Selective inhibition of the gliadin‐specific, cell‐mediated immune response by transamidation with microbial transglutaminase

[摘要] CDisanimmune‐mediatedenteropathycausedbytheingestionofwheatgluten.ThemodificationofglutenbyintestinaltTGaseplaysacrucialroleinCDpathogenesis.Inthisstudy,weobservedthatextensivetransamidationofwheatflourwithK‐C2H5bymTGaseyieldedspfandK‐gliadinsfractions.ByWesternblot,wefoundthatthesemodificationswereassociatedwithstronglyreducedimmunecross‐reactivity.WiththeuseofDQ8tgmiceasamodelofglutensensitivity,weobservedadramaticreductioninIFNγproductioningliadin‐specificspleencellschallengedwithspfandK‐gliadinsinvitro(n=12;medianvalues:813vs.29and99;controlvs.spfandK‐gliadins,P=0.012forspf,andP=0.003forK‐gliadins).Forspf,wealsoobservedanincreaseintheIL‐10/IFNγproteinratio(n=12;medianvalues:0.3vs.4.7;controlvs.spf,P=0.005).InintestinalbiopsiesfromCDpatientschallengedinvitrowithgliadins(n=10),wedemonstratedfurtherthatK‐gliadinsdramaticallyreducedthelevelsofantigen‐specificIFNγmRNAinallspecimensresponsivetonativegliadins(fourof10;P<0.05).Ascytotoxiceffectshavebeendescribedforgliadins,wealsostudiedGSTandcaspase‐3activitiesusingtheenterocyticCaco‐2cellline.Wefoundthatneitheractivitiesweremodifiedbyflourtransamidation.OurresultsindicatethatK‐C2H5cross‐linkingviamTGasespecificallyaffectsgliadinimmunogenicity,reversingtheinducibleinflammatoryresponseinmodelsofglutensensitivitywithoutaffectingotheraspectsofthebiologicalactivityofgliadins...

[学科分类] 生理学

[关键词] celiac disease;T lymphocytes;enterocytes