Maternal Infection & Autism

1. Maternal Infection & Autism PHM 142 Gloria Cheung Shirley Fan Lu Xuan (Lisa) Sun Hilary Chiu PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. What is Autism? • Biologically based disorder of brain development of the CNS • 6-7 cases per 1000 children • Three cardinal features of autism • 1) failure to develop communicative language • 2) failure to develop interpersonal interactions • 3) failure to develop adaptive skills • 50% of autistic children have an intellectual diability • Some have Asperger’s syndrome • Pervasive linguistic and cognitive development

3. Causes of Autism • Genetic and Environmental • Genetic (this only accounts for a small fraction of cases) • gene mutations • gene deletions • copy number variants etc • Concordance in monozygotic twins is reported to be between 70-90% while concordance in dizygotic twins is virtually 0% • Families with autistic children have members with “autistic traits” but not the full-blown characteristic signs

4. Causes of Autism • Geneticand Environmental • Environmental: • Vulnerability of developing brain to toxic exposures especially during embryonic and fetal life • misoprostol • valproic acid • thalidomide, etc. • Correlated with various infections • Prenatal Rubella Infection • Influenza virus • Hypothroxinemia

5. Rodent Model • Two Methods: • Infect pregnant mice or rats via a nasal application of influenza virus • Mimic infections by activating the maternal immune system in the absence of pathogens • Involves a maternal injection of the synthetic double-stranded RNA poly(I:C) or a lipopolysaccharide to evoke an antiviral inflammatory response • Leads to behavioural abnormalities and neuropathologies • Deficits in communication, social interaction & elevated anxiety

6. When does Autism start? • Maternal infections in the first trimester have been associated with development of autism in offspring • Fetal brain development is affected • Acute infection in mother can: • increase cytokine levels or; • initiate an autoimmune process whereby a maternal inflammatory response is observed

7. First Trimester • Months 1-3 of pregnancy is the most critical stage of development • Initial stages of development • Rates of miscarriage noticeably drop after first trimester

8. Month 1 • Amniotic sac is a water tight sac that surrounds the fertilized egg and helps cushion the embryo • Development of the placenta - is the organ that is responsible for the transport of nutrients from mother to baby and waste from baby • At the end of first trimester, only 6-7 mm long

9. Month 2 • Proper development of neural tube (brain, spinal cord, and other neural tissue of the central nervous system) • Initial development of digestive tract and sensory organs • Bone begins to replace cartilage • Embryo  Fetus

10. Month 3 • All basic structures are formed, including limbs • Reproductive organs begin to develop • By the end, fetus is 3-4 inches long

11. Maternal Infection During First Trimester • Viral infection in first trimester leading to development of autism is more common than bacterial infection • Studies have shown highest correlation between influenza and autism • Increased maternal cytokine levels from infection can cross placenta and increase vulnerability to neurobehavioral abnormalities • Disruption in brain development

12. Genetic & Environmental Influences • (Pardo & Eberhart, 2007) • Genetic and environmental factors that influence intrauterine and early postnatal brain development likely alter neurobiological and neurodevelopmental trajectories • Both maternal/intrauterine events may modify the underlying genetic substrate and lead to greater abnormalities in neuronal organization and cortical network development

13. IL-6 • Elevation of proinflammatory cytokine IL-6 associated with abnormal behaviours and changes in offspring brain gene expression • Cytokine: group of protein/peptides that act as humoral regulators/signalling molecules to trigger an adaptive immune response • Injection of IL-6 alone is sufficient to yield the abnormal behaviours • Blocking IL-6 during MIA prevents the development of these behaviours

14. Mechanism of Action – proposal 1 • Elevation of IL-6 also found in CSF of living autistic children • Directly acts on the brain and is known to play a role in brain development, learning, and memory • Central to inflammation induced working memory disruption • IL-6 mRNA and protein are elevated in the fetal brain following maternal poly (I:C) administration • This cytokine has demonstrated both neurodegenerative and neuroprotective properties

15. Mechanism of Action – proposal 2 • Placental response to MIA as an indirect pathway towards altering fetal brain development • Increasing maternally derived IL-6 protein found in the placenta • Changes in endocrine factors lead to acute placental pathophysiology and subsequent effects on fetal development

16. Mechanism of Action – proposal 2

17. IL-6 Indirect Effects • IL-6 could alter transfer of nutrients, hormones and other key molecules to the fetus by altering vascular permeability in the brain • Expression of genes responsible for the integrity of the placental barrier are decreased after MIA • Potential harmful proteins (maternal antibodies) could be transferred to the fetal environment

18. Maternal autoantibody-related (MAR) autism • Autoantibodies are immune cells that target the body itself • Reason for their production is unclear • Theory: these antibodies can cross the placenta to affect proteins in the fetus brain • Mechanism: • Infection  cytokines  inflammatory processes  production of maternal antibodies  interact with fetal antigens

19. Study Using Mice Models • 2003 • Goal: prove the connection between autoantibodies & autism • antibodies from mother of children with autism were injected into pregnant mice • mice offspring showed deficits in social behavior, motor skills, as well as cerebellar abnormalities. • other models such as monkeys showed similar results

