Page - 136 - in Advances in Neuroimmunology

BrainSci. 2017,7, 11 area, the T cells get activated by direct contact with antigen presentation onDCs, macrophages andmicroglia [145,146]. It is this latter activationwhich is the hallmark of a transition from a non-specific innate immuneresponse, toaspecificadaptive immuneresponse;e.g. Tcell recognition ofpresentedantigen. T lymphocytesplayanimportant role in thedevelopmentandmaintenanceofsecondarybrain injury afterTBI, throughengagement ofdifferent cell types andmechanisms. Steady increases in thenumberandcompositionofTcellsat thesiteof injuryarehighlysuggestiveofa transitiontoan adaptive immuneresponse followingaTBI.Thepeakofbrain tissue infiltrationbyTcellsafterTBI, seemstooccurwithinarangeof1–5days,althoughthedataonthis topicare inconsistent [147,148]. Despite these inconsistencies, it appears thatgammadeltaTcells (γδTcells),whichareadistinct class ofTcells largelydevelopedinthymusandexpressγδreceptors, ratherthanαβT-cellreceptor(TCR)on theirsurface,areearlyresponderstothesiteofbraininjury[149].CombinedwithCD8+Tlymphocytes andCD4+T-helper1 (TH1)cells, thesecellsmayworsendamagebycytotoxicandpro-inflammatory actions [150,151].However, somesuggest that the infiltrationof immunecells into theCNSafterTBI canalsobeneuroprotective [120,152,153]. Thishypothesis is substantiatedby the supposition that antigen-activatedTcellsprovideprotection,maintenanceofneurological integrityandrepairof tissue afteraTBI [154]. Reports indicate thatCD4+T-helper2 (TH2)cells specific formyelinbasicprotein (MBP)andCD4+Tcellsmayplaysuchroleofprotection inneuronalsurvival [155,156].Despite the pathogenicpotentialofanti-MBPTcells, theywerealso foundinhumanimmunesystemofhealthy individuals [157,158]. It seemsthatregulatoryTcells (CD4+CD25+Foxp3+)mightalsoplayimportant role inprotectionbysuppressingautoimmuneactivity[159,160]. TheyderivefromnaiveCD4cellsand areknownfor their immunosuppressiveaction,whichdownregulate the inductionandproliferation ofeffectorTcells [159,160]. Thus, it ispossible that afterTBI, the inflammatory sequelae result in antigenprocessingand presentation, aswell as aneventual transition to anadaptive immune response. The implications ofa transition toanadaptive immuneresponseafter aTBIarepoorlyunderstoodandmayhavea positiveand/ornegative impactontheCNS.Here,wewill summarize theexistingdatasupportingan adaptive immuneresponseafterTBI,andwewillprovideanovelhypothesis togeneratea foundation fromwhichensuingstudiescanoccur in thecontextofadaptive immunityandTBI. 4.5.Adaptive ImmuneResponse toTBI Althoughscant, followingTBI, somestudieshaveprovidedstrongevidence foraswitchfroma non-specific innate immuneresponse, toaspecific,adaptive immuneresponse.Assuch,aparadigm shift in thinkingmaybe necessary to fully understand and appreciate the sequelae that occur in the early and chronic stages after a TBI.A switch to an adaptive immune response has occurred, onceantigen isprocessedandpresentedbyprofessionalantigen-presentingcells (APCs),andTcells recognize the presented antigen. The evidence supporting the transition to an adaptive immune response followingTBIhasbeenobservedfollowingretinalcrushstudies [161,162],fluidpercussion injury inmice [116]andinhumanTBIpatients [163]. Thecellularcomponentsof theadaptive immune responsemayentail residentbraincellsand/or infiltrating immunecells, asdescribedabove. In the caseof infiltrating immunecells, theycangainaccess to theCNSvia thecompromisedBBB,aswellas theaforementionedchemotactic signaling. Thehumoralcomponentof theadaptive immunitycanbe initiallymediatedbyBcellsandsubsequentlybyTcells,whichproduceantigen-specificantibodies. Although the evidence is lacking for a direct connection between antibodyproduction byT cells andneurodegeneration, accumulating evidence supports a role in the adaptive immune response in neurodegeneration. Once a transition fromanadaptive immune response occurs, the possible outcomeshavethepotential toprofoundly influence theoutcomesforTBI. In the caseofmostTBIs, the injuries arenon-penetrating; thus, itwould seem, if anadaptive immuneresponse isoccurring, thentheantibodyresponse is likely tobeagainst self-antigen. Indeed, in human patients, evidence for this is found in the fact that antibodies to glial fibrillary acidic 136