NeuroimmunoRegulation&

Neuro-immuno-endocrineNetworkHaixiaLuMD,PhDInstituteofNeurobiology,SchoolofBiomedicalSciencesE-mail:Tel:1.Neuroimmunology*;2.Interactionbetweennervoussystemandimmunesystem*;3.Immune-braincommunication4.Immune-endocrinecommunication5.Neuro-immuno-endocrinenetwork*Outline:References:1.壽天德主編《神經生物學》，第2版，高等教育出版社2.李云慶主編《神經科學基礎》，第2版，高等教育出版社3.Wikipedia

（維基百科）4.ChesnokovaVandMelmedS.Minireview:Neuro-Immuno-EndocrineModulationoftheHypothalamic-Pituitary-Adrenal(HPA)Axisbygp130SignalingMolecules.Endocrinology.2002,143(5):1571–15745.ChaczkoZandMosesP.Neuro-Immune-Endocrine(NIE)ModelsforEmergencyServicesInteroperatibility.LectureNotesinComputerScience.2007,4739:105-1126.KaiserP,WuaZ,RothwellL,etal.Prospectsforunderstandingimmune-endocrineinteractionsinthechicken.GeneralandComparativeEndocrinology.2009,163:83–917.胡格，穆祥，段慧琴，楊佐君，高立云.免疫、神經和內分泌系統間的關系.動物醫學進展，2003，24(1)：5-7NervoussystemEndocrinesystemNeuralinnervationNeurotransmittersNeuropeptidesHormonesInteractionbetweenNervesystemandEndocrinesystem（復習“神經內分泌調節”內容）Driveorinhibition

oftenstartsintheCNS.NegativeorPositiveFeedbackfromperipheralhormonestomaintainlevelsatasetpoint.I.ConceptofNeuroimmunologyStudyofinteractionsbetweentheimmuneandthenervoussystemsArapidlygrowingareaofresearchwithenormouspotentialtocontributetoourunderstandingofphysiologicalanddiseaseprocessesNeuralImmunoregulationNeuroimmunoRegulationImmuneresponsetodiseasesofthenervesystemInfectivediseaseAutoimmunediseaseIschemicdiseaseDegenerativediseaseTraumaticdiseaseNeoplasm(新生物，腫瘤)II.ClassicalfieldsofNeuroimmunology抵抗力排斥反應III.InteractionbetweenNervoussystemandImmunesystemNointeraction!Thecentralnervoussystemwasconsideredasanimmunologicalprivileged(免疫豁免)siteImmuneresponse1.Bloodbrainbarrier(BBB)-circulatingbloodandthebrainextracellularfluid(BECF)血-腦、血-腦脊液和腦脊液-腦三種屏障的總稱2.Pro-apoptoticmolecules(促凋亡因子)

atBBB3.NoMHC(majorpatibilitycomplex)moleculesonnervecells(神經細胞沒有主要組織相容性復合體)4.Noclassicaldendriticcells(樹突狀細胞)intheCNS1.Bloodbrainbarrier(BBB)-circulatingbloodandthebrainextracellularfluid(BECF)However1.ExistenceoflymphdrainageintheCNS(淋巴引流)2.PassageofTandBcellsthroughBBB(hypothalamus)(T,B細胞可以通過BBB)3.Microgliacanprocessandpresentantigens(小膠質細胞)III.InteractionbetweenNervoussystemandImmunesystemSoTheinteractiondoesexist.NeuralinfluencesontheimmunesystemModulationofnervecellfunctionbyimmuneandinflammatorymediatorsSimilaritiesbetweennerveandimmunecellsIII.InteractionbetweenNervoussystemandImmunesystemAgrin:heparansulphateproteoglycan,stabilizessynapsis;rapsyn,inducesclusteringofAchreceptor;EphrinB:receprtortyrosinekinase;NMDAR:N-methyl-D-aspartatereceptor,glutamatereceptor;PSD95:postsynapticdensityprotein95requiredforsynapticplasticity;CD2AP:CD2adaptorprotein,adapterproteinbetweenmembraneproteinsandtheactincytoskeletonNeuralinfluencesontheimmunesystem1.Whatarethestructuresthatareinvolvedinneuroimmunoregulation?Centralnervoussystem(CNS):

Hypothalamus,Pituitary,SpinalcordPeripheralnervoussystem(PNS):

Nerve,Sensoryreceptors,Ganglia,etcNervecells:

Neurons,Glia(Astrocytes,Microglia,etc)III.InteractionbetweenNervoussystemandImmunesystemMicrogliaMicrogliaareatypeofglialcellthataretheresidentmacrophagesofthebrainandspinalcord,andthusactasthefirstandmainformofactiveimmunedefenseinCNS.MicrogliaPartofmononuclearphagocytesystemExpresstypicalmonocytemarkerslikeCD11b,CD45,MHCIIUniqueisabilitytoproliferateDifferentiateuponactivationLongsurvival(over6months)FriendofneuronsPhagocytoseapoptoticneuronsSecreteneuroprotectivefactors(BDNF,NT-3)RestingmicrogliasecreteIL-10Foe

