Home > Science > The Maternal Anti-Fetal Brain Antibody Story – where are we now?

The Maternal Anti-Fetal Brain Antibody Story – where are we now?

We have asked several scientists who gave presentations at the April 10-11 DAN! conference in Baltimore to share their research and perspectives from the meeting with you here on the blog.  The following piece is from Judy Van de Water, Ph.D. Professor of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine and The M.I.N.D. Institute (Medical Investigation of Neurodevelopmental Disorders) at the University of California, Davis. Dr. Van de Water’s laboratory research programs include the identification of the various mechanisms associated with autoimmune and other immune-mediated disorders. Dr. Van de Water is currently part of the NIEHS funded Center for Children’s Environmental Health as the principal investigator of the Immunological Susceptibility in Autism project.  She is also part of a project funded by NIMH in collaboration with an epidemiologist at Kaiser Permanente to examine the plasma of mothers whose children have autism for early biomarkers.

I am extremely fortunate to have been involved in a research project that has provided such rich and satisfying results at this point in my career. We have spent the past few years working on the identification and characterization of antibodies in the blood of mothers that recognized fetal brain proteins. We have found that these specific antibodies are associated with autism in about 13-15% of cases. It has been a bumpy path at times, but the hard work and diligence of the individuals in my laboratory that actually do all of the work, has been worth it.



What are autoantibodies?

The immune system is charged with identifying and destroying unwanted assailants. It is made up of a complex network of specialized cells and molecules that patrol the body seeking out intruders. In order to defend us, the immune system must be able to distinguish between self-tissues and foreign invaders. In healthy individuals, the immune system will mount responses to unfamiliar objects only, and ignore the body itself.

Sometimes this identification system breaks down, and the immune system mistakenly targets the body’s own tissues. This phenomenon is known as autoimmunity, and is observed in diseases like lupus, rheumatoid arthritis, myasthenia gravis, and multiple sclerosis.

A major weapon used by the immune system to protect the body is a group of proteins called antibodies. Produced by highly specialized white blood cells, antibodies work by attacking unwanted invaders, and letting other immune cells know that there is an intruder that needs to be destroyed.

Self-directed antibodies are called ‘autoantibodies’, and are a major contributor to the destruction observed in autoimmune disorders. In autoimmune disorders, antibodies may be directed against various building blocks of the body like DNA or neurons.

From the Beginning…

The first suggestion that maternal antibodies might be involved in autism came from early studies showing that antibodies from mothers of children with an autism spectrum disorder reacted to proteins on lymphocytes (a type of white blood cell) from their affected children. Given that antigens expressed on lymphocytes are also found on cells of the central nervous system, the authors proposed that aberrant maternal immunity might be associated with the development of some cases of autism [1]. More evidence of a link between maternal immunity and autism came from the study of one mother whose antibodies reacted to adult rat cerebellar Purkinje cells. Furthermore, when these antibodies were injected into pregnant mice, the offspring exhibited some behavioral abnormalities [2]. It was subsequently shown that plasma from several women whose children had autism contained antibodies that recognized proteins in fetal rat brain [3].

Most recently, we identified a highly specific pattern of autoantibody reactivity to fetal human brain proteins in the serum of mothers who have a child with autism [4]. This work by my graduate student, Dan, was awarded the very prestigious honor of being named among the Top 10 Research Achievements of 2008 by Autism Speaks, and a mention again in 2009. Our colleagues, Harvey Singer and Andrew Zimmerman at Johns Hopkins University and the Kennedy Krieger Institute [5] also reported similar findings, which helped to confirm our work. In addition we demonstrated that similar antibodies exist in pregnant women whose children were subsequently diagnosed with autism in a study with our colleague Lisa Croen at Kaiser Permanente [6]. It is important to note that in this case the samples were collected during pregnancy, while in the other cases the samples were collected after the child was born and diagnosed. This may lead to the possibility of diagnosing autism at a much earlier age than is currently possible.

Compelling data linking these maternal antibodies to a potential role in autism come from antibody transfer studies in primates. Briefly, antibodies (purified from women with multiple children with autism) were injected into pregnant rhesus monkeys, and the pregnancies were allowed to continue to term. The resultant offspring showed dramatically altered behaviors including hyperactivity, repetitive behavior patterns, and impaired social interactions, not unlike symptoms seen in children with autism. A similar study has now been published using a mouse model, with analogous results: offspring that were exposed in utero to antibodies taken from mothers of children with autism had a number of behaviors consistent with those seen in children with autism [7]. Collectively, these studies suggest that in at least some cases of autism, circulating maternal antibodies directed against certain fetal brain proteins might cross the placenta and bind to targets in the developing fetal brain. These antibodies may interfere with fetal neurodevelopment, potentially leading to neurodevelopmental disorders such as autism.

