醫(yī)學(xué)免疫學(xué)課件：自閉癥的神經(jīng)免疫調(diào)節(jié)

1、Neuro-immune regulation: one of multiple etiology of autism spectrum disorders (ASD) 1CONTEXT 2 3 4 5BACKGROUNDEPIDEMIOLOGY: Relating to ImmunoregulationMECHANISM: ImmunoregulationAPPLICATIONPERSPECTIVE 1CONTEXT 2 3 4 5BACKGROUNDEPIDEMIOLOGY: Relating to ImmunoregulationMECHANISM: ImmunoregulationAP

2、PLICATIONPERSPECTIVEBACKGROUND: ASDAutism spectrum disorders (ASD,自閉癥譜系障礙)Subgroups: Autistic disorder (AD) Asperger syndrome Pervasive developmental disorder-not otherwise specified (PDD-NOS)Epidemiology: 2.00% (US CDC 1 ) 2.87% in Taiwan (20052) 1.6 million in China (20133) Onset in childhood, Hig

3、h male prevalence 1、https:/nchs/data/nhsr/nhsr065.pdf2、Chien, I. C., et al. Journal of Child Neurology 26.7(2011):830-4.3、/jlm/mxfcrxjbxx/201304/t20130402_79390.htmBACKGROUND: ASDBehavioural deficits 1 : Impairment of Social Interaction Impairment of Communication Repetitive and Restrictive Interest

4、 and BehaviorNeuroanatomy: Abnormal patterning in the prefrontal cortex 1、DSM-V (Diagnostic and Statistical Manual of Mental Disorder, 2013)BACKGROUND: ASDAbnormal patterning in the prefrontal cortexStoner, R. et al. New England Journal of Medicine 370, 1209-1219 (2014).BACKGROUND: ASDMatelski, L. &

5、 Van de Water, J. Journal of Autoimmunity 2016BACKGROUND: NeuroimmunologyImmunocytes in the brain? Brain: an immune-privileged organ?There has microgliaVaries in age, region Under specific conditions!BACKGROUND: NeuroimmunologyDiagram from: Dantzer, R. et al. Nature Reviews Neuroscience 2008BACKGROU

6、ND: NeuroimmunologyPlacenta Blood-Brain Barrier 1CONTEXT 2 3 4 5BACKGROUNDEPIDEMIOLOGY: Relating to ImmunoregulationMECHANISM: ImmunoregulationAPPLICATIONPERSPECTIVEEPIDEMIOLOGY: Relating to ImmunoregulationFamily history of autoimmune diseasesWu, S. et al. Neuroscience & Biobehavioral Reviews 2015H

7、ypothyroidism EPIDEMIOLOGY: Relating to ImmunoregulationMaternal immune activation (MIA):Autoimmune diseasesInfection:Bacterial infection (Zerbo, O. et al. Journal of Autism and Developmental Disorders 2015)Viral infection (Choi, G.B. et al. Science 2016)Inflammation:Elevated Maternal C-Reactive Pro

8、tein (Brown AS. et al. Molecular psychiatry. 2014)Auto-antibody: Autoantibodies to proteins in developing brain(Croen, L.A. et al. Biological Psychiatry 2008; Braunschweig, D. et al. Translational Psychiatry 2013)EPIDEMIOLOGY: Relating to ImmunoregulationComplication in ASD: abnormality in immune sy

9、stem (For example:)Circulating autoantibodies to neuronal and glial filament proteins (Singh, V. K. et al. Pediatric Neurology 1997)Decreasing of 5-HT in tissue (Veenstra-Vander Weele, J. et al. Neuropsychopharmacology 2012)Elevated prevalence of specific immune-related comorbidities (Zerbo, O. et a

10、l. Brain, Behavior, and Immunity 2015)Elevated serum levels of CXCL5 and autoimmunity (Mostafa, G.A. et al. Behavioral and Brain Functions 2015)A reduction of CD57+CD3 lymphocyte (Siniscalco, D. et al. In Vivo 2016)Comorbidity of Atopic Disorders (Liao, T. et al. The Journal of Pediatrics 2016)Linka

