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
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).
- 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
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.
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.
- McAllister AK, van de Water J. Breaking boundaries in neural-immune interactions.
Neuron. 2009 Oct 15; 64(1):9-12.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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.
- 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.
- Enstrom AM, Van de Water JA, Ashwood P. Autoimmunity in autism. Curr Opin
Investig Drugs. 2009; 10:463–473.
- 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.
- Rout UK, Mungan NK, Dhossche DM. Presence of GAD65 autoantibodies in the
serum of children with autism or ADHD. Eur Child Adolesc Psychiatry. 2012
- 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.