A cytokines regulate CNS formation they are

A probable environmental insult leading to the development
of ASD in a foetus is maternal infections during pregnancy. Epidemiological
studies have shown a correlation between ASD and maternal infection and so this
has led to the development of animal studies to investigate the potential link.
These studies found that behavioural and neurological abnormalities in some
autistic patients where like those observed in mice whose mothers had an
infection. This led to the activation of the mothers immune system called
maternal immune activation (MIA) which exposes the foetus to the mothers
cytokines, specifically Interleukin-6 which is produced by her macrophages and
T cells. These cytokines, including IL-6, then cross the blood-placental
barrier triggering the foetal immune system. The cytokine IL-6 is inflammatory
and so has a deleterious effect on foetal development and possibly alters gene
expression, crucial in the control of the immune system and formation of the central
nervous system. The neurological damage on the developing foetus caused by the
inflammation may instigate the behavioural phenotypes typical of an individual
with ASD.  

In typical foetal development there are small levels of
cytokines present which are crucial in the formation of the CNS. Although it is
still unclear how the cytokines regulate CNS formation they are involved in all
stages of neurodevelopment. Increases in the concentration of IL-6 as the
result of MIA disrupts the balance between its pathological and physiological
effects leading to the inflammatory response. Whilst it is clear that MIA
increases the levels of cytokines in a foetus it is unknown through what
mechanism this occurs. There are three possible pathways through which IL-6 can
be raised in a foetus following MIA. Firstly, IL-6 originating from the mothers
T-cells and macrophages could pass through the blood-placental barrier affecting
the neurodevelopment of the CNS. Secondly, a maternal infection could lead to
the production of cytokines in the placenta that are passed to the foetus.
Lastly, the maternal infection results in the foetus raising IL-6 levels on its
own that then causes lasting neurological damage. Several conflicting studies
disagree on the ability of cytokines to pass the blood-placental barrier with
some saying that no cytokines can pass through, while others suggest that the
number of cytokines crossing the placenta are too small to affect the foetus.

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However, what is undisputed is the presence of cytokines in
the placenta. These cytokines help to deter maternal-foetal rejection,
resulting in a miscarriage. In the placenta regulatory T cells (Treg)
suppress inflammatory Th17 cells to aid in the prevention of foetal rejection. Interleukin-6
has been proven to control the levels of Treg and Th17 by reducing
the number of Treg cells whilst specialising naïve T cells
into Th17. Following MIA the raised levels of IL-6 increase the inflammation in
the placenta and it is possible this is also linked to ASD.

One study examined the number of women with an infection
during pregnancy and the possible link this has to ASD. The study examined a
population with 407 mothers in the case group and 2075 in the control. The
study found that 50% of both the control and case group had at least one
infection at some point in their pregnancy either in hospital or in an
outpatient setting. Furthermore, the case group had viral infections no more
frequently than the control throughout their pregnancy. However, infections
diagnosed in hospital where 50% more common in the mothers of autistic
individuals. Specifically, bacterial infections in the third trimester which
had an adjusted odds ratio of 1.32 in the case group compared to 1.5 in the
control. Furthermore, the mothers in the case group where more likely to have
more than one infection during their pregnancy at 34.5% vs 29.1% in the
control. The risk of ASD increases further when examining two or more
infections in the third trimester which was 16.5% in the case group and 10.6%
in the control.

Given that certain individuals are more genetically
predisposed to ASD than others it is possible that environmental triggers like
MIA can lead to autism developing. 

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