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HLA-G:  the fetal sentinel

Kelly Carter
Davidson College
BIO 307, Immunology
Dr. A. Malcolm Campbell

What is HLA-G?
What does HLA-G do?
        Alloimmune protection
        Pathogen protection
        Autoimmune protection
Where is it found?
Problems with HLA-G

Goodpasture's Syndrome Paper

What is HLA-G?
Those familiar with allogenic graft rejection may wonder why the fetus, immunologically distinct from the mother, is not rejected by the maternal immune system.  HLA-G may be part of the fetal protection system.  HLA-G has a classic HLA-Class I structure, with a1, a2, a3 domains, covalently associated with a b2 microglobulin domain (Le Gal et al, 1999).  Alternate splicing provides both soluble and membrane bound forms of HLA-G, with two soluble isoforms and four membrane bound isoforms (O'Callaghan and Bell, 1998) (Le Bouteiller et al, 1999).

So what does HLA-G do?

Alloimmune protection
    One function is to decrease or prevent the maternal alloimmune attack on the fetus' paternally inherited MHC (Le Bouteiller et al, 1999).  HLA-G inhibits both the antigen-specific cytotoxic lymphocyte (CTL) response and decreases NK cell function (Le Gal et al., 1999; O'Callaghan and Bell, 1998).   Thus, the low variability may be sufficient to present antigen fragments (O'Callaghan and Bell, 1998).   In comparison to MHC-I and MHC-II molecules, there has been little evolutionary pressure for HLA-G to evolve greater variability because of the limited number of pathogens, and there has been pressure to not evolve variability, to avoid maternal autoimmune reactions to the fetus (Le Bouteiller and Blaschitz, 1999).

Autoimmune Protection
Autoimmune reaction occurs when the appropriate proportion of CD4:CD8 is disrupted (Beer and Kwak, 1999  Changes in the proportion of CD4:CD8 inhibit NK cell adhesion to HLA-G producing an autoimmune response to the placental trophoblast and termination of the developing conceptus (Beer and Kwak, 1999  Such losses are usually repetitive (Beer and Kwak, 1999

Possible autoimmune (ie-against fetal proteins expressed in self-MHC) pathways with pregnancy.  Used with permission of authors.  Source:

    So how does HLA-G inhibit the maternal anti-fetal immune response?  Maternal NK cells have at least three receptors that recognize HLA-G.  One receptor, p49, is a member of the human killer inhibitory receptor (KIR) group (Lopez-Botet, Navarro and Llano, 1999).  These KIRs have cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM) that when phosphorylated recruit protein tyrosine phosphatases that are involved in the downregulation of NK activity (Lopez-Botet, Navarro and Llano, 1999).  The other two identified receptors, LIR-1/ILT-2 and ILT-4, are members of the Leukocyte Ig-like receptors (LIR) or Ig-like transcript (ILT) families (Le Bouteiller and Blaschitz, 1999).   Both receptors are NK-cell response inhibitory (Le Bouteiller and Blaschitz, 1999).  Receptor activation or deactivation may initiate one of two cytokine pathways:  the Th1 response, which is "bad for pregnancy", or the Th2 response, which is "good for pregnancy"(Somigliana, Vigano and Vinali, 1999).

Where is HLA-G found?
One of HLA-G's most interesting qualities is its localization.  HLA-G is expressed on the fetal extravillous trophoblasts, placental macrophages and the endothelial cells in the core of the mesenchymal chorionic villi (Le Bouteiller et al, 1999  (Le Bouteiller and Blaschitz, 1999) (Loke, Hiby and King, 1999).  Soluble HLA-G is found in the amniotic fluid (Le Bouteiller and Blaschitz, 1999).  The trophoblast cells are immunologically neutral:  they express neither MHC-I nor MHC-II molecules (Loke, Hiby and King, 1999).  Cells lacking both MHC's are usually destroyed;  however, HLA-G inhibits this response.
In the image below, cell types that express HLA-G on their surface are outlined in magenta.


Physiology of maternal/fetal interface:  placental villi invasion of endometrium.  Original does not have magenta highlights.  Used with permission of authors.  Source: with HLA-G

Spontaneous Abortions
Women with high NK cell activity levels pre-conception have a 3.5 greater risk of spontaneous abortion than women with normal NK cell activity levels (Somigliana, Vigano and Vinali, 1999).  However, there was no significant difference when the raw numbers of NK cells were compared between women who had recurrent spontaneous abortion and women who had normal pregnancies (Emmer et al, 1999).  It would seem the difference was related to quality, not quantity.  Women who are immunized against their husband's leukocytes may decrease their NK cell activity against paternally inherited MHC molecules (Somigliana, Vigano and Vinali, 1999).  Women who underwent this immunotherapy, and whose NK cell activity was successfully lowered had successful pregnancies (Somigliana, Vigano and Vinali, 1999).
Problems with CD4:CD8 ratios also result in repetitve losses of pregnancy (Beer and Kwak, 1999

As HLA-G helps the fetus escape immunological regulation, HLA-G could confer a similar immunity to tumor cells.  LM Real et al examined samples of solid tumor tissues (melanoma, breast, colon, larynx) and tumor cell lines (melanoma, breast, colon, cervix, pancreas, lung, leukemia and lymphoma) for HLA-G mRNA and surface expression (1999).  Most samples had HLA-G mRNA, but none had surface-expressed HLA-G molecules. However, they only used monoclonal antibodies to two isoforms of HLA-G -- it is possible that the tumors expressed one of the two other isoforms (Real et al, 1999).
Placental HLA-G levels are significantly lower or absent in pre-eclamptic placentas than in normal placentas  (Le Bouteiller et al, 1999).

Works Cited Page


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