簡介:超敏反應(yīng),HYPERSENSITIVITY,西安交通大學(xué)醫(yī)學(xué)院免疫學(xué)與病原生物學(xué)系史霖,是指機(jī)體對(duì)某些抗原初次應(yīng)答(致敏)后,再次接受相同抗原刺激時(shí),發(fā)生的一種以機(jī)體生理功能紊亂或組織細(xì)胞損傷為主的特異性免疫應(yīng)答。,概念,,變應(yīng)原,,機(jī)體,B,T,,,漿細(xì)胞,致敏T細(xì)胞,,抗體,IGE,IGG,IGM,IGA,變應(yīng)原,,,,反應(yīng),,組織損傷、功能紊亂,超敏反應(yīng)分型,,參與的IG類型或免疫活性細(xì)胞,IGE,分型,I型速發(fā)型超敏反應(yīng),IGM、IGG,II型細(xì)胞毒型超敏反應(yīng),,,,,,,III型免疫復(fù)合物型超敏反應(yīng),體液免疫,細(xì)胞免疫,TC細(xì)胞、TDTH細(xì)胞,IV型遲發(fā)型超敏反應(yīng),,速發(fā)型超敏反應(yīng)IMMEDIATEHYPERSENSITIVITY變態(tài)反應(yīng)(ALLERGY),I型超敏反應(yīng),CARLPRAUSNITSGILES18761963PK試驗(yàn),,吸入性變應(yīng)原花粉塵螨或其排泄物真菌或其孢子動(dòng)物皮屑或羽毛,藥物青霉素磺胺普魯卡因有機(jī)碘化物,食入性變應(yīng)原,變應(yīng)原(ALLERGEN),能夠能夠誘導(dǎo)變態(tài)反應(yīng)的抗原性物質(zhì)。,昆蟲,IGE型抗體,IGE,特應(yīng)素質(zhì)患者血清IGE含量明顯增高,強(qiáng)親細(xì)胞性IGEFC段能與靶細(xì)胞FCΕR結(jié)合,變應(yīng)素(ALLERGINS)IGE,FCΕR?,FCΕRП(CD23),位于肥大細(xì)胞、嗜堿性粒細(xì)胞表面高親和力受體,傳遞信號(hào),介導(dǎo)I型超敏反應(yīng)。,與IGE重鏈CH3結(jié)合,放大信號(hào),,,信號(hào)轉(zhuǎn)導(dǎo),表達(dá)B細(xì)胞、活化的T細(xì)胞、嗜酸性粒細(xì)胞、巨噬細(xì)胞等低親和力受體功能(1)膜CD23結(jié)合IGE/IGE免疫復(fù)合物,降低B的IGE合成(2)SCD23與B細(xì)胞的CD21結(jié)合可促進(jìn)IGE合成。,FCΕR,肥大細(xì)胞,參與I型超敏反應(yīng)的細(xì)胞,嗜鹼性粒細(xì)胞,嗜鹼性顆粒,,,嗜酸性粒細(xì)胞,預(yù)先存在的介質(zhì)(脫顆粒),組織胺HISTAMIN趨化因子激肽原酶蛋白水解酶,,白三烯(LEUCOTRIENES,LTS),前列腺素(PGD2),即刻\早期相,晚期相,血小板活化因子(PLATELETACTIVATYFACTOR,PAF),新合成的介質(zhì),,THESEMEDIATORSCOLLECTIVELYCAUSEINCREASEDVASCULARPERMEABILITY,VASODILATION,BRONCHIALANDVISCERALSMOOTHMUSCLECONTRACTION,INCREASEDGLANDSECRETION,ANDLOCALINFLAMMATION,ISCHEMICSHOCK,INCREASEDVASCULARPERMEABILITY,EDEMA,VASODILATION,DECREASEDBLOODPRESSURE,,,,,BRONCHIALORTHROATSMOOTHMUSCLECONTRACTION,,,WHEEZING,DYSPNEA,ASPHYXIATION,INCREASEDGLANDSECRETION,,LOCALINFLAMMATION,,SWELLING,ERYTHEMA,SYSTEMIC,PHLEGM,I型超敏反應(yīng)發(fā)生的機(jī)制,儲(chǔ)存的介質(zhì)新合成介質(zhì),,,,變應(yīng)原初次進(jìn)入機(jī)體,同一變應(yīng)原再次進(jìn)入機(jī)體,B細(xì)胞,SIGE,IGE結(jié)合到靶細(xì)胞表面,組織胺,趨化因子,緩激肽,,,,小血管擴(kuò)張毛細(xì)血管通透性增加平滑肌收縮,白三烯(LTS)血小板活化因子(PAF)前列腺素(PGD2),,中性粒/嗜酸性粒細(xì)胞浸潤,腺體分泌增加,I型超敏反應(yīng)效應(yīng)階段,全身性(過敏性休克),呼吸道(哮喘、過敏性鼻炎),消化道(過敏性腸炎),皮膚(蕁麻疹),效應(yīng)器官,慢性過敏反應(yīng)變應(yīng)原長期反復(fù)刺激的結(jié)果。病變部位有各種白細(xì)胞(尤其是嗜酸性粒細(xì)胞和淋巴細(xì)胞)浸潤,還伴有深層組織的累積性實(shí)質(zhì)性改變。,IGE介導(dǎo)的炎癥反應(yīng)有三種類型,急性過敏反應(yīng)I型超敏反應(yīng)(速發(fā)型超敏反應(yīng))發(fā)生于接觸變應(yīng)原幾分鐘之內(nèi)。變應(yīng)原在局部組織中激活致敏的肥大細(xì)胞,使其迅速脫顆粒,釋放其中貯存的炎癥介質(zhì)(尤以組織胺為主),造成血管平滑肌擴(kuò)張和粘膜腺體分泌。,遲發(fā)相過敏反應(yīng)發(fā)生于急性過敏反應(yīng)之后的幾個(gè)小時(shí)之內(nèi)。被激活的肥大細(xì)胞合成新的炎癥介質(zhì)(如PGD2,LT等)并釋放于組織中,造成炎癥細(xì)胞的繼續(xù)浸潤。,臨床常見的I型超敏反應(yīng),,一過敏性休克,1藥物過敏性休克,2血清過敏性休克,二呼吸道過敏反應(yīng),1支氣管哮喘,2變應(yīng)性鼻炎,EYELIDSWELLINGEDEMA,三消化道過敏反應(yīng)EG過敏性腸炎NAUSEA,VOMITING,DIARRHEA,ABDOMINALPAIN,四皮膚過敏反應(yīng),1蕁麻疹,2特應(yīng)性皮炎,反應(yīng)特點(diǎn),1發(fā)生快,消退也快,2IGE參與,3組胺等介質(zhì)發(fā)揮重要作用,4補(bǔ)體不參與,無明顯組織損傷,5有明顯的個(gè)體差異和遺傳傾向,變應(yīng)原皮膚試驗(yàn),I型超敏反應(yīng)防治原則,生物活性介質(zhì)拮抗藥,組胺受體拮抗劑,,消化道皮膚呼吸道,,,,,IGE,,,支氣管痙攣、黏液分泌、平滑肌收縮,血管擴(kuò)張水腫,,II型超敏反應(yīng),由IGG或IGM類抗體與靶細(xì)胞表面相應(yīng)抗原結(jié)合后,在補(bǔ)體、吞噬細(xì)胞和NK細(xì)胞參與作用下,引起的以細(xì)胞溶解或組織損傷為主的病理性免疫反應(yīng)。,靶細(xì)胞及其表面抗原,改變了的自身抗原,靶細(xì)胞表面的抗原,正常存在于血細(xì)胞表面的同種異型抗原(血型抗原、HLA),外源性抗原與正常組織細(xì)胞之間具有的共同抗原(異嗜性抗原),,1外來半抗原自身組織成分或細(xì)胞,3抗原抗體復(fù)合物吸附于自身組織細(xì)胞上,2感染或其他因素引起自身組織結(jié)構(gòu)改變,免疫穩(wěn)定功能破壞產(chǎn)生抗自身組織抗體,參與II型超敏反應(yīng)的抗體IGM、IGG,IGG,IGM,親細(xì)胞作用,II型超敏反應(yīng)發(fā)生的機(jī)制,一、補(bǔ)體介導(dǎo)的細(xì)胞溶解(CDC),二、ADCC效應(yīng)破壞靶細(xì)胞,三、抗體、補(bǔ)體的調(diào)理吞噬破壞靶細(xì)胞,正常,GRAVES’病,腦垂體,II型超敏反應(yīng)發(fā)生的機(jī)制(二)抗體與抗原靶細(xì)胞結(jié)合刺激細(xì)胞分泌功能亢進(jìn)(刺激型),臨床常見的II型超敏反應(yīng)性疾病,1、輸血反應(yīng)ABO血型不符,2、新生兒溶血母子間RH血型不符,3、自身免疫性溶血性貧血紅細(xì)胞膜表面成分改變,4、藥物過敏性血細(xì)胞減少癥青霉素、磺胺、安替比林、奎尼丁、非那西汀等藥物抗原表位與血細(xì)胞膜蛋白或血漿蛋白結(jié)合而獲得免疫原性,8、甲狀腺功能亢進(jìn)GRAVES病。