HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy

Abstract

Different mechanisms mediated by the expression of the HLA‐class Ib HLA‐G products are suggested to account for the induction of immune tolerance against the paternal antigens of the fetus during pregnancy. Soluble HLA‐G antigens, mainly produced by cytotrophoblast cells at the materno‐fetal interface and circulating in the body fluids, show a capacity analogous to that of membrane‐boundstructures to inhibit NK cells. In the present report we have investigated, using specific ELISA, the presence of sHLA‐G molecules in culture supernatants of early embryos obtained by in vitro fertilization (IVF) before transfer. The data obtained from the analysis of 285 supernatants corresponding to 101 IVF procedures (43 IVF, 58 intracytoplasmic sperm injection) identify two groups of patients on the basis of sHLA‐G antigen presence. No differences in clinical parameters were observed between the groups, but positive embryo implantations occurred only in women showing sHLA‐G molecules in culture supernatants (Fisher's exact p value 2.56×10–3). The results obtained indicate that expression of HLA‐G products in embryo cells is a mandatory, but not sufficient, prerequisite for the development of pregnancy.

Controlling the Immunological Crosstalk during Conception and Pregnancy: HLA-G in Reproduction

“…Furthermore, HLA-G and sHLA-G has been detected in the male reproductive system and in semen (14, 56). After fertilization, HLA-G is expressed by the blastocyst and the early embryo (57, 58). HLA-G is also expressed at other immune privileged sites such as the cornea and thymic epithelial cells (59, 60).…”

“…Also, in in vitro fertilization (IVF) treatments, the measurement of sHLA-G in the embryo culture medium can be used as a marker for improving successful assisted reproductive technology, by choosing the fertilized oocytes with highest potential, as sHLA-G positive culture medium correlates with pregnancy success (10, 58, 106). …”

Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side

“…Another molecule identified in embryo culture media and supposed to be involved in the regulation of local maternal immune response is represented by sHLA-G 13 . HLA-G1/G5 protein expression has been detected in human preimplantation embryos in association with β2-microglobulin and the soluble spliced isoform has been proposed as a noninvasive tool for embryo selection in ART 14 . Very recently, miRNAs secreted by the embryos were suggested to be involved in endometrial cell growth and proliferation, proposing the existence of a previously unrecognized alternative communication system 15 .…”

The Male Role in Pregnancy Loss and Embryo Implantation Failure

“…Furthermore, consensus from a rather large number of studies is that the media from 2-to 3-day-old embryo cultures from in vitro fertilization treatments is positive for sHLA-G in approximately 30-40 % of the cases, although not supported by all studies (Fuzzi et al 2002 ;Van Lierop et al 2002 ;Sher et al 2004 ;Noci et al 2005 ;Yao et al 2005 ;Sageshima et al 2007 ;Vercammen et al 2008 ;Kotze and Kruger 2013 ). Interestingly, a considerable number of independent studies have observed that the pregnancy rate in women who have embryos transferred from cultures, where sHLA-G is detected, is signifi cantly higher than that in women, who have embryos transferred from sHLA-G-negative cultures (Fuzzi et al 2002 ;Sher et al 2004 ;Noci et al 2005 ;Yie et al 2005 ;Vercammen et al 2008 ;Kotze and Kruger 2013 ). However, the source of the sHLA-G, or the detection assays, is controversial because it does not seem plausible that the two-to eight-cell blastocyst should be capable of producing the amounts of sHLA-G measured (Sargent et al 2007 ).…”