HLA-G polymorphism, NK cells and Autism: At the cross road between in utero inflammation and fetal neurodevelopment

HLA-G polymorphism, NK cells and Autism:

At the cross road between in utero inflammation and fetal neurodevelopment

During pregnancy, the Human Leukocyte Antigen (HLA) system plays a major role in the development of immune tolerance. HLA proteins are expressed on the surface of all nucleated cells, presenting peptides to T cell receptors (TcR) on T lymphocytes, thus triggering adaptive immune responses.

During implantation and early pregnancy, the uterus hosts a large number of Natural Killer (NK) cells representing 50-70% of immune cells at the feto-maternal interface. Uterine NK cells express Killer-cell immune globin-like receptor (KIR) proteins that bind to HLA molecules localized on the fetal trophoblast.

Among trophoblastic HLA proteins, HLA-G is a tolerogenic molecule playing a key role in the development of immune tolerance and protecting the fetus from maternal immune system damages. KIR/HLA interaction and immune activation play a major role during fetal development. A dysregulation of this process could constitute risk factors for autism through an immune noxious environment that will alter fetal neurodevelopment.

HLA-G polymorphism and autism

A recent study led by Dr Guerini (Don C. Gnocchi Foundation IRCCS, Milan, Italy) showed an association between a 14-bp insertion in the HLA-G gene that significantly reduces soluble-HLA-G level and increases autism prevalence.

To do so, they analyzed 71 families with at least one autistic child for a total of 248 individuals.

The 14bp + allele was present in 50% of ASD children and in 49.3% of their mothers (which was similar to that seen in women with complication during pregnancy).

Homozygosity for HLA-G 14bp +/14bp + genotype results in a reduced level of HLA-G that would be involved in the development of an inflammatory environment throughout pregnancy (lack of immune tolerance) that may ultimately cause alterations during fetal neurodevelopment.

It is interesting to note that three HLA-G 14bp +/ 14bp + homozygous patients were healthy female. This put into light and confirmed the hypothesis that steroid dimorphism may take part in the development of autism with female steroid acting as a shield during brain development.

KIR2DL4–HLA-G interactions and endosomal signaling impact the placenta

Besides HLA-G tolerogenic role in preventing NK cells from attacking the fetus, evidences accumulate to show a more constructive role of HLA-G in modulating placentation. A recent study led by Dr Rajagopalan from the National Institutes of Health (Rockville, MD) proposes an alternative mechanism where homozygous HLA-G 14bp +/14bp + genotype that leads to reduced quantities of soluble HLA-G, is associated with an alteration of fetal development.
Soluble HLA-G secreted by fetal trophoblast cells is the ligand for the NK cells receptor KIR2DL4. This activating KIR receptor is of particular interest because of its singularity. It is not localized at the cell surface of maternal NK cells as all the others KIR receptors but it is rather present in endosome (intra cellular localization). So HLA-G can be endocytosed (absorbed by the cell into KIR2DL4-containing endosomes) and induces signaling that leads to NK cells cellular senescence. Although, senescent cells are quiescent (they don't multiply or die by apoptosis), they are metabolically active and secrete an array of soluble factors senescent-associated secretory phenotype (SASP).

SASP molecules shape the immune environment and remodel vascularization to promote fetal growth and trophoblast invasion during the implantation process. Reduced level of HLA-G in homozygous HLA-G 14bp +/14bp + results in a lower placental blood flow and impairment in the fetal development.

These recent studies clearly demonstrate that ASD is associated with NK cells activity and KIR/HLA interaction. Besides its role in ASD development, HLA-G 14bp + allele is also detected in patients suffering from pregnancy complications such as recurrent miscarriages, intrauterine growth restriction, conditions that have been linked to an immune activation.

Thus, immune tolerance toward the fetus appears to be the key process whose dysregulation could be the cause of multiple complications.

Categories: Autism
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