How can these brain-reactive antibodies affect the developing fetus?

During pregnancy, antibodies are passed from the mother to the developing fetus. These antibodies have a protective role, serving as a temporary immune system until the child’s own system matures during the first year of life.

If autoantibodies are present in maternal circulation, the fetus will receive them as well. Autoantibodies passed from the mother are capable of reacting with targets in the body of the developing fetus (see diagram). In some autoimmune disorders, including lupus, rhematoid arthritis, myasthenia gravis and Grave’s disease, autoantibodies produced by the mother can have a damaging or altering effect on the developing fetus.

So, where are we now?

The above observations suggest that detection of antibodies directed against fetal brain proteins may in the future serve as valuable biomarkers to identify women who have an increased risk of having a child with autism. It is anticipated that the presence of these antibodies would identify those women who are at particularly high risk for having a subsequent child with autism.  Therefore, the primary goal of our current work is the identification of the proteins that the maternal antibodies recognize. Therein lies a more difficult task.  I recently presented an update of this work in a science session at the DAN! meeting in Baltimore.  It was a wonderful experience, with a full audience and lots of great questions following the presentations. Many of the researchers in the field feel that bringing the most recent science to the DAN! community is important, and we value our interaction with the families and practitioners at the conference. During my session at the April 2010 meeting, I presented our more recent studies through which we are working to identify the proteins recognized by the maternal antibodies. While we have identified two of the proteins, the third remains frustratingly elusive. However, we are confident that we will eventually get it, thus allowing us to design a better test for these antibodies. Unfortunately, we do not yet know what causes these antibodies to be made. We are working on what triggers the immune system of some women to produce these antibodies to brain proteins. Another thing to keep in mind is that the antibodies are associated with only 13-15% cases, and there are lots of other causes of autism.  Finally, we hope that through the identification of the targets for these antibodies, we can someday provide a therapeutic to those individuals who have the antibodies, and wish to have more children while potentially reducing the risk that their next child will also be on the spectrum.

1.         Warren, R.P., et al., Detection of maternal antibodies in infantile autism. Journal for the American Academy of Child & Adolescent Psychiatry, 1990. 29(6): p. 873-7.

2.         Dalton, P., et al., Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol, 2003. 53(4): p. 533-7.

3.         Zimmerman, A.W., et al., Maternal antibrain antibodies in autism. Brain Behav Immun, 2007. 21: p. 351-357.

4.         Braunschweig, D., et al., Maternal serum antibodies to fetal brain in autism. Neruotoxicology, 2008. 29: p. 226-231.

5.         Singer, H.S., et al., Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol, 2008. 194(1-2): p. 165-72.

6.         Croen, L.A., et al., Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study. Biol Psychiatry, 2008. 64(7): p. 583-8.

7.         Singer, H.S., et al., Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: A pregnant dam mouse model. J Neuroimmunol, 2009. 211(1-2): p. 39-48.

UPDATE:

I want to thank everyone for their interest in our work and for their responses and questions regarding the research presented in the AS blog.  I thought that I would take this opportunity to clear up a few things and answer some general questions.  First, and foremost, we do not know at this time what causes someone to start making antibodies to fetal brain proteins.  While we know from research on other autoimmune diseases that some individuals are more susceptible to breaking tolerance to self-proteins, we don’t know the cause for most autoimmune disorders. 

We are investigating one gene that we think may contribute to the susceptibility to make these antibodies, but the work is still too early to report.  However, there is not likely to be just one cause, just like there are multiple ways that a child can develop autism.  I would also like to stress that while it is true that the tendency towards getting an autoimmune disease can be inherited, we still cannot predict who will ultimately become affected. What we now know about autoimmune disorders in general is that there is likely a genetic susceptibility combined with an environmental ‘hit’ of some kind, which can include infectious agents, certain medications, and/or toxicants, that pushes the immune system past its regulatory mechanisms thereby resulting in loss of tolerance to self.  The majority of the time, this occurs long before an individual shows signs of an autoimmune disorder, making it very difficult to determine the inciting factor.  So while we know that in a subset of cases maternal antibodies to fetal brain proteins may play a role in changing neurodevelopment, we may never know what the trigger is that causes the generation of these antibodies.  But, we will keep working on it!!

