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Genetic links between brain and immune system

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GeneticGeneticlinks between brainlinks between brainand immune system and immune system FFabioabioMacciardiMacciardiProf. Prof. AssocAssoc. Genetica Medica . Genetica Medica ––U degli Studi di Milano U degli Studi di Milano &&J. J. Murphy AssocMurphy Assoc. Prof. of . Prof. of Behavioural NeuroscienceBehavioural Neuroscience––Center Center for Addictionfor Addictionand and Mental HealthMental Health, U of Toronto, U of TorontoThe immune system and the nervous system maintain extensive communication […]. Neurotransmitters such as acetylcholine, norepinephrine, vasoactiveintestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and α-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior.Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.Elaborate interactions between the immune and nervous systems Lawrence SteinmanNature Immunology 5: 575, 2004The CK pathway of IFNB (> 300 genes)The Toll-like rec pathway of IFNB (>60 genes)The JAK-Stat pathway of IFNB (> 20 genes)Schizophrenia?CK and the CNSCK and the CNS neuronal differentiation and migration neurodegenerative processes (acute and chronic)  Modify synaptic plasticity  Modify metabolism of neurotransmitters(Licinio e Wong, 1999)IL-1 ßTGF-αBDNFDA SynthesisGlu Transmission5-HT TransmissionCNS development and specializationEnvironmental Factors--Interaction between CK and Neuronal modulator Factors ( Nawa et al., 2000)IL-1 ßTGF-αBDNFDA SynthesisGlu Transmission5-HT TransmissionCNS development and specializationEnvironmental Factors--Interaction between CK and Neuronal modulator Factors ( Nawa et al., 2000)(ca)nReelin and Autism: a complexmodel for a complex disorder12 and 13 GGC allelesReelin-inhibiting toxins (organo-phosphates)5th week ofgestation (?)E13 in mouseMale sexUSAEUFIUKDE0100200300400500= tons (x 1000)= Kg / Km2Total sales of organophosphate pesticides during the year 1996PON1 –108 C/T and Q192R in 105 complete Caucasian-American triosC tr 17T tr 17AGREC tr 21T tr 26C tr 12T tr 19PON1 –108C/TC tr 50T tr 62χ2=1.28, P=0.128PON1 –108 C/T and Q192R in 105 complete Caucasian-American triosQ tr 9R tr 18Q tr 15R tr 21AGREQ tr 11R tr 17PON1 Q192RQ tr 35R tr 56χ2=4.85, P=0.013= Reelin protease activity= Threshold for correct neuronal migration>12 GGC7-10 GGCHIGH PON ACTIVITY LOW PON ACTIVITYInteractions between Abl family kinases and receptors.Regulation of neuronal morphogenesis and synaptic function by Abl family kinasesMoresco and Koleskey -Current Opinion in Neurobiology 2003, 13:535–544A model for cytoskeletal regulation by Abl family kinases in the growth coneRegulation of neuronal morphogenesis and synaptic function by Abl family kinasesMoresco and Koleskey - Current Opinion in Neurobiology 2003, 13:535–544146.0 Mb136.0 Mb 140.0 Mb 142.0 Mb134.0 Mb 138.0 Mb 144.0 MbABabcdefghijklmn opqr st1-1234560100 110 120 130 140 150 160 170 180 190Chromosome 6q[cM]NPL1 2 34567 891011 12 1314151617 181920 21 2223NPL-1NPL-2NPL-1…NPL-2Haplotypers9321501 rs11154801 rs7750586 rs9647635 rs1475069FrequencyTKTC (0.22)A (0.18)0.00000 0.20BTC (0.36)C (0.70)0.00046 0.16TKTC (0.22)A (0.18)G(0.17)0.00046 0.17BTC (0.36)C (0.70)A (0.73)0.00032 0.13TKTC (0.22)A (0.18)G(0.17)C(0.19)0.00046 0.18BTC (0.36)C (0.70)A (0.73)A(0.72)0.00047 0.10TKTC (0.22)A (0.18)G(0.17)C(0.19)C(0.14)0.00016 0.11BTC (0.36)C (0.70)A (0.73)A(0.72)A(0.76)0.00415 0.10SNPs Cohort P-valueDaniela Amann-ZalcensteinNili AvidanKyra KanyasRichard P. EbsteinYoav Kohn Adnan HamdanEdna Ben-Asher Ronnen H. SegmanOsnat KarniJacques S. BeckmannDoron Lancet Bernard LererDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelSara Herzog Memorial Hospital, Jerusalem, IsraelRegional Mental Health Center, Taibe, IsraelDépt de Génétique Médicale, CHUV-UNIL, Lausanne, Switzerland.Antonio M. PersicoMarcello D’Amelio Michela MarongiuMaria PerriThomas H. Wassink Val SheffieldLab. of Molecular Psychiatry & Neurogenetics, U.C.B.M., Rome,


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