產(chǎn)生針對(duì)甲狀腺細(xì)胞表面甲狀腺刺激素(TSH)受體的自身抗體,5、抗腎小球基底膜腎炎異嗜抗原,6、GOODPASTURE’SSYNDROME,7、MYASTHENIAGRAVISPRODUCEBLOCKINGAUTOABTOTHEACHR,主要特點(diǎn),1抗體主要是IGG和IGM,2補(bǔ)體、巨噬細(xì)胞、NK細(xì)胞參與致病,3靶細(xì)胞主要是血細(xì)胞和某些組織成分,免疫復(fù)合物?。↖MMUNECOMPLEXDISEASE),III型超敏反應(yīng),由中等大小可溶性免疫復(fù)合物沉積于局部或全身毛細(xì)血管基底膜后,通過激活補(bǔ)體和血小板、嗜堿性、嗜中性粒細(xì)胞參與作用下,引起的以充血水腫、局部壞死和中性粒細(xì)胞浸潤為主要特征的炎癥反應(yīng)和組織損傷。,外源性病原微生物、異種血清等,內(nèi)源性變性的IGG、SLE的核抗原等,SSEDIMENTATIONCOEFFICIENT,,,III型超敏反應(yīng)發(fā)生的機(jī)制(一),IC,,補(bǔ)體,C3A、C5A,嗜堿性粒細(xì)胞、肥大細(xì)胞脫顆粒,組織胺、激肽原酶,趨化因子,PAF,,,血管,,,,免疫復(fù)合物一定條件下滯留沉積于局部組織,激活補(bǔ)體產(chǎn)生的過敏毒素介導(dǎo)嗜堿性粒細(xì)胞脫顆粒,,,,,III型超敏反應(yīng)發(fā)生的機(jī)制(二),,,,,,,趨化因子細(xì)胞因子,PAF,,,,血小板凝集、破壞,,血栓形成,,,血管炎癥,毛細(xì)血管通透性增強(qiáng)、局部組織水腫,IC進(jìn)一步沉積,中性粒細(xì)胞在吞噬沉積的IC時(shí)釋放多種酶損傷局部組織,激活的血小板凝集、破壞形成微血栓,使局部組織缺血、出血,免疫復(fù)合物沉積后引起的損傷,①補(bǔ)體的作用,②中性粒細(xì)胞的作用,③血小板的作用,MAC造成局部組織損傷;過敏毒素C3A、C5A吸引、活化中性粒細(xì)胞,導(dǎo)致滲出性炎癥損傷,釋放溶酶體酶、蛋白水解酶等,造成血管基底膜和鄰近組織損傷,釋放組胺等血管活性胺類物質(zhì),加劇局部滲出性反應(yīng),并激活凝血過程,形成微血栓,引起局部缺血、出血及壞死。,臨床常見的III型超敏反應(yīng)性疾病,1、ARTHURS反應(yīng)經(jīng)抗原反復(fù)免疫之后,注射抗原的皮下出現(xiàn)局部紅腫、出血和壞死等劇烈炎癥反應(yīng)。,2、類ARTHURS反應(yīng)胰島素依賴型糖尿病患者反復(fù)注射胰島素。,一、局部免疫復(fù)合物病,1、血清病初次大量注射抗毒素馬血清后12周出現(xiàn)發(fā)熱、皮疹、淋巴結(jié)腫大、關(guān)節(jié)腫痛和蛋白尿等癥狀。使用大劑量青霉素和磺胺類藥物也能出現(xiàn)類似癥狀。,2、鏈球菌感染后腎小球腎炎A族溶血性鏈球菌感染后23周??贵w與鏈球菌可溶性抗原形成復(fù)和物,沉積于腎小球基底膜處。,二、全身性免疫復(fù)合物病,自身抗體與可溶性自身抗原形成免疫復(fù)和物,沉積于皮下、關(guān)節(jié)和腎小球基底膜等處。