contrast to classical HLA class I gene, is highly polymorphic in the non-coding 3 ′ untranslated region (UTR) and in the 5 ′ upstream regulatory region (5 ′ URR). Variability in these regions influences HLA-G expression by modifying mRNA stability or allowing posttranscriptional regulation in the case of 3 ′ UTR or by sensing the microenvironment and responding to specific stimuli in the case of HLA-G promoter regions (5 ′ URR). The influence of genetic variations on the expression of HLA-G makes it an attractive biomarker to monitor disease predisposition and progression, or response to therapy. Here, we summarize the current knowledge, efforts, and obstacles to generate a general consensus on the correlation between HLA-G genetic variability, protein expression, and disease predisposition. Moreover, we discuss perspectives for future investigation on HLA-G genotype/expression in association with disease predisposition and progression.

HLAncPred: A method for predicting promiscuous non-classical HLA binding sites

“…The non-classical HLA such as, HLA-G acts as an immunomodulatory molecule and natural guard while providing protection during fetus development [60, 61], whereas, HLA-E triggers immune responses via activating inflammatory cytokines during viral infections [9, 32, 62, 63]. Of note, the over-expression of HLA-G may induce the immune suppressive microenvironment, which may help in evading tumor cells from our innate and adaptive immune system.…”

Genetic polymorphism of HLA-G gene (G*01:03, G*01:04, and G*01:05N) in Iraqi patients with inflammatory bowel disease (ulcerative colitis and Crohn’s disease)

“…The G*01:05N allele represents a single base deletion causing a frame-shift reading that leads to a premature stop codon at the beginning of exon 4. As a consequence, this allele is associated with incomplete formation of the HLA-G isoforms G1, G4, and G5 that possess the α3 domain, while G2, G3, and G7 isoforms (lack the α3 domain) show normal expression and sustain the immune tolerogenic function of HLA-G [15,38]. The allele is also associated with low serum level of sHLA-G, and unlike G*01:04, it coincided with Ins allele of the 14-bp Ins/Del polymorphism [39].…”

“…Subsequently, HLA-G was shown to be involved in modulating innate and adaptive immune responses in a variety of pathological conditions; for instance, viral infections, malignancies, autoimmune diseases, transplant outcomes, and inflammatory diseases. These results highlighted that HLA-G encodes for molecules important for immune system functions [15]. Seven isoforms of HLA-G have been identified; four of them are membrane-bound (G1-G4), and three are soluble (G5-G7) [16].…”

“…Numerous studies have examined the association between HLA-G variants and various diseases, especially inflammatory and immune-mediated diseases. Despite inconsistent observations made, it is suggested that HLA-G alleles are important biomarkers for monitoring the disease predisposition and progression [15].…”

Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome

“…The latter is dependent on the intrinsic stability of mRNA, which depends on the nucleotide sequence and the action of microRNAs (14). The HLA-G 3'UTR harbors several polymorphic sites (+3001C/T, +3003C/T, +3010C/G, +3027C/ A, +3032C/G, +3035C/T, 3052C/T, +3092G/T, +3111A/G, +3121C/T, +3142C/G, +33177G/T, +3183A/G, +3187A/G, +3196C/G, and +3227A/G) and a 14-bp insertion/deletion (IN/ DEL), which have been associated with differential HLA-G expression profiles or disease susceptibility (15)(16)(17). As these single-nucleotide polymorphisms (SNP) and the 14-bp IN/DEL are present in a short mRNA sequence and are just some nucleotides apart, it has to be considered that each polymorphic site in the HLA-G 3'UTR may not be independent of other polymorphic sites (14).…”