(敵人)ofneuronsSecreteneurotoxicmoleculesTNFandIL-1,glutamate,freeradicalspeciesCaninduceapoptosisInteractwithastrocytesAstrocyte-MicrogliaInteractionNeuralinfluencesontheimmunesystem2.CommunicationBetweenNerveSystemandImmuneSystem*III.InteractionbetweenNervoussystemandImmunesystem2.1Innervation2.2Communicationthroughneutrotransmittersandneuropeptides-Immunecellsexpressthereceptorsofneuralproducts2.3CytokinesproducedbyNervecellsNeuralinfluencesontheimmunesystem2.1Innervationthymus,spleen,lymphnodesSympatheticnerves:

來自頸胸段交感神經鏈

Parasympatheticnerves:

來自迷走神經

Peptidergicnerves：如SP、VIP、NPY、CGRP等肽能神經纖維

Cholinergicanti-inflammatorypathway(膽堿能抗炎通路)III.InteractionbetweenNervoussystemandImmunesystem2.CommunicationBetweenNerveSystemandImmuneSystem*Neuralinfluencesontheimmunesystem2.2Communicationthroughneutrotransmittersandneuropeptides-ImmunecellsexpressthereceptorsofneuralproductsAcetylcholine:增加淋巴細胞和巨噬細胞的數量，促進其產生IL

Monoamines(一元胺)Norepinephrine(NE)：抑制干擾素的作用

Dopamine(多巴胺)：刺激免疫反應

Serotonine(5-HT)：抑制體液免疫，B細胞分泌Ig能力下降

Histamine(組胺)：抑制巨噬細胞的功能，減少干擾素以及IL-2的產生III.InteractionbetweenNervoussystemandImmunesystem2.CommunicationBetweenNerveSystemandImmuneSystem*NeuralinfluencesontheimmunesystemAcetylcholine:增加淋巴細胞和巨噬細胞的數量，促進其產生IL

Monoamines(一元胺)：

Neuropeptides

Endorphines(內啡肽)：刺激免疫反應，也有相反報道

SubstanceP(P-物質)：刺激免疫反應

VasoactiveIntestinalPeptide(血管活性腸肽)：抑制免疫反應

Enkephaline(腦啡肽)：刺激免疫反應為主III.InteractionbetweenNervoussystemandImmunesystem2.2Communicationthroughneutrotransmittersandneuropeptides-Immunecellsexpressthereceptorsofneuralproducts2.CommunicationBetweenNerveSystemandImmuneSystem*NeuralinfluencesontheimmunesystemAcetylcholine:增加淋巴細胞和巨噬細胞的數量，促進其產生ILMonoamines(一元胺)：

Neuropeptides

Others：GABA,Glycine（氨基乙酸）,Glutamate,NitricoxideIII.InteractionbetweenNervoussystemandImmunesystem2.2Communicationthroughneutrotransmittersandneuropeptides-Immunecellsexpressthereceptorsofneuralproducts2.CommunicationBetweenNerveSystemandImmuneSystem*Neuralinfluencesontheimmunesystem2.3CytokinesproducedbyNervecellsGlialcellssecretILs,TNF,IFN,etc-Astrocytes:IFN,TNF-Microglia:IL-10,IL-1,TNFIII.InteractionbetweenNervoussystemandImmunesystem2.CommunicationBetweenNerveSystemandImmuneSystem*NeuralinfluencesontheimmunesystemInnervation:

SympatheticnervesandparasympatheticnervesNeurotransmitters:

acetylcholine,norepinephrine,serotonin,etcNeuropeptides:

SubstanceP,endorphin,etcCytokines:IL,IFN,TNFIII.InteractionbetweenNervoussystemandImmunesystemModulationofnervecellfunctionbyimmuneandinflammatorymediatorsIII.InteractionbetweenNervoussystemandImmunesystemModulationofnervecellfunctionbyimmuneandinflammatorymediators1.Evidencesofimmunemodulationofnervecells

Nervecellsexpressreceptorsofimmunoregulators

神經細胞表達免疫調質的受體III.InteractionbetweenNervoussystemandImmunesystem

Passageofimmunoregulator(IL-1)throughBBB

免疫調質（白細胞介素-1）通過血腦屏障

Neurotransmittersandneuropeptidesproducedbyimmunecells

免疫細胞可產生神經遞質和神經肽

PassageofTandBcellsthroughBBB

免疫細胞通過血腦屏障NGFandNT-ssecretedbyTlymphcellsBraincellsexpressreceptorsforimmuneproductsModulationofnervecellfunctionbyimmuneandinflammatorymediators2.Immunemodulationofnervecells-8aspects2.4Modulatingthesynthesisandreleasingofneurotransmittersandneuropeptides調節神經遞質、神經肽的產生和釋放2.3Affectingthefunctionofvegetativenerve(automaticsystem)

