The Many Faces of Human Leukocyte Antigen-G: Relevance to the Fate of Pregnancy

Abstract

Pregnancy is an immunological paradox, where fetal antigens encoded by polymorphic genes inherited from the father do not provoke a maternal immune response. The fetus is not rejected as it would be theorized according to principles of tissue transplantation. A major contribution to fetal tolerance is the human leukocyte antigen (HLA)-G, a nonclassical HLA protein displaying limited polymorphism, restricted tissue distribution, and a unique alternative splice pattern. HLA-G is primarily expressed in placenta and plays multifaceted roles during pregnancy, both as a soluble and a membrane-bound molecule. Its immunomodulatory functions involve interactions with different immune cells and possibly regulation of cell migration during placental development. Recent findings include HLA-G contributions from the father and the fetus itself. Much effort has been put into clarifying the role of HLA-G during pregnancy and pregnancy complications, such as preeclampsia, recurrent spontaneous abortions, and subfertility or infertility. This review aims to clarify the multifunctional role of HLA-G in pregnancy-related disorders by focusing on genetic variation, differences in mRNA stability between HLA-G alleles, differences in HLA-G isoform expression, and possible differences in functional activity. Furthermore, we highlight important observations regarding HLA-G genetics and expression in preeclampsia that future research should address.

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

“…Moreover, proteolytic cleavage of cell surface HLA-G1 by metalloproteinases (MMPs) such as MMP-2 results in another soluble isoform called shedding HLA-G1 ( 17 ). Different HLA-G isoforms are distinguished by the number of extracellular immunoglobulin-like domains and whether intronic sequence encoded residues are included or not; however, all seven reported HLA-G isoforms have the extracellular α1 domain ( 18 ). The conformation of HLA-G1 and -G5 is similar to that of the classical HLA class I antigens, which contain three extracellular domains including α1, α2, and α3 non-covalently bound to β 2 -macroglobulin (β 2 m).…”

Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer

“…It means that HLA-G expression is not strictly associated with protection of embryo/fetus against attack of maternal cells, but it is engaged with tissue remodeling. Expressed or secreted HLA-G molecules by extravillous trophoblast cells (EVT) regulate their decidual and endovascular invasion (10)(11)(12). Namely, EVT cells progressively replace endothelial cells on the walls of uterine spiral arteries, increasing their diameter that ensures proper blood flow to the intervillous space for fetal nutrition.…”

A Phenotypic Analysis of Regulatory T Cells and Uterine NK Cells from First Trimester Pregnancies and Associations with HLA‐G

“…If this assumption holds true, different properties of sHLA-G and mHLA-G could possibly help clarify discrepancies in HLA-G association studies related to pregnancy complications like preeclampsia. 50 Because novel non-conventional regulatory T cells, which are distinguished by a lower surface expression of CD4 and CD8, were identified in a transplantation study by Naji et al, 51 we sought to investigate whether T cells in placental blood had a decreased surface expression of these markers. Indeed, we found that this was evident for T cells isolated from 'uterine blood'.…”