HLA‐G and immune tolerance in pregnancy

Abstract

Multiple mechanisms underlie the surprising willingness of mothers to tolerate genetically different fetal tissues during pregnancy. Chief among these is the choice of HLA-G, a gene with few alleles, rather than the highly polymorphic HLA-A and -B genes, for expression by the placental cells that interface directly with maternal blood and tissues. Novel aspects of this major histocompatibility complex class Ib gene include alternative splicing to permit production of membrane and soluble isoforms, deletions that dampen responses to interferons, and a shortened cytoplasmic tail that affects expression at the cell surface. Placental cells migrating into the maternal uterus synthesize both membrane and soluble isoforms, which interact with inhibitory receptors on leukocytes such as ILT2 and ILT4. Cytotoxic T lymphocytes either die or reduce production of one of their major coreceptor/activator cell surface molecules, CD8; natural killer cells are immobilized and mononuclear phagocytes are programmed into suppressive modes characterized by high production of anti-inflammatory cytokines. The idea that placental HLA-G proteins facilitate semiallogeneic pregnancy by inhibiting maternal immune responses to foreign (paternal) antigens via these actions on immune cells is now well established, and the postulate that the recombinant counterparts of these proteins may be used as powerful tools for preventing immune rejection of transplanted organs is gaining in popularity.

The transplantation of mesenchymal stem cells derived from unconventional sources: an innovative approach to multiple sclerosis therapy

“…Moreover, FA-MSCs exhibit rare chromosomal changes, a stable karyotype, late senescence, and incapacity to generate teratomas that suggest their genetic stability (Shin et al 2009). In addition, these cells are poorly antigenic, expressing HLA-G for immune tolerance during pregnancy and thus are less likely to be rejected by transplant receivers (Hunt et al 2005). Therefore, they can be used in autologous as well as in allogenic transplantation.…”

Disturbances in placental immunology: ready for therapeutic interventions?

“…Its distinct expression pattern in very select placental trophoblast cells led the authors to raise the question of whether this molecule could provide new insight into the immune relationship between mother and fetus [32]. In the interim, it has been shown that HLA-G differs largely from other HLA class I molecules in that it is largely monomorphic and that very few differences exist between population groups [33][34][35]. The structural features of HLA-G have been determined to be quite complex in that five distinct forms exist, three membrane-anchored forms and two soluble forms.…”

“…The structural features of HLA-G have been determined to be quite complex in that five distinct forms exist, three membrane-anchored forms and two soluble forms. While the expression of the fulllength HLA-G1 molecule seems to be restricted to invasive cytotrophoblast and thymic epithelium, the expression of the other variants, especially the soluble HLA-G5 variant, is more widespread, occurring throughout the placenta, chorionic membrane and decidua [34].…”

“…HLA-G has been shown to possess a number of immune-suppressive or immunemodulatory activities, especially in reducing the lytic activity of NK cells [34,35]. The activation of NK cells differs largely from that of T cells in that these cells of the innate arm of the immune system are not triggered by a specific antigen presented on either class I or class II HLA molecules [36].…”

“…Although the true function of HLA-G is not clear, its highly specific expression in certain placental tissues implies that it may play a significant role in human pregnancy [34]. It is consequently no great surprise that alterations in HLA-G expression have been proposed to be involved in RFL and preeclampsia [33,35].…”