HLA-G and its role in implantation (review)

Abstract

Background: Human leukocyte antigen G (HLA-G) is thought to play a key role in implantation by modulating cytokine secretion to control trophopblastic cell invasion and to maintain a local immunotolerance.

Method of study: The literature is reviewed to provide a description of the genetic background, properties of the protein, and the function of HLA-G. Data are presented on potential clinical applications of HLA-G including the use of evaluation of HLA-G gene polymorphisms in the diagnosis of patients experiencing recurrent pregnancy loss and evaluation and testing of soluble HLA-G (sHLA-G) in embryo culture media for the selection of embryos for transfer after in vitro fertilization (IVF).

Results: The literature supports a central role of HLA-G for successful implantation. Of couples experiencing recurrent pregnancy loss, 32% demonstrated the -1725G HLA-G polymorphism. Our data showed that when embryos were selected for transfer after IVF based on culture media concentrations of sHLA-G > or = 2 U/ml and good morphologic grade, a 65% pregnancy rate compared with a 0% pregnancy rate in those with <2 U/ml sHLA-G.

Conclusions: HLA-G is important for successful implantation in human beings. The HLA-G -725 promoter polymorphism is a risk factor for recurrent miscarriage. Measurement of sHLA-G in embryo culture media can help select embryos for transfer after IVF allowing fewer embryos to be transferred in an attempt to lower multiple gestation rates.

Fig. 1

a HLA-G isoforms [Three messages encode membrane isoforms (HLA-G1, -G2, -G3) and two encode soluble isoforms (HLA-G5 and -G6, also known as sG1 and sG2, respectively). HLA-G1 and -G5 associate with light chain. Isoforms HLA-G4 and -G7 remain poorly defined and are not included]. b The HLA gene is composed of 8 exons arranged in the same sequence as other HLA class I genes. The gene is alternatively spliced to yield 7 transcripts. In two of these, a stop sequence in intron 4 results in soluble isoforms. A 14 bp insertion/deletion is present in exon 8 in the 3′ UTR. al, a2, a3 extra-cellular domains

Fig. 2

Receptors on immune cells targeted by HLA-G

Fig. 3

Frequency of HLA-G gene polymorphisms among women in couples experiencing recurrent miscarriages

Fig. 4

HLA-G concentration in embryo culture media and pregnancy outcome, pregnancy and implantation (# of embryos implanted per # embryos transferred). (N = 49 couples; 326 embryos)

Fig. 5

Pregnancy outcome after selection of embryos for transfer using embryo culture media sHLA-G concentrations