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Autism and Autoimmunity

Autism and Autoimmunity. Andrea Li Trevor Teel Janet Gin Maple Gu. PHM142 Fall 2012 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. Introduction. What is autism?

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Autism and Autoimmunity

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  1. Autism and Autoimmunity Andrea Li Trevor Teel Janet Gin Maple Gu PHM142 Fall 2012 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

  2. Introduction • What is autism? • Neural development disorder characterized by social impairments, communication difficulties and restricted, repetitive patterns of behaviour • Failure of CNS integration at the level of the pre-frontal cortex, amygdala, hippocampus and cerebellum

  3. Autoimmunity • How can autoimmunity cause autism? • Pro-inflammatory cytokines in the mother during pregnancy • Maternal antibodies • Environmental agents

  4. Pro-inflammatory Cytokines • Signalling proteins which promote systemic inflammation • Every time an immune response (infection, bacteria, autoimmune disease etc.) is activated, cytokines are released and produces an inflammatory response • Cytokines can cross the placenta and enter the fetal circulation • It can then enter the BBB and cause a “cytokine storm” in the CNS which can lead to neurological pathologies and autism

  5. Maternal Antibodies • Maternal antibodies (IgG, IgM) can be passed from mother through placental barriers and cross the BBB • Can cause brain damage: • obstruction of blood flow to the fetus • direct immunopathological damage to developing neural tissue  may result in autism

  6. Autoimmune Connections • Some autoimmune diseases more common in mothers of ASD children than mothers of typically developing children • Rheumatoid arthritis • Celiac disease • Type 1 diabetes

  7. Maternal Antibodies • Higher rate of plasma IgG directed towards golgi cells in ASD individuals • Can also be found in neurotypical people • Require facilitated access through blood-brain barrier

  8. Maternal Antibodies • Ig can react with antigens expressed on the trophoblast or extraembryonic tissues of the developing embryo • IgG binds to fetus lymphoids and/or neuronal tissue • Neuronal cell death • IgM binds to paternal lymphocytes

  9. Maternal Inflammation • Cytokines • Pro-inflammatory • interleukin(IL)-1β, IL-6, IL-8, IL-12p40, MCP-1, THF-β • Anti-inflammatory • IL-10 • ↑ protects against maternal infection activation (MIA)

  10. Maternal Inflammation

  11. Blood Brain Barrier: Howcan Cytokines Get Through? • Possible explanations: • BBB is responsive to cytokines • Cytokines directly activate endothelial cells • Increased permeability • BBB in fetus is incomplete • Does not begin to form until the 2nd trimester • Dysfunction in tight junctions allows paracellular entry

  12. Blood Brain Barrier: Can Cytokines Get Through? • NOW: Studies show cytokines can cross BBB by diffusion* at: • Choroid Plexus • Meninges *Based on rodent model • EVIDENCE in human brain: presence of maternal brain-reactive antibodies, and pro-inflammatory cytokines (TNF-α, IL-1β)

  13. Blood Brain Barrier: SO WHAT if Cytokines can Penetrate the BBB? • Brain monitors for infection and generates an immune response • Innate Immune System: • Microglial Cells (in hippocampus, cortex, etc.) have Toll-Like Receptors and IL-1β Receptors • Pro-Inflammatory Cytokines activate microglial cells • RESULT: quick, inflammatory response and neuronal degradation

  14. Blood Brain Barrier: SO WHAT if Cytokines can Penetrate the BBB? • PROBLEM: • Activated microglial cells then produce more of the same pro-inflammatory cytokines • Release of: TNF-α, IL-1β, IL-6 • RESULT: • Neuroinflammation • Up-regulation of microglial cell formation • Increased microglial cell: neuron (ratio) • CYTOKINE STORM (positive feedback)

  15. Pro-Inflammatory Cytokines and Autism • Fetal brain can withstand a certain threshold level • In autism, threshold is exceeded: • pro-inflammatory cytokines generated by Mother+ Fetus CYTOKINE STORM • Increased levels of TNF-α regulates levels of nerve growth factor (NGF) • NGF contributes to neuronal cell proliferation, differentiation and migration • ↑ TNF-αα ↑ NGF • Aberrant neuron growth and density (causing greater plasticity in individuals with autism)

  16. Elevated Pro-Inflammatory Cytokine Levels May Lead to Other Negative Effects • Chronic infections • may cause development of their own autoimmune diseases (e.g. enterocolitis) • ↑ Activity of Hypothalamic-Pituitary-Adrenal (HPA) axis • elevating levels of corticotropin releasing hormone (CRH ) • RESULT: depression • Possible symptom of autism

  17. Potential Treatments • Objective: ↑ Anti-inflammatory cytokines • Child: improve symptoms of autism • ↓ Microgial cell activation (↓ Cytokine Storm) • Mother: preventative measure to alleviate low anti-inflammatory cytokine levels, and inflammation • Anti-inflammatory medication: • E.g. pioglitazone (NSAID) • Acute anti-psychotic drugs: • E.g. risperidone, aripiprazole

  18. Summary Proposed Mechanisms of Autism: ANTIBODIES • IgG binds to fetal lymphoid and/or neuronal tissue  cell death • IgM bind to antigens on paternal lymphocytes  neuronal death or blocked blood flow CYTOKINES • MIA induces pro-inflammatory cytokines in mother and passes through placenta via JAK-STAT3 pathway to fetus • Cytokines travel through BBB because fetal BBB is not fully developed and cytokines increase permeability • CYTOKINE STORM (positive feedback) • Pro-inflammatory cytokines activate microglial cells • Microglial cells produce more of the same pro-inflammatory cytokines (e.g. TNF-α) • Neuroinflammation, and abberant neuron growth and density • Abberant neuron growth and density due to increasing levels of TNF-α which causes increased levels of NGF (nerve growth factor)

  19. References • Buehler, M.R. (2011) “A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder.” Medical Hypothesis, 76, 863-870. • Cohly, HariHarParshad, and AsitPanja. (2005) “Immunological findings in autism.” International Review of Neurobiology, 71, 317-341. • Coisne, Caroline, and Engelhardt, Britta (2011) “Tight Junctions in Brain Barriers During Central Nervous System Inflammation.” Antixidants & Redox Signaling, 15:5, 1285-1303. • Diamond, Betty, Heurta, Patricio T., Mina-Osorio, Paola, Kowal, Czeslawa, and Volpe, Bruce T. (2009) “Losing your nerves? Maybe it’s the antibodies.” Nature Reviews Immunology, 9, 449-456. • Goines, Paula, and Judy Van de Water. (2010) “The immune system’s role in the biology of autism.” Current Opinion in Neurology, 23, 111-117. • Onore, Charity, Careaga, Milo, and Paul Ashwood. (2012) “The role of immune dysfunction in the pathophysiology of autism.” Brain, Behavior, and Immunity, 26, 383-392. • Patterson, Paul H. (2011) “Maternal infection and immune involvement in autism.” Trends in Molecular Medicine, 17:7, 389-394. • Warren, Reed P., Cole, Phyllis, Odell, J. Dennis, Pingree, Carmen B., Warren, W. Louise, White, Ellen, Yonk, Jeanne and Vijendra K. Singh. (1990) “Detection of Maternal Antibodies in Infantile Autism.” American Academy of Child and Adolescent Psychiatry, 29:6, 873-877.

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