Maternal Inflammation, Th17 and IL-17a production: Potent disruptor of fetal brain development leading to Autism

A recent study published in the latest issue of the Journal Science (January 29th 2016) emphasized the key role of maternal inflammation during pregnancy, that disrupts fetal brain development and could lead to Autism (/documents/Choi_2016.pdf).

Previous study in mice showed that the induction of inflammation during pregnancy, with a viral infection that triggers maternal immune activation (MIA), affects fetal brain development with dramatic consequences on pups that develop autism-like behavioral abnormalities (1-3).

The present study goes a step further by identifying immune cells whose secretion directly impact fetal brain formation, Th17 cells and clearly demonstrated thatblocking IL17 pathway could prevent autism-like behavior in the offspring.

1- Th17 cells and IL17a production in Autism

T helper 17 (Th17) cells are involved in immune responses against bacteria. Via the production of pro-inflammatory cytokines, with interleukin -17a (IL-17a) being the predominant Th17 cytokine, these cells play a central role in inflammatory and autoimmune diseases including but not limited to asthma, rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD) and multiple sclerosis (4).

a- What is known about IL-17 in relation to Autism?

IL-17a was found in the serum of a subset of autistic children (5-6).
A recent study has also shown that higher levels of IL-17 were detected in the serum of autistic children when compared to healthy controls and these levels were even higher when the autistic children were affected by asthma too (7). In addition, genome-wide copy number variant (CNV) analysis identified IL17a as one of many genes enriched in autistic patients (8).

Animal studies have similarly shown (MIA mouse model) that affected offspring produced higher levels of IL-17a (9-10). Although IL-17a was shown as a potential factor involved in autism development, studies did not focus on showing what were the specific immune cell population involved.

b- What does this new study bring?

The authors of the current study created a mice model lacking a specific factor, namely retinoic acid receptor–related orphan nuclear receptor γt (RORγt KO mice model), crucial for the Th17 cells differentiation. These knock out mice would not express Th17 cells, therefore they won’t be able to synthesize IL-17a.

They showed that despite inducing maternal inflammation in pregnant mice, the pregnant KO mothers failed to produce IL-17a and their offspring had a totally normal brain development with no autism-like behavioral abnormalities.

On the other hand, infected wild type pregnant mice (WT) developed an acute immune response with high levels of IL-6, IL-17 and other pro-inflammatory factors such as TNF-α.

High IL-17 levels were detected in the placenta and the decidual tissue and IL-17 receptors expression (IL-17R) was strongly augmented in the fetal brain.

This led to:

  • Abnormal cortical development in the offspring
  • ASD-like behavioral abnormalities in the offspring

Interestingly, when the IL17/IL17R pathway was blocked using IL-17a blocking antibody before the induced infection in the pregnant mice, the offspring did not express higher levels of IL-17R and had a normal brain development and no autistic behaviors.

Altogether, these data clearly pinpoint the key role of high IL-17 levels as a cause for ASD development.

Most importantly, the study suggest that Autism is preventable by inhibiting IL-17/IL17R pathway either by blocking IL17a production or action.

2- Th17 cells and IL-17a in Reccurent Pregnant Losses (RPL) or pregnancy complications

Some T cells can trigger an inflammatory response to fetal antigens leading to miscarriages or pregnancy complications. Among others, Th17 cells producing the inflammatory IL-17 have been reported to play a role in RPL.
A recent study conducted on 60 idiopathic RPL cases and 40 age-matched fertile controls showed higher serum levels in RPL patients when compared to controls (11). Another set of data confirmed these results and showed that IL17 serum levels were even higher in obese RPL patients when compared to lean RPL patients or fertile controls (12). Further, recent studies attributed a role of Th17 and IL-17 in pre-eclampsia (13)

Interestingly, the pro-inflammatory effector cytokine IL-6, a key factor for TH17 cell differentiation (14) was reported to be also highly expressed in RPL patients when compared to controls (15) and high levels have been correlated with severe case of pre-eclampsia (16).

Because, maternal inflammation is a risk factor for pregnancy loss, pregnancy complications such as pre-eclampsia and could potentially disrupt fetal brain development thus leading to Autism, it is crucial to detect, treat and reduce any maternal immune alterations potentially deleterious to pregnancy maintenance and fetal health.

By detecting and counteracting any increase in IL-17 producing cells, with appropriate immune therapy, we, at Braverman Reproductive Immunology, strongly believe that we can help you to minimize your risk of having a baby affected with Autism.

References

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