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
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.
+ 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
+ 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
It is interesting to note that three HLA-G 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
+ 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
+ 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,
+ 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.
immune tolerance toward the fetus appears to be
the key process whose dysregulation could be the cause of multiple complications.