Functional Characterization of Aquaporin-4 Specific T Cells Towards a Model for Neuromyelitis Optica 英文参考文献.docVIP

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Functional Characterization of Aquaporin-4 Specific T Cells Towards a Model for Neuromyelitis Optica 英文参考文献.doc

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Functional Characterization of Aquaporin-4 Specific T Cells Towards a Model for Neuromyelitis Optica 英文参考文献

FunctionalCharacterizationofAquaporin-4SpecificT Cells:TowardsaModelforNeuromyelitisOptica SudhakarReddyKalluri1,VeitRothhammer1,OriStaszewski2,RajneeshSrivastava1 ,Franziska Petermann1,MarcoPrinz2,BernhardHemmer1,ThomasKorn1* 1Department of Neurology, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Mu¨nchen, Germany, 2Department of Neuropathology, Institute of Pathology, Universita¨tsklinikum Freiburg,Freiburg,Germany Abstract Background:Antibodiestothewaterchannelproteinaquaporin-4(AQP4),whichisexpressedinastrocyticendfeetatthe bloodbrainbarrier,havebeenidentifiedintheserumofNeuromyelitisoptica(NMO)patientsandarebelievedtoinduce damagetoastrocytes. However, AQP4 specificThelper cellresponses that arerequired forthegeneration of anti-AQP4 antibodiesandmostlikelyalsofortheformationofintraparenchymalCNSlesionshavenotbeencharacterized. Methodology/Principal Findings: Using overlapping 15-meric peptides of AQP4, we identified the immunogenic T cell epitopesofAQP4thatarerestrictedtomurinemajorhistocompatibilitycomplex(MHC)I-Ab.TheN-terminalregionofAQP4 was highly immunogenic. More precisely, the intracellular epitope AQP422–36 was detected as major immunogenic determinant.AQP482–108 (locatedinthesecondtransmembranedomain),AQP4139–153 (locatedinthesecondextracellular loop),AQP4211–225 (locatedinthefifthtransmembranedomain),AQP4235–249 (locatedinthesixthtransmembranedomain), aswellasAQP4289–306 intheintracellularC-terminalregionwerealsoimmunogenicepitopes.AQP422–36 andAQP4289–303 specificTcellswerepresentinthenaturalTcellrepertoireofwildtypeC57BL/6miceandTcelllineswereraised.However, activeimmunizationwiththeseAQP4peptidesdidnotinducesignsofspinalcorddisease.Rather,sensitizationwithAQP4 peptidesresultedinproductionofIFN-c,butalsoIL-5andIL-10byantigen-specificTcells.Consistentwiththiscytokine profile,theAQP4specificantibodyresponseuponimmunizationwithfulllengthAQP4includedIgG1andIgG2,whichare associatedwithamixedTh2/Th1Tcellresponse. Conclusionsa