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

Giada Amodio,Silvia Gregori

doi:10.3389/fimmu.2020.01178

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.

Highlights

HLA-G, a non-classical HLA class I molecule, was first described to play a critical role in maintaining fetal–maternal tolerance [1]
HLA-G protein expression is driven by genetic variations in the 3′ untranslated region (UTR), and by those landing in the promoter region; variability of the microenvironment associated with specific disease could affect the HLA-G protein expression
The discovery that HLA-G genetic variants represent target of gene expression regulation led to intensive research for the identification of HLA-G genetic association with disease predisposition or progression and HLA-G protein expression

Summary

Introduction

HLA-G, a non-classical HLA class I molecule, was first described to play a critical role in maintaining fetal–maternal tolerance [1]. HLA-G protein levels can be associated with specific genotypes; a number of studies have been performed trying to correlate HLA-G haplotypes with disease susceptibility and morbidity or to use them as a predictive factor for response to therapy or in transplantation outcome [24].

Results

Conclusion