Maternal Infection and Autism

Transcription

1 Maternal Infection and Autism Kristen Wierda Jackie Luu Nicole Chang Larysa Santavy October 17, 2017

2 Outline - What is autism? - Analyzing maternal infection - Model of Maternal Immune Activation (MIA) - Evidence - Specific effectors - IL-6, IL-17A - Other relevant cytokines (IL-10) - Prevention

3 Defining Autism Spectrum Disorder - Neurodevelopmental disorder - Impaired social interaction, communication - Restricted and repetitive behaviors and interests - 1 in 68 children in Canada are diagnosed - Typically diagnosed between months - No single cause; etiology involves both genetic and environmental factors - A variety of organ systems exhibit inflammatory-like changes

4 Maternal infection and autism - Maternal viral infection in the first trimester associated with ASD - Maternal infection during pregnancy associated with 30% increase risk of ASD in a large Swedish cohort - Maternal immune activation (MIA) induces proinflammatory cytokines in the fetal brain - In the animal models used to study this correlation: - Offspring of infected or immune-activation display behavioural features of ASD - Neuropathology is consistent with that of human ASD

5 Poly(I:C) Model of Maternal Immune Activation - Polyinosinic:polycytidylic acid (Poly(I:C)) mimics viral RNA - Activates the innate immune system -> release of interferons and pro-inflammatory cytokines - Cytokines can cross the placenta and influence the fetal immune system - Cytokine imbalances in the fetus can impact brain development, increasing the risk of developing neuropsychiatric disorders

6 Evidence - Epidemiology - Rodent models: Maternal infection risk factor reveals offsprings with features of autism and immune-related effects in the brain - Inflammatory-like changes in autism - Postmortem autism brains (5-44 years old) had elevated cytokines and activate microglia and astrocytes - Indicates that immune-activated state was established early and long-lasting - Dysregulation of immune-related genes - cytokines and chemokines

7 Specific Effectors - Interleukin-1β (IL-1β), IL-6, IL-8 and IL-17A are elevated in ASD plasma of very young children (ages 2 5 years old) - Associated with more impaired communication and aberrant behaviors - Proinflammatory IL-6 - Induced by MIA - Essential for the development of the abnormal behaviours and changes in br expression - Proinflammatory IL-17A - Induced by MIA as well - Neuroinflammation causing disrupted neurodevelopment

8 Specific Effectors: IL-6 - Infection of pregnant rodent models - Mimicking infection via MIA (poly(i:c)) - Increased levels of IL-6 - Activate Janus Kinase (JAK) & Transcription 3 (STAT3) - Expression of acute phase genes - IL-6 dependent disruption of growth hormone-insulin-like growth factor - Alters fetal development

9 Specific Effectors: IL-17A - IL-6 activates RORyT - Naive CD4+ T cells differentiate into Th17 cells - Th17 cells are pro-inflammatory and release the cytokine IL-17A - IL-17A can disrupt the blood-brain barrier and induce neuroinflammation, leading to disrupted neurodevelopment

10 Other Relevant Cytokines: IL-10 - Human cytokine synthesis inhibitory factor (CSIF) - Anti-inflammatory cytokine - Produced primarily by monocytes, and to a lesser extent by lymphocytes - Down-regulates expression of Th1 cytokines - Involved in regulation of the JAK-STAT pathway - Elevation of IL-10 protects against MIA

11 Possible Intervention and Prevention Manipulation of cytokines during pregnancy can prevent the development of abnormal behaviours (possible intervention) - Anti-inflammatory IL-10: Elevation of IL10 protects againsts MIA - Also, endogenous IL-10 is essential for resistance to LPS-induced preterm labor and fetal loss - However, increased IL-10 in the absence of MIA can lead to behavioral abnormalities or inflammation in the adult offspring - postnatal cytokine perturbations would potentially be a safer therapeutic approach Postnatal therapies - Idea that administration of acute drugs in a MIA offspring, before the onset of behavioural abnormalities - Further studies need to be conducted Prevention of infection before and during pregnancy (CDC recommendations) - Wash your hands with soap and water after: using bathroom, touching raw meat and unwashed vegetables, preparing food and eating, gardening or touching dirt or soil, handling pets, being around sick people, etc. - Avoid unpasteurized milk and foods made from it - Do not touch or change dirty cat litter - Stay away from wild or pet rodents and their droppings - Talk to your healthcare provider about vaccinations - Avoid people who have an infection

12 Summary - Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, impaired communication, restricted and repetitive behaviors and interests - Maternal infection during pregnancy is associated with ASD - Polyinosinic:polycytidylic acid (Poly(I:C)) mimics viral DNA in animal models of maternal immune activation (MIA) - Cytokines can cross from the mother to the fetus and disrupt the cytokine balance in the fetus - MIA induces proinflammatory cytokines in the fetal brain - Inflammation induced by Interleukins (e.g. IL-6 & IL-17A) is thought to disrupt fetal neurodevelopment - Elevation of IL-10 protects against MIA - More studies required, so prevention is key

13 References Patterson, P. H. (2011). Maternal infection and immune involvement in autism. Trends in molecular medicine, 17(7), Centers for Disease Control and Prevention. (2017, March 16). 10 Tips for Preventing Infections Before and During Pregnancy. Retrieved October 10, 2017, from Gabay, C. (2006). Interleukin-6 and chronic inflammation. Arthritis research & therapy, 8(2), S3. Human Gene Database. IL-10 Gene (Protein-Coding). Retrieved October 14, 2017, from Autism Speaks. Facts and FAQs. Retrieved October 8, 2017, from Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V.,... & Huh, J. R. (2016). The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 351(6276), Atladóttir, H. Ó., Thorsen, P., Østergaard, L., Schendel, D. E., Lemcke, S., Abdallah, M., & Parner, E. T. (2010). Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. Journal of autism and developmental disorders, 40(12), Lee, B. K., Magnusson, C., Gardner, R. M., Blomström, Å., Newschaffer, C. J., Burstyn, I.,... & Dalman, C. (2015). Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain, behavior, and immunity, 44, Reisinger, S., Khan, D., Kong, E., Berger, A., Pollak, A., & Pollak, D. D. (2015). The poly (I: C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery. Pharmacology & therapeutics, 149, Kugelberg, E. (2016). Neuroimmunology: IL-17A mediates a path to autism. Nature Reviews Immunology, 16(4),