Pregnant women with Rheumatoid Arthritis (RA): How can this affect fetal neurodevelopment and increase my risk of having an autistic child?

‚Äč‚ÄčNumerous 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.

  1. 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.

  1. 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, in utero , 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).

  1. 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, Blog-Latest-News-Updates/2015/April/Maternal-inflammation-during-pregnancy-catalyst-.aspx).
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 during pregnancy” http://www.preventmiscarriage.com).

References

  1. Crespi BJ, Thiselton DL. Comparative immunogenetics of autism and schizophrenia.Genes Brain Behav. 2011 Oct; 10(7):689-701.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-reactive antibodies and disease. Annu Rev Immunol. 2013; 31:345-85.
  7. 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.
  8. 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.
  9. Pardo CA, Eberhart CG. The neurobiology of autism. Brain Pathol 2007; 17: 434–447.
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