11、geOrCause Effect 1CONTEXT 2 3 4 5BACKGROUNDEPIDEMIOLOGY: Relating to ImmunoregulationMECHANISM: ImmunoregulationAPPLICATIONPERSPECTIVENEURO-IMMUNE AYATEM NEURO-IMMUNE AYATEM: Maternal-foetal transfer Diagram from: Braunschweig, D., & Van de Water, J.Archives of Neurology (2012)NEURO-IMMUNE AYATEM: M

12、aternal-foetal transfer Braunschweig, D. et al Translational Psychiatry (2013)Croen, L.A. et al. Biological Psychiatry (2008)NEURO-IMMUNE AYATEM: Maternal-foetal transfer Zaretsky, M.V. et al. Obstetrics & Gynecology (2004)NEURO-IMMUNE AYATEM Molecular： Cytokines MHCImmunocyte： Innate immune system

13、Adaptive immune system5-HT systemNEURO-IMMUNE AYATEM: Cytokines Inflammation cause sick behavior Diagram from: Baganz, N.L. & Blakely, R.D. ACS Chemical Neuroscience (2013)IL-1; IL-1; TNF-; IL-6 (Hart BL. Neurosci Biobehav Rev 1988)MCP-1 (Vargas DL. Et al. Ann Neurol. 2005)IFN- ; IL-4; IL-5(Goines P

14、. et al. Mol Autism. 2011)NEURO-IMMUNE AYATEM: MHCGenome-wide association studies (GWAS) MHC locusbrain development and plasticityTABLE: HLA-G 14bp insertion/deletion (14bp+/14bp) genotype and allele distribution in 74 ASD childrenGuerini, F.R. et al. Brain, Behavior, and Immunity (2015)NEURO-IMMUNE

15、 AYATEM: Immunocyte in innate immune microgliaDiagram from: Knuesel, I. et al. Nat Rev Neurol (2014)NEURO-IMMUNE AYATEM: Immunocyte in innate immune microgliaBialas, Allison R., and Beth Stevens.Nature neuroscience(2013)NEURO-IMMUNE AYATEM: Immunocyte in innate immune monocyte in peripheral tissueEn

16、strom, A.M. et al. Brain, Behavior, and Immunity (2010)NEURO-IMMUNE AYATEM: Immunocyte in adaptive immuneT cellRadjavi A. et al. Brain, behavior, and immunity. (2014)NEURO-IMMUNE AYATEM: Immunocyte in adaptive immuneT cellDiagram from: Filiano, A.J. et al. Brain Research (2015)NEURO-IMMUNE AYATEM: 5

17、-HT system 5-HT function in neurodevelopment as neurotransmitterDiagram from: Baganz, N.L. & Blakely, R.D. ACS Chemical Neuroscience (2013)NEURO-IMMUNE AYATEM: 5-HT systemDiagram from: Baganz, N.L. & Blakely, R.D. ACS Chemical Neuroscience (2013)NEURO-IMMUNE AYATEM: 5-HT system Diagram from: Jaiswal

18、, P., Mohanakumar, K.P. & Rajamma, U. Neuroscience & Biobehavioral Reviews (2015)NEURO-IMMUNE AYATEM: 5-HT system TregDiagram from: Patrick, R.P. & Ames, B.N. The FASEB Journal (2014) 1CONTEXT 2 3 4 5BACKGROUNDEPIDEMIOLOGY: Relating to ImmunoregulationMECHANISM: ImmunoregulationAPPLICATIONPERSPECTIV

19、EAPPLICATION: Model Maternal immune activation model (MIA)Polyinosinic: polycytidylic acid (PolyI:C) Bacterial endotoxin lipopolysaccharide (LPS)Valproic acid (VPA, 丙戊酸) APPLICATION: Biomarker for prophylaxis diagnose Suzuki, Katsuaki, et al. Plos One 2011Siniscalco, D. et al. In Vivo 2016 1CONTEXT

