Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies 英文参考文献.docVIP

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Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies 英文参考文献.doc

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Liuetal.ArthritisResearchTherapy2012,14:R25 /content/14/1/R25 RESEARCH ARTICLE OpenAccess Specificpost-translationalhistonemodifications ofneutrophilextracellulartrapsasimmunogens andpotentialtargetsoflupusautoantibodies ChihLongLiu1,4,StephanieTangsombatvisit1,JacobMRosenberg1,GilMandelbaum1,EmilyCGillespie2, OrPGozani4,AshAAlizadeh3*andPaulJUtz1* Abstract Introduction:Autoreactivitytohistonesisapervasivefeatureofseveralhumanautoimmunedisorders,including systemiclupuserythematosus(SLE).Specificpost-translationalmodifications(PTMs)ofhistoneswithinneutrophil extracellulartraps(NETs)maypotentiallydrivetheprocessbywhichtolerancetothesechromatin-associated proteinsisbroken.WehypothesizedthatNETsandtheiruniquehistonePTMsmightbecapableofinducing autoantibodiesthattargethistones. Methods:Wedevelopedanovelandefficientmethodfortheinvitroproduction,visualization,andbroadprofiling ofhistone-PTMsofhumanandmurineNETs.WealsoimmunizedBalb/cmicewithmurineNETsandprofiledtheir seraonautoantigenandhistonepeptidemicroarraysforevidenceofautoantibodyproductiontotheir immunogen. Results:Weconfirmedspecificitytowardacetyl-modifiedhistoneH2BaswellastootherhistonePTMsinsera frompatientswithSLEknowntohaveautoreactivityagainsthistones.Weobservedenrichmentfordistinctive histonemarksoftranscriptionallysilentDNAduringNETosistriggeredbydiversestimuli.However,NETsderived fromhumanandmurinesourcesdidnotharbormanyofthePTMstowardwhichautoreactivitywasobservedin patientswithSLEorinMRL/lprmice.Further,whilemurineNETswereweakautoantigensinvivo,therewasonly partialoverlapintheimmunoglobulinG(IgG)andIgMautoantibodyprofilesinducedbyvaccinationofmicewith NETsandthoseseeninpatientswithSLE. Conclusions:IsolatedinvivoexposuretoNETsisinsufficienttobreaktoleranceandmayinvolveadditionalfactors thathaveyettobeidentified. Introduction from apoptosis and necrosis, termed “NETosis” [2]. In Neutrophil extracellular traps (NETs) were first additiontoneutrophilantimicrobialproteins,NETsare described in 2004 as we