Abstract
HLA-G is a non-classical HLA class I molecule with immunomodulatory properties. It was initially described at the maternal-fetal interface, and it was later found that this molecule was constitutively expressed on certain immuneprivileged tissues, such as cornea, endothelial and erythroid precursors, and thymus. The immunosuppressive effect of HLA-G is exerted through the interaction with its cognate receptors, expressed on immunocompetent cells, like ILT2, expressed on NK, B, T cells and APCs; ILT4, on APCs; KIR, found on the surface of NK cells; and finally, the co-receptor CD8. Because of these immunomodulatory functions, HLA-G has been involved in several processes, amongst which organ transplantation, viral infections, cancer progression, and autoimmunity. HLA-G neo-expression on tumors has been recently described in several types of malignancies. In fact, tumor progression is tightly linked to the presence of the molecule, as it exerts its tolerogenic function, inhibiting the cells of the immune system and favoring tumor escape. Several polymorphisms in the 3’UTR region condition changes in HLA-G expression (14bp and +3142C/G, among others), which have been associated with both the development and outcome of patients with different tumor types. Also, in recent years, several studies have shown that HLA-G plays an important role in the control of autoimmune diseases. The ability of HLA-G to limit the progression of these diseases has been confirmed and, in fact, levels of the molecule and several of its polymorphisms have been associated with increased susceptibility to the development of autoimmune diseases, as well as increased disease severity. Thus, modulating HLA-G expression in target tissues of oncology patients or patients with autoimmune diseases may be potential therapeutic approaches to treat these pathological conditions.
Highlights
Reviewed by: Christophe Picard, Etablissement Francais du Sang (EFS), France Nuala Mooney, Institut National de la Santeet de la Recherche Medicale (INSERM), Specialty section: This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology
Given the tolerogenic function of HLA-G, this molecule plays a key role in modulating the immune response in several pathologies
Measuring the protein levels or analyzing the gene polymorphisms involved in its expression, is of interest in cancer susceptibility and progression and in autoimmune diseases
Summary
The constitutive and inducible expression of HLA-G is primarily controlled by its promoter, which has unique structural characteristics such as enhancer A, interferon-stimulated regulatory element (ISRE) and SXY modulator, which contains regulatory sequences common to class I and II HLA genes [10, 11]. Population studies have found nine polymorphic sites in the 3’UTR region of the HLA-G gene. The 14 base pair (14bp) INS/DEL (rs371194629), +3142C/G (rs1063320) and +3187A/G (rs9380142) polymorphisms are implicated in HLAG expression [14] (Figure 2). The DEL allele provides a higher stability of the mRNA [15], associated with a high expression of HLA-G [16] (Figure 2A). Should a C be found at this position, miRNAs affinity will decrease, increasing the mRNA availability and the production of HLA-G [8] (Figure 2B). The +3187A/G polymorphism (rs9380142) is implicated in the stability of HLA-G mRNA: the presence of an adenine (A) at this position modifies an AU-rich motif in the corresponding mRNA, decreasing its stability, while the G allele is associated with increased production of HLA-G [19] (Figure 2C)
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