HLA-G as a Tolerogenic Molecule in Transplantation and Pregnancy

Abstract

HLA-G is a nonclassical HLA class I molecule. In allogeneic situations such as pregnancy or allograft transplantation, the expression of HLA-G has been related to a better acceptance of the fetus or the allograft. Thus, it seems that HLA-G is crucially involved in mechanisms shaping an allogeneic immune response into tolerance. In this contribution we focus on (i) how HLA-G is involved in transplantation and human reproduction, (ii) how HLA-G is regulated by genetic and microenvironmental factors, and (iii) how HLA-G can offer novel perspectives with respect to therapy.

HNRNPR Regulates the Expression of Classical and Nonclassical MHC Class I Proteins

“…It has a very unique expression pattern, in which it is upregulated on cancer cells, whereas on normal tissues its expression is mainly restricted to the extravillous cytotrophoblasts of the placenta, which is of fetal origin (7). Although HLA-G mRNA can be found in several tissues, HLA-G protein is absent, suggesting for regulation of HLA-G expression at the mRNA level.…”

Immunobiology of HLA Class-Ib Molecules in Transplantation

“…It is interesting that HLA-E mismatches were observed in patients with matched HLA-Ia [59][60][61]. Paradoxically, the immunomodulatory mechanisms mediated by HLA-Ib can be expected to play a role in promoting graft acceptance [47,62], particularly in patients without viremia. This aspect of immunomodulation by HLA-Ib may clarify the variability observed in the duration of graft survival in transplants with HLA-Ia and -II matches and in mismatched ones when the time between DSA appearance and graft rejection was substantial [12].…”

“…Histocompatibility of HLA-Ib molecules is attributed to their cell-surface expression and their release into circulation as sHLA [38,62]. Although, HLA-Ib molecules are oligomorphic, they can induce in transplant patients a cellular and/or humoral immunological response directed against their polymorphic residues; and, like minor histocompatibility antigens, they can affect allograft survival [12,47].…”

“…Indeed, the coding and non-coding allelic regions-respectively, exons and introns (plus 5' and 3' untranslated regions)-and the nature of the peptide presented affect the stability of the messenger (m) RNA and the mature protein. This leads to variable levels of protein expression [19,43,45,[62][63][64]. On the other hand, HLA-F is expressed on the cell surface of lymphocytes only upon activation [52] and can be released into the circulation in a soluble form [32]; however, there is not yet any evidence of the effect of specific genotypes of HLA-F or the level of cell-surface expression.…”

“…Most often, it is agreed that higher levels of HLA-Ib expression is associated with better allograft survival outcome [47,62], but some exceptions exist, such as in BMT, where higher levels of HLA-G expression is associated with higher risk of acute graft-versus-host disease (GvHD) [71]. Since heart, liver, kidney and lung allografts express HLA-Ib on their cell surface [47,62,73], even if the expression of HLA-Ib is low compared with that of HLA-Ia, both cell-surface expression and release in circulation of HLA-Ib are capable of affecting transplantation outcome. Selected patients with a high level of HLA-Ib expression, based on HLA-Ib genotypes, could benefit from lower immunosuppressive protocols while others could benefit from alternate therapeutic strategies.…”