影響植物神經功能如：IL-1andINFstimulatethefoodintakeandinducefever

2.1Effectsonnervecellproliferationanddifferentiation

影響神經細胞生長、分化如：IL-6促進PC12分化為神經元，促使星形膠質細胞分泌NGFIII.InteractionbetweenNervoussystemandImmunesystem2.2Neuroprotectionandneurotoxicity神經保護和神經毒性如：TNF引起少突膠質細胞死亡以及脫髓鞘,IL-6抑制NMDA毒性Modulationofnervecellfunctionbyimmuneandinflammatorymediators2.Immunemodulationofnervecells-8aspects2.6EffectsonAnalgesia參與鎮痛如：INF通過影響中樞阿片類物質的功能而參與鎮痛

2.7Inducingandmediatinggeneexpression刺激和介導基因表達

如：血小板激活因子PAF誘導神經元的基因表達2.8Effectonhighbrainfunction(memoryandlearning)

影響腦的高級功能如：IL-6，IL-1，TNF等抑制LTP，使記憶力下降III.InteractionbetweenNervoussystemandImmunesystem2.5Adjustingnervecellactivity調節神經細胞的活動狀態

IL-2,TNF,IL-6,IFNNatureReviewsImmunologyISSN:1474-1733EISSN:1474-1741Cytokinehypothalamic-pituitary-adrenalaxis

iii).Influencesonimmunefunctionthroughneurotransmittersorneuropeptidesii).Neuralcellsproduce/release

immuneregulatorsi).InnervationofimmunesystemNervecellproliferationanddifferentiationNeuralprotectionandneuraltoxicityNervecellactivityNervecellfunction-transmitters,peptidesNeuralfunction-automaticsystemHighbrainfunctionOtherfunction-AnalgesiaGeneexpression-mechanismIII.InteractionbetweenNervoussystemandImmunesystemNeuralinfluencesontheimmunesystem

Innervation:Neurotransmitters:

acetylcholine,norepinephrine,serotonin,etcNeuropeptides:

SubstanceP,endorphin,etcCytokines:

IL,IFNTNFModulationofnervecellfunctionbyimmuneandinflammatorymediatorsCytokinesReactiveoxygenandnitrogenspecies(活性氧、活性氮)III.InteractionbetweenNervoussystemandImmunesystemIV.InteractionbetweenEndocrinesystemandImmunesystemInfluenceofimmuneregulatorsonneuroendocrineEvidenceofinteractionbetweenendocrinesystemandimmunesystemImmunecellsexpressthereceptorofneurohormoneNeurohormonereceptorsarefoundoninmunecells:

corticortrophin-releasingfactorgrowthhormoneadrenocorticotrophinhormoneprolactinIV.InteractionbetweenEndocrinesystemandImmunesystem2.InteractionpathwaysCytokineHPAaxisInfluenceofimmuneregulatorsonneuroendocrineCytokineHypothalamusPituitaryglandAdrenalglandCRHACTHGlucocorticoidImmunesystemIL1,IL2,IL6,IL11,IL12,TNFa,INFgNatureReviewsImmunologyISSN:1474-1733EISSN:1474-1741Cytokinehypothalamic-pituitary-adrenalaxis

IV.InteractionbetweenEndocrinesystemandImmunesystem2.InteractionpathwaysCytokine-HPAaxis*Cytokine-HPGaxisInfluenceofimmuneregulatorsonneuroendocrineIV.InteractionbetweenEndocrinesystemandImmunesystem2.InteractionpathwaysCytokine-HPAaxis*Cytokine-HPGaxisPituitary-thymusaxisthymosin

α1,thymulininducethereleasingofACTH,LHandLHRHGHandPRLinducethedevelopmentofthymusInfluenceofimmuneregulatorsonneuroendocrineIV.InteractionbetweenEndocrinesystemandImmunesystem2.InteractionpathwaysCytokine-HPAaxis*Cytokine-HPGaxisPituitary-thymusaxisHormonecanbesynthesizedandreleasedfromimmunecellsthymusproduceGH,PRLLymphcellsproduceTSH,ACTHInfluenceofimmuneregulatorsonneuroendocrineIV.InteractionbetweenEndocrinesystemandImmunesystem1.GlucocorticoidssuppressimmunereactionGlucocorticoidsuppressesthesynthesisofIL-1,IL-2Glucocorticoidsuppressesthereleasingoflymphokines(淋巴因子)GlucocorticoidinducesthymuscelldeathLymphokinesareasubsetofcytokinesthatareproducedbyTcellstodirecttheimmunesystemresponse.LymphokinesaidBcellstoproduceantibodies.Itisnotantibodyorantigen.-FromWikipediaModulationofimmunesystembyendocrinesystemIV.InteractionbetweenEndocrinesystemandImmunesystem2.SynthesizeofimmuneregulatorsbyendocrinecellsIL-6frompituitaryglandIL-1fromadrenalglandNotmanyreportsbasedonthistopicModulationofimmunesystembyendocrinesystemIV.InteractionbetweenEndocrinesystemandImmunesystemModulationofimmunesystembyendocrinesystem3.Feedbackbetweenmelatonin(MLT,褪黑素)andcytokinesMLTup-regulatesthereleasingofIL-2fromlymphcellanddendriticcell,whileIL-2reducesthereleasingofMLTTNFincreasesthereleasingofMLT,howeverMLTinhibitsthethesynthesis