Seite - 137 - in Advances in Neuroimmunology

BrainSci. 2017,7, 11 protein (GFAP)-fragmentshavebeenobserved in thecerebral spinalfluid (CSF), atvarious timepoints afteraTBI [164].Moreover,proteolytic fragmentsofMBP,neuronspecificenolaseandtoubiquitin D-terminalhydrolase-L-1 (UCH-L1),which isahighlyspecificprotein toneuronsandanessential component of the ubiquitin proteasome system, have also been observed in humans and animal modelsofTBI [165–168].Moreover,auto-reactiveTcell responses toMBPhavebeendocumentedin humansafterTBI[169], furthersupportingaswitchtoanadaptive immuneresponse.Consideringthat whitematter losshasbeenreportedafterTBI inhumansandanimals, theobservationofantibodies andT cells toMBP could have a tremendous implication on the loss ofwhitematter and axonal degenerationthat isobservedatchronic timepointsafteraTBI.Apotential consequenceofantibody production and the implied transition to an adaptive immune response is thatmemory immune cellsare formed. It ispossible that reactivationof thememoryTcells,byanother injuryorperhaps byotherneuroinflammatorystimulus, suchasbacterialorviral infections [170],might re-open the BBBandexpose thememory immunecells toself-antigens, suchasGFAP,UCH-L1orMBP. In this scenario, thesubsequentappearanceofpost-traumatic syndromesmayonlyappearafterappropriate spatial andtemporal stimuli,henceexplaining thewidevariation inwhen,whyandwhat typesof post-traumaticsyndromesappear. Therefore, thedevelopmentofpost-TBIauto-antibodyresponse mightbehighlypathogenicandcontribute tochronicneuropathologythatpersists forarelatively long duration(days,week,months,years)after injury,andthere isevidence insupportof thisnotionfrom awideswathofneurologicalandimmunological studies [171–174]. Resident brain immune cells, such asmicroglial cells, infiltrate the CNS very early during development [175,176] anddonot seemas likely a candidate to present self-antigen, despite the fact that these residentmicroglial cells arehighlycompetent,professionalAPCs, andtheycanalso expressmajor histocompatibility complex class II molecules (MHCII). Considering that resident microglial cells in thebrainarecontinuouslyexposedtoGFAP,UCH-L1andMBPandtheredoesnot seemtobeanyauto-reactivity innormalconditions,onealternativescenariois that infiltratingimmune cellsare respondingto theantigenicpeptide fragmentsofGFAP,UCH-L1andMBP[165–167,177–180]. Another important factor toconsider in thecontextofanadaptive immuneresponseafterTBI is therecentreportsoftwodistinct lymphaticportalsthatdirectlyservicethebrain. First, sittingsubjacent to thesuperiorsagittal sinus isa lymphaticarea thathasrecentlybeenshowntohavewhitebloodcells thatdipinandoutoftheCNS,eveninnormalconditions[181,182]. ImmunesignalsfromtheCNShave beenshowntodirectlysignal throughthis lymphaticportalandto initiateaglobal immuneresponse thatcanexacerbate theseverityofan injury[147,183,184]. Secondis the“glymphatic”system,which allowsforclearanceofCNSwasteproductsandsolubleproteins. Thissystemalsohasbeenshownto provideasubstrate for thesignalingofCNScomponents to themoreclassically-definedperipheral lymphatic system[184–187]. Ineitherof these twoCNS“lymphatic compartments”, therecanbea rapidcommunicationbetweentheCNSandtheperiphery,andthissignalingcanexacerbate injuries, such as stroke or TBI [184,188]. In the stroke literature, removing the spleen (splenectomy) and, therefore, reducingthenumberofBandTcells capableof respondingto theTBIresults inasignificant improvement in lesionsizeandfunctionaloutcomemeasures.However, thedatawere inconsistent betweenhumansandrodentmodels [189–191]; thus, the true functional implicationsrequire further examination. Interestingly,otherstudies thathaveblockedtheexpansionandactivationofBandT cells in thespleenafteraTBIhavedemonstratedsignificantneuroprotection[116]. Thus, theroleof peripheral immunecells afterTBImightprovidenovel targets for thedevelopmentof therapeutic options to treatTBIsandpost-traumaticsyndromes. 5.Conclusions TBI remainsacomplex,multi-systempathology,withawide-rangingpotential for short- and long-termdetrimentaloutcomes.Usingtheexistingandnewly-developedanimalmodels,aswellas clinicalandtranslational studies, researchcontinues tounravel thecomplex interactionsbetweenthe 137