Maternal inflammation during pregnancy: catalyst of autism development

In view of the many potential causes responsible for autism development, an alteration of the immune system seems to occupy a place of choice as a major event triggering the neuro developmental abnormalities in the fetal brain during pregnancy that lead to ASD (1).
The fetal brain is not a confined organ that is isolated from the immune system. In fact there is a cross-talk between the nervous and the immune systems.
During pregnancy, the developing fetus interacts with its environment (uterus). The maternal immune system has a protective role during pregnancy in allowing fetal growth, but a dysregulation of the maternal immune system during pregnancy (in response to a flare in autoimmune diseases, infection or many other environmental factors) could have dramatic and irreversible effects on fetal development particularly the brain and could induce long lasting damages.

  1. Autism: an inflammatory disease

It is now largely accepted that immune system alterations (inflammation) lead to abnormal development of the brain in autistic children. An accumulation of studies shows that autistic subjects have a disruption in the Th1/Th2 cytokine balance with high levels of plasmatic (blood borne) inflammatory cytokines such as IL-2, IL-12 or IFN-gamma.

A recent meta-analysis published in the journal Molecular Psychiatry (2), regrouping 17 independent studies comparing plasmatic cytokine expression between autistic individuals (n=743) and healthy controls (n=592), found that the inflammatory cytokines IL-1 beta, IL-6 and IFN-gamma were much higher in the participants with autism than in the controls. In addition, IL-8, eotaxin and MCP-1, factors associated with recruitment of inflammatory cells (neutrophils, monocytes) from the circulation to the site of inflammation, are also elevated. This study strengthens the theory that a T cell dysregulation (most likely arising during pregnancy) may be important in autism (3).

  1. Maternal inflammation during pregnancy: A trigger in autism development

If the genetic component of autism is irrefutable, recent accumulation of evidence shows the involvement of inflammation, which most likely starts in the womb, as a significant cause of ASD. The maternal immune system plays a central role during pregnancy by allowing embryo implantation and the maintenance of pregnancy by switching the maternal immune system toward a more tolerant state. Maternal inflammation occurring early during pregnancy can induce miscarriages. As the pregnancy progresses, the placenta becomes more resilient to maternal inflammation, allowing the fetal survival but still vulnerable to immune challenges as seen by pregnancy complications such as pre-eclampsia or intra uterine growth retardation (IUGR), two conditions suspected to have a common etiology with autism (for more information, read our blog Pre-eclampsia, IUGR and Autism: Their association is expected due to the same etiology for all: failure to generate maternal immune tolerance to the pregnancy”).

Cytokine storm: New theory in the etiology of ASD

Maternal inflammation has been clearly linked to brain damage in the developing offspring. Many studies in rodents have shown that prenatal maternal immune activation (MIA) induces perinatal brain injuries (4-5) and autistic-like behaviors (6) by altering DNA methylation (epigenetic process) in genes involved in neurodevelopment (7).

In women, dysregulations of inflammatory cytokine and chemokine levels such as IL4, IL-5, IL-6, IL-8 IFN-γ, TNF α and MCP-1 have been reported in the maternal serum or amniotic fluid during early- or mid-gestation of autistic children (8-9) and the changes in inflammatory cytokines correlates with the severity of ASD (10). Many of these are the cytokines we follow on our pregnant patients with immune related pregnancy complications and miscarriages.

IL-6 is a very interesting cytokine that can cross the human placenta (unlike many other cytokines) and may directly alter the placental environment thus impacting the fetus. Several clinical studies suggest that IL-6 levels in the amniotic fluid predict development of cerebral lesions and impairment in spatial learning (10-11). As the composition of the amniotic fluid is more from fetal than maternal origin, an elevated IL-6 level could reflect an inflammation in the fetal brain.

Maternal anti-brain autoantibodies

In many cases, mothers of autistic children are affected by autoimmune diseases such as diabetes (for more information, read our blog “ Diabetes in pregnant women: a population at risk for autism development in the offspring) , rheumatoid arthritis or systemic lupus erythematosus and produce deleterious antibodies that target protein in the brain of their children (12). Maternal auto-antibodies have been detected in the serum (13) and the brain of autistic children (14) showing that they can transfer during pregnancy from the maternal to the fetal circulation to finally reach and target the developing brain. Because, the Blood Brain Barrier (BBB) is still developing during the fetal period, maternal antibodies are able to have direct access to the brain during pregnancy. Recent work has demonstrated that IgG (antibodies) from mother of autistic children trigger autistic-like behavior when injected in mice (15) suggesting that maternal auto-antibodies may play a role in ASD.

Maternal inflammation can trigger irreversible neuron damage in utero and affect fetal brain development in genetically susceptible individuals.


At Braverman Reproductive Immunology, we are working on detecting any immune alterations that could be detrimental to pregnancy establishment and safe progression. By running an early immune profile screening in the high risk population, we can detect maternal inflammatory changes (in many cases patients are completely unware of these changes, and the only symptoms are previous pregnancy complications or of course a history of a child with ASD) and possibly minimize its impact on fetal health by treating these abnormalities.

References

  1. McAllister AK, van de Water J. Breaking boundaries in neural-immune interactions. Neuron. 2009 Oct 15; 64(1):9-12.
  2. Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, Guastella AJ. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry. 2015 Apr; 20(4):440-6.
  3. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Altered T cell responses in children with autism. Brain Behav Immun. 2011 Jul; 25(5):840-9.
  4. Burd I, Balakrishnan B, Kannan S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol. 2012 Apr; 67(4):287-94.
  5. Elovitz MA, Brown AG, Breen K, Anton L, Maubert M, Burd I. Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury. Int J Dev Neurosci. 2011 Oct; 29(6):663-71.
  6. Le Belle JE, Sperry J, Ngo A, Ghochani Y, Laks DR, López-Aranda M, Silva AJ, Kornblum HI. Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells. Stem Cell Reports. 2014 Nov 11; 3(5):725-34.
  7. Basil P, Li Q, Dempster EL, Mill J, Sham PC, Wong CC, McAlonan GM. Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain. Transl Psychiatry. 2014 Sep 2; 4: gte434.
  8. Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM. Amniotic fluid chemokines and autism spectrum disorders: an exploratory study utilizing a Danish Historic Birth Cohort. Brain Behav Immun. 2012 Jan; 26(1):170-6.
  9. Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel HM. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014 Feb; 19(2):259-64.
  10. Yoon,B.H.,Romero,R.,Park,J.S.,Kim, C. J.,Kim,S.H.,Choi,J.H.,and Han,T.R.(2000).Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am.J.Obstet. Gynecol. 182, 675–681.
  11. Samuelsson AM, Jennische E, Hansson HA, Holmäng A. Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning. Am J Physiol Regul Integr Comp Physiol. 2006 May; 290(5):R1345-56.
  12. Enstrom AM, Van de Water JA, Ashwood P. Autoimmunity in autism. Curr Opin Investig Drugs. 2009; 10:463–473.
  13. Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, Van de Water J. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun. 2009 Jan; 23(1):64-74.
  14. Rout UK, Mungan NK, Dhossche DM. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. Eur Child Adolesc Psychiatry. 2012 Mar; 21(3):141-7.
  15. Camacho J, Jones K, Miller E, Ariza J, Noctor S, Van de Water J, Martínez-Cerdeño V. Embryonic intraventricular exposure to autism-specific maternal autoantibodies produces alterations in autistic-like stereotypical behaviors in offspring mice. Behav Brain Res. 2014 Jun 1; 266:46-51.
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