自身耐受和免疫调节异常与免疫介导的炎症性疾病免疫调节的重要性免疫调节的方式免疫耐受中枢性耐受外周性耐受免疫细胞调节——调节性T细胞作用免疫耐受自身免疫Theprincipalfateoflymphocytesthatrecognizeselfantigensinthegenerativeorgansisdeath(deletion),BUT:SomeBcellsmaychangetheirspecificity(called“receptorediting”)SomeCD4Tcellsmaydifferentiateintoregulatory(suppressive)TlymphocytesConsequencesofselfantigenrecognitioninthymusTcellanergy“Activation-inducedcelldeath”:deathofmatureTcellsuponrecognitionofselfantigensRegulatoryTcellsTRegulatoryCellPropertiesPeripheral(adaptive,inducible)regulatoryTcellsSignalsforthegenerationandmaintenanceofregulatoryTcellscellulartherapywithRegulatoryTcells?Immune-mediatedinflammatorydiseasesPathogenesisofautoimmunityGeneticsofautoimmunityNOD2:polymorphismassociatedwith~25%ofCrohn’sdiseaseMicrobialsensorPTPN22:commonestautoimmunity-associatedgene;polymorphisminRA,SLE,othersPhosphataseCD25(IL-2R):associatedwithMS,others;genome-wideassociationmappingRoleinTregsInfectionsandautoimmunity卫生假说的内容ThenatureofthediseaseisdeterminedbythetypeofdominantimmuneresponseTh1response:inflammation,autoantibodyproduction;autoimmunediseasesTh2response:IgE+eosinophil-mediatedinflammation;allergicreactionsTh17response:acute(andchronic?)inflammation;increasinglyrecognizedinimmune-mediateddiseasesImmunologicaldiseasestendtobechronicandself-perpetuating,because–Theinitiatingtriggercanoftennotbeeliminated(selfantigen,commensalmicrobes)Theimmunesystemcontainsmanybuilt-inamplificationmechanismswhosenormalfunctionistooptimizeourabilitytocombatinfections“Epitopespreading”“Molecularminicry”Amplificationloopincell-mediatedimmunityAfteramicrobialinfection,activa-tedmicrobe-speci-ficTH1(mTH1)cellsmigratetotheinfectedorgan.A.Molecularmimicry.B.Epitopespre-ading.C.Bystanderactivation.D.Crypticantigen.Pathogenesisoforgan-specificautoimmunityTreatmentofautoimmunedisease(cont’d)ReduceinflammationTNF-alphablockers(RA,Crohn’sdis.,psoriasis)e.g.,Enbrel,Remicade,HumiraIL-1receptorantagonist(RA)Ab’sagainstIL6RandIL-15R