20. Combination of antibodies carried by the mother • A project called “childhood autism risk from genetics and environment (CHARGE) was launched in 2003 • Main finding: certain antibodies in the mother’s blood are associated with different deficits in the child • The study is based on 520 women, including 204 who have children with autism, as well as 2,000 children with autism ranging in age from 2 to 5 years. • The gold standard diagnostic tests were used to assess the children

21. Recent Findings • A study published in July 2013 showed that specified antibodies linked to MAR autism has been identified • Mothers of children with autism were 21 times more likely to have these antibodies than mothers of children who did not have autism. • These antibodies can be detected within 13 weeks of pregnancy • This finding could help to screen pregnant women for harmful anti-brain antibodies and also develop drugs that could block these antibodies.

22. Future Directions • Increase vaccinations to prevent maternal infections • Administration of antigenic material to stimulate the immune system to develop adaptiveimmunity to a pathogen • Active agent of the vaccine may be intact but inactivated (non-infective) or attenuated (with reduced infectivity)  • Causes body to create more antibodies • Types of vaccines • inactivated vaccine • attenuated vaccine • virus-like particle vaccine • subunit vaccine

23. Summary • Three cardinal features of autism which are failure to develop communicative language, interpersonal interactions and adaptive skills • Both genetic and environmental causes (maternal infections such as influenza, rubella) • Maternal Infection affects fetal brain development in the first trimester of pregnancy • Vaccinations can lower the risk of maternal infections that may lead to autistic newborns • Both maternal/intrauterine events may modify the underlying genetic predispositions and lead to greater fetal abnormalities in neuronal organization and cortical network development • Elevation of proinflammatory cytokine IL-6 associated with abnormal behaviours and changes in offspring brain gene expression • In addition, placental response to maternal infection is an indirect pathway towards altering fetal brain development, resulting in increasing IL-6 produced by decidual cells of the placenta • Autoantibodies produced by women can lead to the development of autism in the fetus. This type of autism is called Maternal Autoantibody-Related (MAR) autism. These antibodies increase the risk of developmental problems by crossing the placenta and targeting certain proteins in the fetus’s brain.

24. References Atladottir, H., Thorsen , P., Ostergaard, L., Lemcke, S., Schendel, D., Abdallah, M., & Parner, E. (2010). Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. Autism and Developmental Disorders, 40(12), 1423-1430. Retrieved from http://biopop.pophealth.wisc.edu/wp/wp-content/uploads/2012/12/Maternal-Immune-Function-and-Autism.pdf Conrick, T. (2013, July 22). Maternal antibodies and autism and flu shots oh why?. Age of autism. Retrieved from http://www.ageofautism.com/2013/07/maternal-antibodies-and-autism.html Davila, R. D. (2013, July 11). Ucdavis study finds link between maternal antibodies and autism read more here: http://www.sacbee.com/2013/07/11/5559197/uc-davis-study-finds-link-between.html Diamond, B., Brimberg , L., & Gregersen, P. (2012, February 21). Maternal anti-brain antibodies may play a role in autism. Simons foundation autism research initiative. Retrieved from http://sfari.org/news-and-opinion/viewpoint/2012/maternal-anti-brain-antibodies-may-play-a-role-in-autism Hughes, V. (2011, December 15). Studies of early development reveal immune link to autism. . Simons foundation autism research initiative. Retrieved from http://sfari.org/news-and-opinion/news/2011/studies-of-early-development-reveal-immune-link-to-autism Landrigan, P. J. (2010). What causes autism? exploring the environmental contribution. Current Opinion in Pediatrics, 22(2), 219-225. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20087185 Libbey, J. E., & Sweeten, T. L. (2005). Autistic disorder and viral infections. Journal of Neurology, 11, 1-10. Retrieved from http://www.jneurovirol.com/o_pdf/11(1)/001-010.pdf Nihira, M. (2012, 07 08). The first trimester: Your bab'ys growth and development in early pregnancy. Retrieved from http://www.webmd.com/baby/1to3-months Patternson, P. (2011). Maternal infection and immune involvement in autism. Trends in Molecular Medicine,17(7), 389-394. Patterson, P. (2009). Immune involvement in schizophrenia and autism: Etiology, pathology and animal models.Behavioural Brain Research, 204, 313-321. Retrieved from http://www.cco.caltech.edu/~phplab/pubs/10 PHP BBR rev09.pdf Pardo , C., & Eberhart , C. (2007). The neurobiology of autism. International Society of Neuropathology, (17), 434-447. Patterson, P. (2012). Maternal infection and autism. Elsevier, (26), 393. Smith, S., Li, J., Garbett, K., Mirnics, K., & Patterson, P. (2007). Maternal immune activation alters fetal brain development through interleukin-6. Neurobiology of Disease, 27(40), 10695-10702. Yong, E. (2013, July 9). Maternal antibodies linked to autism. The scientist. Retrieved from http://www.the-scientist.com/?articles.view/articleNo/36379/title/Maternal-Antibodies-Linked-to-Autism/