Universidad Autnoma de Ciudad Jurez

Instituto de Ciencias Biomdicas

Departamento de ciencias de salud

Programa de mdico cirujano

Impact of maternal immune activation in Autism Spectrum Disorders

Kricel Prez Andreu 135904

Asesora de proyecto: Bianca Gutirrez Amavisca

Ciudad Jurez, Chihuahua

27 de Junio del 2017

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Summary

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders

characterized by core deficits in three domains: social interaction, communication, and

repetitive or stereotypic behavior. Genetic and environmental factors are thought to

contribute to neurodevelopmental of ASDs. The maternal immune activation may serve

as a risk factor of autism spectrum disorder and other neurodevelopmental disorders

like schizophrenia. It increases inflammatory cytokines in the fetal environment, as well

as in the fetal brain. Resulting from inflammatory stimuli such as viral or bacterial

infections during pregnancy.

Key words

Autism spectrum disorders (ASDs), maternal immune activation (MIA), cytokines,

GABA, IL-17a, IL-6, and Vitamin D.

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Introduction

Autism spectrum disorders (ASD), a heterogeneous group of neurodevelopmental

disorders characterized by communication and social interaction impairments, restricted

interests, and repetitive behaviors. The causes of most cases of autism spectrum

disorders (ASD) are unknown. Some epidemiological studies suggest that maternal

gestational inuenza virus infection may increase the risk of ASD in offspring

(Mahic, 2017).

Results of animal studies suggest that maternal immune activation (MIA) during

pregnancy is associated with deviations in brain development.24 Infectious disease is

the most common path to maternal immune activation during pregnancy. Several

previous studies have investigated infection during pregnancy as a part of a larger

assessment of various prenatal factors. The association between various self-reported

infections, febrile episodes, and use of antibiotics during pregnancy and ASD in the

offspring were studied (Henriksen, 2012 ).

MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-

17a, in the fetal brain. Data suggest that therapeutic targeting of TH17 cells in

susceptible pregnant mothers may reduce the likelihood of bearing children with

inflammation-induced ASD-like phenotypes. (Choi, 2016).

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There has not been a single gene candidate discovered for ASD, although several

genes have been identified as abnormally expressed or polymorphic at a higher rate

within the autistic population. Among these genes have been those involved in neuronal

and synaptic formation and function, including, those involved in immune regulation,

such as cytokine receptor glycoprotein 130 (Parker, 2010).

The role of MIA and cytokine regulation, as a key mediator in the neuropathological,

behavioral and possibly genetic irregularities observed clinically in autism are important

factors that warrant further investigation (Wong, 2017).

TH17 cells and their cytokine mediators have been suggested to have a role in ASD.

For example, elevated levels of IL-17a, the predominant TH17 cytokine, have been

detected in the serum of a subset of autistic children. (Wong, 2017)

Analysis identified IL17A as one of many genes enriched in autistic patients. Similarly,

in the MIA mouse model, CD4+ T lymphocytes from affected offspring produced higher

levels of IL-17a upon in vitro activation. While these data suggest that TH17 cells may

be involved in ASD patients, whether TH17 cells are the specific immune cell population

that is necessary for MIA phenotypes is unknown (Choi, 2016).

RORt is a critical regulator of the IL-17a pathway. The role of maternal RORt in MIA-

induced behavioral phenotypes in offspring. TH17 cells and IL-17a have been detected

in the decidua as well as in the serum during pregnancy in humans. CD45+

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mononuclear cells, including CD4+ T cells, isolated from placenta and decidua of

immune-activated WT mothers (Choi, 2016).

The pro- inflammatory cytokine interleukin-6 (IL-6) has been idenfied as a casual factor

in ASD- like phenotypes associated with MIA. Increased expression of Il-6 is often noted

in ASD. Besides its function in inflammation, IL-6 has a immunoregulatory cytokine

transforming growth factor beta, nave CD4 T cells co- express RORt and the

transcription factor forkhead box P3 (Wong, 2017).

Cytokines such as IL-6, activate Janus tyrosine kinase, mitogen-activated protein and/or

other kinases, which in turn activate transcription factors such as signal transducer and

activator of transcription (STAT). During inflammation for example, IL-6-mediated

STAT3 activation leads to the increased expression of other cytokines and immune

regulatory genes, and ultimately proteins. These observations may explain the changes

in gene expression seen in Fetal inflammatory response syndrome (FIRS) and ASD

patients and animal models of MIA. In the fetal brain, exposure to maternally derived

inflammatory cytokines may have effects similar to what is seen in these neurological

disorders (Parker, 2010).

Experimental work in animals indicates that this link is mediated by maternal immune

activation (MIA) involving interactions between cytokine-associated inflammatory

events, oxidative stress, and other pathophysiological processes such as hypoferremia

and zinc deficiency (Vuillermot, 2017).

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Another epidemiologically valid developmental risk factor for later psychiatric disease is

developmental vitamin D (DVD) deficiency. Birth cohort studies have provided evidence

that maternal vitamin D deficiency is associated with a range of later autism-related

outcomes including impaired language development and cognitive development in

offspring (Vuillermot, 2017).

Vitamin D interferes with pro-inflammatory transcription factors and signaling pathways,

regulates the expression of proinflammatory enzymes, and modulates cytokine gene

expression, protein production, and signaling. More specifically, vitamin D inhibits the

production of pro-inflammatory cytokines such as IL-6 (Vuillermot, 2017).

Inflammatory factors produced early in brain development either directly, by inducing

MIA, or indirectly, by the maternal absence of a potent anti-inflammatory factor such as

vitamin D may, represent a convergent pathway towards developmental brain

abnormalities and psychiatric conditions later in life (Vuillermot, 2017).

The objectives for this article is to verify whether behavioral dysfunctions relevant to

ASD, including deficits in social interaction, stereotyped behavior, innate anxiety, and

emotional learning are present at a more translationally relevant prepubertal age and

does IL-6 and IL-7A induced inflammatory response in either dams or fetal brains.

Its important to perform more for studies involving the maternal immune activation and

learn more about the risk factors that can have an effect in ASD so it can be prevented

in future pregnancies.

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References

1. Mahic, M. (2017). Epidemiological and Serological Investigation into the Role of

Gestational Maternal Inuenza Virus Infection and Autism Spectrum

Disorders. Msphere, 1-8.

2. Henriksen, T. (2016). Autism after Infection, Febrile Episodes, and Antibiotic Use

during Pregnancy: An Exploratory Study. HHS Public Access, 1-18.

3. Choi, G. B. (2016). The maternal interleukin-17a pathway in mice promotes

autismlike phenotypes in offspring. HHS Public Access , 1-3.

4. Parker, Carla (2010). Maternal Immune Activation and Autism Spectrum Disorder:

Interleukin-6 Signaling as a Key Mechanistic Pathway . Neuro signals, 1-16.

5. Wong, H. (2017). Experimental Neurology, 1-13.

6. Vuillermot, S. (2017). Vitamin D treatment during pregnancy prevents autism-

related phenotypes in a mouse model of maternal immune. Researcher gate, 1-14.