加州大学分校免疫学课程15(part1)

Lecture15AutoimmunityAutoimmunityTypesofautoimmunityPossiblemechanismsDefectsinthymictolerance,AIREDefectsindownregulationofimmuneresponsesFasLCTLA4Roleofinflammation/adjuvants/costimulationSuppressor/regulatoryTcellsEnvironmentalfactorsCrossreactivityCrosslinkingRoleofMHC"horrorautoxicus"PaulEhrlichca.1890Ehrlich,whowasstudyingtheabilityofantibodiesandcomplementtodestroyxenogeneicredbloodcells,recognizedthatifantibodiestoselferythrocyteswereproduced,theresultswouldbedevastating.2-5%ofthepopulationsuffersfromautoimmunediseaseAutoimmunediseasesaretissueandantigenspecificTypeIjuvenileonset(insulin-dependent)diabetesTypeIdiabetesisaTcell-mediateddiseaseinwhichtheisletscellsofthepancreasareattackedandkilled.Theantigenrecognizedisnotknown,butthereisaverylargecorrelationwiththeexpressionoftheDR3/4HLAtypes.TheculpritappearstobeavariantofthelinkedDQ-betagenelackingachargedasparticacidatposition57.Diabeticautoimmunityischaracterizedbyself-reactiveBandTlymphocytesthattargetasetofproteinsexpressedinpancreaticcells.Proinsulin(PI),IA2,GAD65and67,andisletcellautoantigenof69kDa(ICA69)arethemajorexamples.Thesetargetself-Agsarenotisletcellspecific,andneitherisdiabeticautoimmunity;signsofceliacandthyroidautoimmunityarefairlycommoninpatients,anddiabetes-proneNODmicedevelopsignsofthyroidandSjögren’sdisease.Occasionalislet-reactiveTcellsarefoundinalmost10%ofthegeneralpopulation,but<0.5%ofthesesubjectsarelikelytodevelopovertdiabetes.AlthoughitisuncertainwhatexpandsautoimmuneTcellpoolsandwhatdeterminestheirtissue-destructivepotential,accesstoislettargettissuehasbeensuggestedasacriticalelementindiabetes-pronehosts,despiteavailabilityofmostrelevantautoantigensinothertissues.Processiveinsulitisandisletcelldestructionindiabetes-proneNODstrainmiceHealthyisletsLymphocyteinfiltrateFigure13-34Someautoantibody-mediateddiseasesFigure11-2Figure11-14Figure11-5GravesdiseaseinvolvesantibodiestothyroidstimulatinghormonereceptorInsomecases,itisclearthatantibodiesarepathogenicFigure11-7part2of2SystemlupuserythematosisThediagnosisofSLEismadewhenotherillnesseshavebeenruledout,andwhenapersonhas4of11criteria.Thesecriteriainclude:discoidrash,malar(butterfly)rash,photosensitivity,mouthsores,arthritis,serositis(usuallyheartorlunginflammation),kidneydisorder,neurologicalproblems,bloodchanges,immunechanges,abnormaltitreofantinuclearantibody(ANA).Itisimportanttorememberthat4ormoreoftheaboveneedtobepresent.SometimesSLEissuspectedwithfewersymptomspresent.Forexample,ifapersonhasapositiveANA,thediagnosismaynotbeconfirmedunlessothersymptomsarepresent.Itcanbefrustratingtonotknowforsure.Theaveragetimefromtheonsetofsymptomsanddiagnosisisabout3years.SLEcontinuedSLEcandamagealmostanypartororganofthebody.ManypeopleareinitiallythoughttohavearthritisbecauseSLEhascausedinflammationofthejoints.Kidneysarefrequentlyaffected.IfSLEaffectsthebrain,forexample,apersonmightbeinitiallydiagnosedaspsychotic,epilepticorsufferingfromastroke.

TherespiratorysystemisoneofthemostfrequentlyinvolvedsystemsinSLE.Infectionspresentfrequentproblems.CertainmedicationsusedinSLEmaypredisposeapersontounusualkindsofinfections.Themoreseriousproblemsinvolvelungdiseaseincludinginterstitiallungdisease,pulmonaryhemorrhage.Treatable.TreatmentofSLEdependsontheseverityofthecase.Somepeoplerequireonlyanti-inflammatorymedicine(i.e.aspirin)tocontrolpainandswelling.Othersmayneedcorticosteroidsorcytotoxicmedicationsincludingazathioprineorcyclophosphamide.Insomecases,medicationsmaybeusedtosuppresstheimmunesystem.Antimalarialmedicationsarefrequentlyused.Figure11-9ProbablemodeofantinuclearantibodyproductioninSL