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 . 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 . It was subsequently shown that plasma from several women whose children had autism contained antibodies that recognized proteins in fetal rat brain .
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 . 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  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 . 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 . 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.
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.