20、2 3 4 5BACKGROUNDEPIDEMIOLOGY: Relating to ImmunoregulationMECHANISM: ImmunoregulationAPPLICATIONPERSPECTIVEPERSPECTIVECause effect subgroups researching modelprophylaxis diagnose drugsReferenceBaganz, N.L. & Blakely, R.D. A Dialogue between the Immune System and Brain, Spoken in the Language of Ser

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22、teins in developing brain. Translational Psychiatry 3, e277 (2013).Canetta, S., Sourander, A., Surcel, H. M., Hinkkaylisalomki, S., Leivisk, J., & Kellendonk, C., et al. Elevated maternal c-reactive protein and increased risk of schizophrenia in a national birth cohort.Molecular Psychiatry,19(2), 22

23、7-229. (2014).Chen, S. et al. Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: A systematic review and meta-analysis. Behavioural Brain Research 296, 61-69 (2016).Choi, G.B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in off

24、spring. Science 351, 933-939 (2016).Croen, L.A. et al. Maternal Mid-Pregnancy Autoantibodies to Fetal Brain Protein: The Early Markers for Autism Study. Biological Psychiatry 64, 583-588 (2008).Dantzer, R., OConnor, J.C., Freund, G.G., Johnson, R.W. & Kelley, K.W. From inflammation to sickness and d

25、epression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9, 46-56 (2008).Enstrom, A.M., Onore, C.E., Van de Water, J.A. & Ashwood, P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain, Behavior, and Immunity 24, 64-71 (2010).F

26、iliano, A.J., Gadani, S.P. & Kipnis, J. Interactions of innate and adaptive immunity in brain development and function. Brain Research 1617, 18-27 (2015).Goines PE, Croen LA, Braunschweig D, Yoshida CK, Grether J, & Hansen R. et al. Increased midgestational ifn-, il-4 and il-5 in women bearing a chi

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28、dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nature Communications 5, 5748 (2014).Hart, B. L. Hart, b. l. biological basis of the behavior of sick animals. neurosci. biobehav. rev. 12, 123-137.Neuroscience & Biobehavioral Reviews,12(2), 123-137. (198

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30、ulation and neural functions: Complicity in the aetiology of autism spectrum disorders. Neuroscience & Biobehavioral Reviews 55, 413-431 (2015).Knuesel, I. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol 10, 643-60 (2014).Liao, T., Lien, Y., Wang

31、, S., Huang, S. & Chen, C. Comorbidity of Atopic Disorders with Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder. The Journal of Pediatrics 171, 248-255 (2016).Matelski, L. & Van de Water, J. Risk factors in autism: Thinking outside the brain. Journal of Autoimmunity 67, 1-7 (20

32、16).McDougle, C.J. et al. Toward an immune-mediated subtype of autism spectrum disorder. Brain Research 1617, 72-92 (2015).Mostafa, G.A. & AL-Ayadhi, L.Y. The possible link between elevated serum levels of epithelial cell-derived neutrophil- activating peptide-78 (ENA-78/CXCL5) and autoimmunity in a

33、utistic children. Behavioral and Brain Functions 11 (2015).Patrick, R.P. & Ames, B.N. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. The FASEB Journal 28, 2398-2413 (2014).Radjavi, A., Smirnov, I., & Kipnis, J. Brain antigen-reactive CD4+T cells are sufficient to supp

34、ort learning behavior in mice with limited T cell repertoire.Brain, Behavior, and Immunity,35, 10.1016 (2014).Singh, V. K., Warren, R., Averett, R., & Ghaziuddin, M. Circulating autoantibodies to neuronal and glial filament proteins in autism.Pediatric Neurology,17(1), 88-90. (1997).Siniscalco, D. e

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