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Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients.doc

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Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients

Raijmakersetal.ArthritisResearchTherapy2012,14:R114 /content/14/3/R114 RESEARCH ARTICLE OpenAccess Elevatedlevelsoffibrinogen-derivedendogenous citrullinatedpeptidesinsynovialfluidof rheumatoidarthritispatients ReinoutRaijmakers1*,JoyceJBCvanBeers2,MahmoudEl-Azzouny1,NatasjaFCVisser1,BorutBo?i?3,GerJMPruijn2 andAlbertJRHeck1* Abstract Introduction:Rheumatoidarthritis(RA)isanautoimmunediseasecharacterizedbyinflammationofthejointsand thepresenceofautoantibodiesdirectedagainstproteinscontainingthenon-standardarginine-derivedaminoacid citrulline.Theproteinfibrinogen,whichhasanessentialroleinbloodclotting,isoneofthemostprominent citrullinatedautoantigensinRA,particularlybecauseitcanbefoundintheinflamedtissueofaffectedjoints.Here, wesetouttoanalyzethepresenceofcitrullinatedendogenouspeptidesinthesynovialfluidofRAandarthritic controlpatients. Methods:EndogenouspeptideswereisolatedfromthesynovialfluidofRApatientsandcontrolsbyfiltrationand solidphaseextraction.Thepeptideswereidentifiedandquantifiedusinghigh-resolutionliquidchromatography- massspectrometry. Results:OurdatarevealthatthesynovialfluidofRApatientscontainssolubleendogenouspeptides,derivedfrom fibrinogen,containingsignificantamountsofcitrullineresiduesand,insomecases,alsophosphorylatedserine. SeveralcitrullinatedpeptidesarefoundtobemoreabundantlypresentinthesynovialfluidofRApatients comparedtopatientssufferingfromotherinflammatorydiseasesaffectingthejoints. Conclusions:TheincreasedpresenceofcitrullinatedpeptidesinRApatientspointstowardapossiblespecificrole ofthesepeptidesintheimmuneresponseatthebasisoftherecognitionofcitrullinatedpeptidesandproteinsby RApatientautoantibodies. Introduction diagnosisofRA.ACPAareoftendetectedusingtheso- Rheumatoid arthritis (RA) isoneofthemostcommon calledcycliccitrullinatedpeptide,orCCPtest[5]. autoimmunediseases,forwhichmanyautoantigenshave Fibrinogenisaheteromultimericproteinconsistingof beenidentifiedoverthelastdecades.Themostremarkable twocopieseachofthreediffere