Finally, for all of you who are interested in participating in our research, please contact me and I will get your contact information. 

Thank you all again for your generous support of our work, and for sharing your stories with me. I learn so much from each of you.

  1. Jennifer
    April 19, 2010 at 4:45 pm

    Would ulcerative colitis fit into the list of auto-immune disorders that could result in these autoantibiodies?
    This is facinating and amazing research, thank you!!!!
    Finn’s mom

  2. Carla Wilson
    April 19, 2010 at 4:56 pm

    Good Afternoon! Need any volunteers for blood testing? My son has Aspergers. I have said for years that the DNA link had to be their. He is now 23 years old. I am certain, knowing the checlist like I do that my son, possibly myself, my father and my uncle (fathers brother) has had some form of autism. Please let my son and I know what we can do to help. I also have another son who has none of these issues. I was told when I was pregant with both boys that I have extremely high antibodies, which might account for why I now have trouble with my immune system in the form of allergies. Please let us know. thank you

  3. Allison Albano
    April 19, 2010 at 5:39 pm

    Our daughter who is almost 3 years old received an Anne Connolly test and tested positive for IgG autoantibodies and another autoantibody that indicate brain inflammation. Are there any suggestions for treatment that may help her?

  4. Patricia Myers
    April 19, 2010 at 6:04 pm

    I have always thought there might be a connection with Autism and the immune system. I have a Granddaughter that started loosing skills & speech at 3 yrs. of age. Both of her Grandmothers (maternal & paternal) have severe Rheumatoid Arthritis. My daughter, her mother, also develops hives and other allergic reactions to many things. I think those that have a compromised immune system are more prone to environmental factors that may trigger Autism. I mentioned this to a Neurologist we took her to in 2002 – and he was very dismissive. I am so glad this study is finally being taken seriously. Please keep us posted. Thank you.

  5. Kim Collins
    April 19, 2010 at 7:00 pm

    I wondered is there a way I could get tested? I would be more than willing. I have a 14yr old girl who is autistic and would love to know if this is what happened.

  6. Veronica Chaisson
    April 19, 2010 at 8:32 pm

    My son will be 2 1/2 at the end of May and he got his autism diagnosis from Children’s Boston December 2nd, 2009. We have had him in Early Intervention services since he was 12 months old and now receives 15 hours of autistic tutoring weekly ontop of his E.I. services. Life is busy!

    I find this article interesting and often question if my body had something to do with him being autistic. When I got pregnant I was 155ish pounds (healthy) but developed gestational diabetes around 25 weeks gestation. I controled my sugars with diet and exercise. I was also diagnosed with PCOS at the age of 15. He was born at 37 weeks and I was put on Pitocin to start my labor after my water broke the day before. 5 hours later we had a beautiful baby!

    I know first hand what its like living with PCOS and for having delt with diabetes for a short while…what that could have done to him while he was “cooking,” makes me wonder if that could have caused the autism? I will also note that besides my daily viatimns, I took no other medications during pregnancy and consumed no alcohol and have never touched drugs in my life time.

    Any ideas on this would be great! I would also be up for some testing if need be for research purposes.

  7. Moira Oliver
    April 19, 2010 at 9:50 pm

    Wow – this is interesting stuff. There is a long line of autism in my family from both sides so there’s no doubt something is being passed along. What is strange is that my ex-husband has multiple sclerosis. I wonder if that played into the soup that made up my son……. My daughter is not on the autism spectrum although she has a pretty low processing speed.

  8. Heather Menges
    April 20, 2010 at 1:38 pm

    I do believe autoimmune issues are causing a host of problems in the world today, that perhaps were not so prevelant in the past, or were much more mild. I have a family history and so does my husband of endometriosis which I believe has an autoimmune system problem at the root cause. I would be able to believe that one thing leads to another with the fetus having autoimmune issues when the Uterus, and the genetics show predispostion to autoimmune issues. WHY….allergies, autoimmune issues, and there derivitives are on the rise? It would seem it might be the enviroment as a large contributing factor. We now frogs grow extra body parts, and their offsprig do as well when living in a polluted pond. We live on a pulluted planet therefore we are having autoimmune sensitvities show up in places similar to the frogs in the pond. So who is to blame? Who is allowing for so much pullution to enter the environment of the people and the frogs. How do we change it? How do we cope with it as altered biological organisms? Or is this the future…we will all be autistic and are bodies will be fighting the environmental problems interenally seeing no one wants to fight them externally. It will be expensive? Yes, expenisve to all and everything on the planet. Good research….keep searching, what do we do now? Therapy and pain management for all those effected on a autoimmune suffering environment, how about better methods to pay for it all, in order to keep the species alive and coping!

