Numerous studies suggested that individuals with ASD have a family history
of autoimmune diseases and highlighted the high prevalence of Rheumatoid
Arthritis (RA) among these families. Because there was no incidence of
RA in fathers of autistic children, the possibility of autoimmune mechanisms
involved in ASD has been focused in mothers and more specifically during
the highly sensitive period of pregnancy.
- What is Rheumatoid Arthritis (RA)?
Rheumatoid arthritis is a chronic inflammatory joint autoimmune disease
that affect up to 1% of the population in the USA, mostly women. As a
result people affected endure painful swelling in the joint but also possibly
in skin, eyes, lungs and blood vessel.
- Maternal RA and autism in children: few facts
A possible common genetic background
Several lines of evidence incriminate the HLA class II gene complex that
has been associated with an increased risk for both RA and autism (1).
Particularly, the third hypervariable region on the
HLA-DRB1 gene has been linked to RA and autism, with the strongest association
being found for HLA-DRB1*0401, HLA-DRB1*0404 or HLA-DRB1*0101 alleles.
On the other hand, HLA-DRB1*13 allele protects from RA and autism. These
results strongly suggest
a common genetic etiology between RA and autism.
Higher prevalence of auto-antibodies in women with RA or having an autistic child
Several epidemiologic studies have shown a high prevalence of autoimmune
diseases in mothers of autistic children particularly RA, suggesting that
environmental factors could,
, contribute to ASD (2).
Indeed, anti-brain antibodies, secreted by the immune system of people
affected by autoimmune conditions, were found to be elevated in mothers
of autistic children.
In a large cohort study (3) regrouping n=2431 mothers of autistic children
and n=653 control women of child-bearing age, the authors showed that
anti-brain antibodies were 4 times more likely to be found in mothers of
autistic children (10.5%) compared to control women (2.6%). In addition, anti-nuclear antibodies
were found to be co-expressed with anti-brain antibodies in 53% of women
with an autistic child compared to 15% in control women. Interestingly,
women with RA were found to be as likely as mother of autistic children
to have anti-brain antibodies. Others studies have found a higher prevalence of these antibodies in
sera of mothers having an autistic child (4). Ultimately, anti-brain antibodies
in maternal sera during pregnancy have even been considered as
early marker of autism in the offspring (5).
- How can RA alter fetal neurodevelopment and lead to autism?
By crossing the placenta and passing through the blood-brain barrier that
is not fully formed, maternal antibodies can affect the vulnerable fetal brain.
In utero exposure to maternal anti-brain antibodies has been shown to
induce abnormal brain development (6).
In pregnant animal (mice or monkey) injected with anti-brain antibodies
from mothers of an ASD child, studies have shown some behavioral impairments
in the offspring similar to those seen in ASD children (7-8). Interestingly,
these anti-brain antibodies target regions in the brain shown to be involved
in ASD (9).
Moreover, anti-nuclear antibodies such as anti-DNA antibodies are
neurotoxic to the developing brain in mice models.
In addition to the high level of autoantibodies that could target the fetal
brain and alter its development, many of our RA patients have markedly
elevated inflammatory cytokine levels (INF gamma, TNF alpha, IL17) which
have also been associated with ASD (for more information,
Altogether these studies show that
RA may predispose to autism in offspring of mothers affected by the disease, most likely through
anti-brain antibodies production and
systemic inflammation that can injure the developing fetal brain.
At Braverman Reproductive Immunology, we are using a full immune screening panel allowing us to detect the
presence of auto-antibodies among other inflammatory factors, through
the pregnancy. In fact, we are able to make the diagnosis of RA prior
to the presentation of symptoms in patients that are coming to us for
an evaluation of their recurrent miscarriages. To prevent and limit the
damages caused by an antibody-mediated inflammation on fetal development,
we recently optimized a novel dual therapy that could help to prevent
or minimize alterations in fetal development (for more information read
our blog “Rituximab and Apheresis: novel dual therapy in use
at Braverman Reproductive Immunology to prevent antibody-mediated inflammation
- Crespi BJ, Thiselton DL. Comparative immunogenetics of autism and schizophrenia.Genes
Brain Behav. 2011 Oct; 10(7):689-701.
- Atladottir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton
WW et al. Association of family history of autoimmune diseases and autism
spectrum disorders. Pediatrics 2009; 124: 687–694.
- Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates
with autoimmunity in mothers of a child with an autism spectrum disorder.
Mol Psychiatry. 2013 Nov; 18(11):1171-7.
- Singer HS, Morris CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies
against fetal brain in sera of mothers with autistic children. J Neuroimmunol
2008; 194: 165–172.
- Croen LA, Braunschweig D, Haapanen L, Yoshida CK, Fireman B, Grether JK
et al. Maternal mid-pregnancy autoantibodies to fetal brain protein: the
early markers for autism study. Biol Psychiatry 2008; 64: 583–588.
- Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-reactive antibodies
and disease. Annu Rev Immunol. 2013; 31:345-85.
- Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW, Pletnikov M. Prenatal
exposure to antibodies from mothers of children with autism produces neurobehavioral
alterations: A pregnant dam mouse model. J Neuroimmunol 2009; 211: 39–48.
- Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral
DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from
mothers of children with autism. Brain Behavior Immunity 2008; 22: 806–816.
- Pardo CA, Eberhart CG. The neurobiology of autism. Brain Pathol 2007; 17: