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Key Concepts in Neuroimmunology,
a dialogue between Philosophers and Scientists
Which cells are the immune cells of the brain?
Agnès Nadjar NutriNeuro, UMR INRA 1286
University of Bordeaux, France
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MICROGLIA:THEBRAININNATEIMMUNESYSTEM
BRAIN IMMUNESYSTEM
THECNS:ASITEOFLIMITEDIMMUNESURVEILLANCE
BBB
MICROGLIA:THERESIDENTIMMUNECELLSOFTHEBRAIN(Ransohoff,2016)
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(Rio-HortegaPdel.1932.Volume2.EditedbyWPenfield,Hoeber,NewYork,pp.482-534)
PIODELRIOHORTEGA(1882-1945)
√FIRSTCALLED“MICROGLIA”AROUND1920√BASEDONNISSLSTAINING
THEDISCOVERYOFMICROGLIALCELLS
SANTIAGORAMONYCAJAL(1852-1934)
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1.Microgliaenterthebrainduringearlydevelopment.2.Theseinvadingcellshaveamoeboidmorphologyandareofmesodermal
origin.3.TheyusevesselsandwhitemaAertractsasguidingstructuresfor
migraBonandenterallbrainregions.4.Theytransformintoabranched,ramifiedmorphologicalphenotypeinthemorematurebrain(knowntodayastheresBngmicroglia).
5.Inthematurebrain,theyarefoundalmostevenlydispersedthroughoutthecentralnervoussystemanddisplayliAlevariaBon.
6.Eachcellseemstooccupyadefinedterritory.7.ALerapathologicalevent,thesecellsundergoatransformaBon.8.Transformedcellsacquireamoeboidmorphologysimilartotheone
observedearlyindevelopment.9.Thesecellshavethecapacitytomigrate,proliferateandphagocytose.
S`llvalidtoday4
ORIGINALSTATEMENTSFROMHORTEGA
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CNSIMMUNEREGULATION:THECLASSICALVIEW
HEALTHYTISSUE LARGEINSULTSMALLLOCALDAMAGE
(HanischandKebenmann,NatureNeuroscience,2007)
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THEYINANDYANGOFMICROGLIALACTIVATION
(Gentleman, Neuropathology and Applied Neurology, 2013; Patel et
al., Int J Physiol Patho Pharm, 2013; Aguzzi et al., Science,
2013)
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PHENOTYPICPLASTICITYOFMICROGLIA
EACHPATHOLOGICALSITUATIONISASSOCIATEDTOAUNIQUEPHENOTYPICSHIFT
(Perry et al., Nature Reviews Neurology, 2010)
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MICROGLIAISNOTJUSTANIMMUNECELL
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(Ginhouxetal.,Fron`ersinCellularNeuroscience,2013)
BBBForma`on
Prolifera`onEarlyInvasion
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MICROGLIAENTERSTHEBRAINVERYEARLYDURINGDEVELOPMENT
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MICROGLIAISINVOLVEDINCNSDEVELOPMENT
(FrostandSchafer,TrendsinCellBiology,2016)
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MICROGLIA:FARFROMBEING«DORMANTSOLDIER»
SENTINELS
(Nimmerjahnetal.,Science,2005)
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MICROGLIAMAKESCONTACTSWITHNEURONS
(Wakeetal.,JournalofNeuroscience,2009;Kebenmannetal.,2012)
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MICROGLIANEVERWALKSALONE
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THEBRAINIMMUNESYSTEMANATOMYMATTERS
(Engelhardt et al., Nature Immunology, 2016)
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CNS-ASSOCIATEDLEUKOCYTEDIVERSITYINTHESTEADY-STATE
(Mrdjen et al., Immunity 2018)
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CNS-ASSOCIATEDLEUKOCYTEDIVERSITYINTHESTEADY-STATE
(Mrdjen et al., Immunity 2018)
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BORDER-ASSOCIATEDMACROPHAGES(BAM)
√DIFFERENTLOCATIONSWITHINTHECNS
(Mrdjen et al., Immunity 2018)
√4SUBSETSOFBAMS.
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DENDRITICCELLS
(Mrdjen et al., Immunity 2018)
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LEUKOCYTESTURNOVER
(Mrdjen et al., Immunity 2018)
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AGINGCAUSESANALTEREDCNSIMMUNELANDSCAPE…
(Mrdjen et al., Immunity 2018)
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…ANDASUBSETOFREACTIVEMICROGLIAEMERGES
(Mrdjen et al., Immunity 2018)
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AUTOIMMUNENEUROINFLAMMATIONEAEMODEL
(Mrdjen et al., Immunity 2018)
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CONCLUSIONTHECNSIMMUNESYSTEM:NEWCONCEPT
NEUROINFLAMMATION
STATE1
STATE2
STATE3
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√WHATISTHEBRAINIMMUNESYSTEM?√WHATISITSROLE?STEADY-STATE,PATHOLOGY?√HOWDOLEUKOCYTESCOORDINATETHEIRRESPONSEINTHECNS√WHATISTHEROLEOFMICROGLIAUNDERIMMUNEACTIVATION?√INTERACTIONWITHPERIPHERALIMMUNESYSTEM?√ISTHEREAFRONTIERBETWEENPERIPHERALANDCENTRALIMMUNE
SYSTEMS?ROLEOFTHATFRONTIERINIMMUNERESPONSE
CONCLUSIONTHECNSIMMUNESYSTEM:NEWCONCEPT
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Thank you for your attention
