Histocompatibility Antigen, Class I, G (HLA-G)’s Role during Pregnancy and Parturition: A Systematic Review of the Literature

Abstract

Introduction: Immune homeostasis of the intrauterine cavity is vital for pregnancy maintenance. At term or preterm, fetal and maternal tissue inflammation contributes to the onset of labor. Though multiple immune-modulating molecules are known, human leukocyte antigen (HLA)-G is unique to gestational tissues and contributes to maternal–fetal immune tolerance. Several reports on HLA-G’s role exist; however, ambiguity exists regarding its functional contributions during pregnancy and parturition. To fill these knowledge gaps, a systematic review (SR) of the literature was conducted to better understand the expression, localization, function, and regulation of HLA-G during pregnancy and parturition. Methods: A SR of the literature on HLA-G expression and function reported in reproductive tissues during pregnancy, published between 1976–2020 in English, using three electronic databases (SCOPE, Medline, and ClinicalTrials.gov) was conducted. The selection of studies, data extraction, and quality assessment were performed in duplicate by two independent reviewers. Manuscripts were separated into three categories: 1) expression and localization of HLA-G, 2) regulators of HLA-G, and 3) the mechanistic roles of HAL-G. Data were extracted, analyzed, and summarized. Results: The literature search yielded 2554 citations, 117 of which were selected for full-text evaluation, and 115 were included for the final review based on our inclusion/exclusion criteria. HLA-G expression and function were mostly studied in placental tissue and/or cells and peripheral blood immune cells, while only 13% of the studies reported data on amniotic fluid/cord blood and fetal membranes. Measurements of soluble and membranous HLA-G were determined mostly by RNA-based methods and protein by immunostaining, Western blot, or flow cytometric analyses. HLA-G was reported to regulate inflammation and inhibit immune-cell-mediated cytotoxicity and trophoblast invasion. Clinically, downregulation of HLA-G is reported to be associated with poor placentation in preeclampsia and immune cell infiltration during ascending infection. Conclusions: This SR identified several reports supporting the hypothesized role of immune regulation in gestational tissues during pregnancy. A lack of rigor and reproducibility in the experimental approaches and models in several reports make it difficult to fully elucidate the mechanisms of action of HLA-G in immune tolerance during pregnancy.

Molecular Development of Placenta and Its Relationship with Preeclampsia and Fetal Growth Restriction

“…The presence of HLA-G protein in the preimplantation embryos has been reported [19]. Downregulation of HLA-G is reported to be associated with poor placentation in PE and immune cell infiltration during ascending infection [20].…”

Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm*

“…Although tremendous heterogeneity exists in the definition of the FIR, inflammation of the intrauterine cavity can determine mortality and morbidity in premature babies 98‐107 . A majority of the studies referenced here describe increased inflammatory cytokines and chemokines, 100,102,108‐110 immune cell migration into fetal tissues (fetal membranes [histologic chorioamnionitis] and the umbilical cord [funisitis]), 43,111‐118 increased reactive oxygen species in the amniotic fluid 46,116,117,119 and fetal tissues, 45,46,120,121 changes to antimicrobial defense mechanisms, 122‐125 and HLA molecules 92,126‐129 . The FIR can respond to an infectious 104,130 or non‐infectious (sterile) process, 131‐133 either an endogenous or an exogenous exposure by the fetal tissue 134 .…”

“…[98][99][100][101][102][103][104][105][106][107] A majority of the studies referenced here describe increased inflammatory cytokines and chemokines, 100,102,[108][109][110] immune cell migration into fetal tissues (fetal membranes [histologic chorioamnionitis] and the umbilical cord [funisitis]), 43,[111][112][113][114][115][116][117][118] increased reactive oxygen species in the amniotic fluid 46,116,117,119 and fetal tissues, 45,46,120,121 changes to antimicrobial defense mechanisms, [122][123][124][125] and HLA molecules. 92,[126][127][128][129] The FIR can respond to an infectious 104,130 or non-infectious (sterile) process, [131][132][133] either an endogenous or an exogenous exposure by the fetal tissue.…”

Fetal membrane at the feto-maternal interface: An underappreciated and understudied intrauterine tissue

“…Chorion trophoblast cells modulate the immune environment by producing anti-inflammatory hormones [9,36,54,55] and cytokines, [12] and by buffering maternal (decidual) immune cell invasion [47,56] and immune intolerance by abundant expression of human leukocyte antigen G (HLA-G). [3] These endocrine and paracrine signalers help to maintain immune cell homeostasis at the choriodecidual interface. [12,57] At term, close to 40 weeks gestation, both fetal and maternal tissue contribute to an increased inflammatory load and immune cell activation that promotes myometrial contractions and cervical ripening leading to delivery of the baby.…”

“…While most intrauterine tissues are thoroughly studied for their role in pregnancy maintenance and their contribution to labor initiation, the fetal membranes (i.e., amniochorionic membranes) are primarily overlooked. [1,2] The fetal membrane lines the intrauterine cavity (Figure 1A) and provides critical mechanical, immune, and endocrine support to protect the fetus during gestation [1,[3][4][5][6][7][8][9][10][11][12] and has been shown to provide vital labor initiating signaling at term and preterm. [2,5,[13][14][15][16][17][18][19][20] The function of the fetal membrane is derived from its unique makeup of multiple collagen layers, [21][22][23] along with fetal-derived cells that line with maternal decidua, forming the feto-maternal interface.…”