  9. Katie Wright
    April 20, 2010 at 2:22 pm

    Dr. Van de Water’s research is so important. She is one of the few scientists rigorously studying autism’s environmental triggers.

    Autoimmune diseases run in so many families w/ ASD kids. IVIG was the intervention that helped restore my son’s health, but every kid is different. What we do know is that far too few treatments exist for this population and more autoimmune intervention grants need to be funded.

    There was zero autism in my family but so many autoimmune diseases. As a baby, my son could not tolerate the injection of so many viruses at once- along w/ a dozen toxic adjuvants. His adverse vaccine reactions were horrible. Kids like mine regress for a reason.

  10. Sarah
    April 21, 2010 at 4:24 am

    Me and my sisters? Allergies, hypothyroid (in a big way), my kid’s cousins? ADHD/anxiety akimbo with asthma and allergies. My parents? Mom – allergies and very serious bowel problems. Dad – Huge allergies and my uncle is still resentful (at 84) re: all the attention my father received as a child as he was always so sickly. My husband’s family – He’s covered in rashes daily of all sorts. But, “he’s healthy” – yeah right. His mother? Hypothyroid as well.

    Both of my pregnancies with my two children are VERY significant (but will remain private). Both were very damaged by their very different gestations for very different reasons.

    But, of course this set my first son up in a big way – he reacted and couldn’t process a host of issues thrown his way – antibiotics, vaccines (he has a scar from one of them), culminating in me SCREAMING from the bottom of my very being when my belief system was shattered – when he received his flu shot post 2 years old – even daycare, who had been telling me I was crazy, that he was fine – even they were terrified. So my first kid is clearly both – ASD from birth and vaccine damaged.

    My second kid – NT w/issues and sadly will remain vaccine free for now (I’m NOT happy about this – but cannot split up the vaccination schedule, as it is simply not available where I live. I’ll start when he’s ten years old).

    Oh – and did I mention I live in one of the most polluted cities? Love that EARLI study!

  11. Julie
    April 21, 2010 at 2:30 pm

    My 3 1/2 year old son is in the Autism Spectrum. I have history of Lupus and so does my mother. Are you stating with your research that because of my Lupus I have a son with Autism?!?!?!

  12. Katie Wright
    April 21, 2010 at 5:04 pm

    I don’t know who you were asking Julie, but I’ll answer. I have no idea what caused your child’s autism. I would never presume to know better than a parent regarding their own child.

    I think Van de Water’s research is important because she has uncovered a link. There is a disporportionately high rate of autoimmune disease in families affected by autism. The theory is that when a baby inherits a genetic predisposition for a weaker than average immune system, that baby is more vulnerable to challenges to his immune system, so when he is injected w/ numerous live and preserved viruses, his autoimmune system goes into overdrive attacking itself causing cognitive and physiological damage. The result being a series of illnesses and a regression. I believe this happened to my child. Julie, I hope your son is well.

  13. Vesa Ruuska
    May 26, 2010 at 5:20 pm

    I also think Van de Water’s research is interesting. However, I would like to point out that maternal antibodies reacting to fetal antigens is NOT an autoimmune reaction because the fetus usually has a completely different set of proteins than the mother. If the mother is exposed to the fetal brain proteins alien to her, it is completely natural that she will form antibodies against those proteins. What needs to be explained is when and how the mother gets exposed. The fetal proteins do not cross the placenta.

    Could anybody clarify me why the word autoimmune is used in this context at all?

  14. Pam
    February 14, 2011 at 11:23 pm

    I have lupus and both my children have autism. I always thought there might be a link.

  15. February 24, 2011 at 11:02 am

    Research already shows that as the number of family members with autoimmune diseases increases, the risk of having an autistic child increases. What we need now is diagnostic testing for antibodies that can cause autism, and treatment. It is also possible that these antibodies are just markers of a genetic over-reactive immune system.

  16. John Scatchard
    June 18, 2011 at 10:04 pm

    Researchers:
    Is it possible that some adjuvant in vaccines have, over the years dysregulated mothers’ immune systems such that they produce anti-fetal brain antibodies? Maybe some complement or epitope which hasn’t even been suspected causes a mother’s immune system to react in a bazaar way.
    Sincerely, John Scatchard

  1. February 24, 2011 at 11:04 am

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