,3、類風(fēng)濕性關(guān)節(jié)炎(RA)抗自身變性IGG的抗體(IGM)4、系統(tǒng)性紅斑狼瘡(SLE)INDIVIDUALSPRODUCEAUTOANTIBODIESTOAVASTARRAYOFTISSUEANTIGENS,SUCHASDNA,HISTONES,RBCS,PLATELET,LEUKOCYTESINTERACTIONOFTHESEAUTOANTIBODIESWITHTHEIRSPECIFICANTIGENSPRODUCEVARIOUSSYMPTOMSEGHEMOLYTICANEMIA,VASCULITIS,Ⅲ型超敏反應(yīng)的特點(diǎn),1參與抗體主要為IGG、IGM,2中等大小可溶性免疫復(fù)合物在致病上起主要作用,3補(bǔ)體及中性粒細(xì)胞釋放的溶酶體酶是引起組織損傷的主要原因,4病變局部主要是中性粒細(xì)胞浸潤為主的炎癥,遲發(fā)型超敏反應(yīng)DELAYEDTYPEHYPERSENSITIVITY,DTH),IV型超敏反應(yīng),由效應(yīng)T細(xì)胞再次接觸相同的抗原后,于24小時(shí)后出現(xiàn)的以單核細(xì)胞、淋巴細(xì)胞浸潤為主的病理性損傷。,抗原、免疫細(xì)胞,抗原病原生物胞內(nèi)寄生菌(如結(jié)核菌)病毒真菌寄生蟲細(xì)胞抗原(腫瘤、移植細(xì)胞),免疫細(xì)胞,T細(xì)胞CD4TH1CD8TC,活化的單個(gè)核吞噬細(xì)胞,APC,IV型超敏反應(yīng)發(fā)生的機(jī)制(一),局部的APC攝取處理抗原,APC將抗原多肽以MHCII多肽復(fù)合物表達(dá)在其表面,提呈給特異性的TH1識(shí)別并被活化。,IV型超敏反應(yīng)發(fā)生的機(jī)制(二),活化的TH1釋放細(xì)胞因子活化血管上皮細(xì)胞,增加粘附分子的表達(dá),,募集MΦ、更多TH1進(jìn)入局部浸潤,激活的MΦ釋放炎癥因子,血漿滲出,擴(kuò)大炎癥反應(yīng)。,IV型超敏反應(yīng)發(fā)生的機(jī)制(三),靶細(xì)胞(腫瘤細(xì)胞、病毒感染細(xì)胞)將抗原肽段MHCI復(fù)合物表達(dá)在其表面給TC識(shí)別。,TC在殺傷靶細(xì)胞的同時(shí)造成局部組織的損傷,IV型超敏反應(yīng)發(fā)生的機(jī)制,APC,致敏T細(xì)胞,,CD4TH1釋放細(xì)胞因子(IL2,IFNR,TNF,LT),,TH、TC增殖,MΦ活化,血管內(nèi)皮細(xì)胞活化粘附分子表達(dá)增加,MΦ浸潤,,,,,,,CD8TC釋放穿孔素、細(xì)胞毒素直接殺傷靶細(xì)胞,,TCRAGMHC三元體,協(xié)同刺激分子,,,,,FAMILIARDISEASESINCLINICOFTYPEIVHYPERSENSITIVITY,INFECTIVITYALLERGYCELLMEDIATEDIMMUNERESPONSESTOMICROBESANDOTHERFOREIGNANTIGENSMAYALSOLEADTOTISSUEINJURYATTHESITESOFINFECTIONORANTIGENEXPOSUREEXAMPLES1INTRACELLULARBACTERIAMYCOBACTERIUMTUBERCULOSISINDUCESTRONGTCELLANDMACROPHAGERESPONSETHATRESULTSINGRANULOMATOUSANDFIBROSISTHESEMAYCAUSEEXTENSIVETISSUEDESTRUCTIONANDFUNCTIONALIMPAIRMENT,2CTLRESPONSESTOVIRALINFECTIONCANLEADTOTISSUEINJURYBYKILLINGINFECTEDCELLSEVENIFTHEVIRUSITSELFHASNOCYTOPATHICEFFECTSEGVIRALHEPATITISINHUMANS,2CONTACTDERMATITISAVARIETYOFSKINDISEASESTHATRESULTFROMTOPICALEXPOSURETOCHEMICALSANDENVIRONMENTALANTIGENSEGNICKEL,POISONIVY/OAK,DRUGS,COSMETIC,AREDUETODTHREACTION,PRESUMABLYAGAINSTNEOANTIGENSFORMEDBYTHEBINDINGOFTHECHEMICALSTOSELFPROTEINSDEVELOPSERYTHEMA,ITCHING,VESICLES,ORNECROSISOFSKINWITHIN1248HOURS,3GRAFTREJECTION,4INSULINDEPENDENTDIABETESMELLITUSIDDMINFILTRATEOFLYMPHOCYTESANDMACROPHAGESAREFOUNDAROUNDTHEISLETSOFLANGERHANSINTHEPANCREAS,WITHDESTRUCTIONOFINSULINPRODUCINGΒCELLSINTHEISLETSANDARESULTANTDEFICIENCYININSULINPRODUCTION5MULTIPLESCLEROSISMSANAUTOIMMUNEDISEASEOFTHECENTRALNERVOUSSYSTEMINWHICHCD4TCELLSOFTHETH1SUBSETREACTAGAINSTSELFMYELINANTIGENSTHEDTHREACTIONOFMACROPHAGESAROUNDNERVESINTHEBRAINANDSPINALCORD,DESTRUCTIONOFTHEMYELIN,ABNORMALITIESINNERVECONDUCTION,ANDNEUROLOGICDEFICITS,Ⅳ型超敏反應(yīng)引起的皮膚損傷,THECHARACTERISTICOFTYPEIVHYPERSENSITIVITY⒈DEVELOPSLOWLY,DELAYED⒉THEREISNORELATIVETOABANDCOPLEMENT⒊TISSUEDAMAGEISCAUSEDBYCYTOTOXIONANDCK4THECHARACTEROFLOCALINFLAMMATIONISNEUTROPHILSINFILTRATION⒌THEREISALMOSTNOINDIVIDUALDIFFERENCE,各型超敏反應(yīng)與疾病的關(guān)系,超敏反應(yīng)性疾病常為混合型,但以某型為主。,II型超敏反應(yīng)損傷與IV型超敏反應(yīng)損傷可同時(shí)存在,同一疾病過程可有幾種類型免疫損傷共同參與,相同變應(yīng)原可通過不同途徑導(dǎo)致多種類型的超敏反應(yīng),腎小球腎炎,腫瘤細(xì)胞、移植細(xì)胞的損傷,過敏性哮喘可由Ⅰ、Ⅲ型超敏反應(yīng)引起,青霉素可致Ⅰ、Ⅱ、Ⅲ、Ⅳ型超敏反應(yīng),各型超敏反應(yīng)特性比較,,,,IGE肥大細(xì)胞嗜堿性粒細(xì)胞,,分型,I型速發(fā)型,機(jī)理,,IGM/IGG補(bǔ)體NK中性粒細(xì)胞巨噬細(xì)胞,,II型細(xì)胞毒型,,III型免疫復(fù)合物型,APCTH1/TC細(xì)胞巨噬細(xì)胞,IV型遲發(fā)型,參加成分,IGG/IGM補(bǔ)體血小板中性粒細(xì)胞嗜堿性粒細(xì)胞,,機(jī)體致敏變應(yīng)原與細(xì)胞表面的IGE結(jié)合FCΕRI交聯(lián)導(dǎo)致脫顆?;钚越橘|(zhì)作用于效應(yīng)器官,抗體與自身抗原靶細(xì)胞結(jié)合激活補(bǔ)體溶解靶細(xì)胞(CDC)增加巨噬細(xì)胞等調(diào)理吞噬作用NK通過ADCC殺傷靶細(xì)胞,中等大小IC沉積血管壁激活補(bǔ)體,激活嗜堿性粒、中性粒細(xì)胞使血管透性增加,溶酶體釋放,血小板凝集形成血栓,APC將抗原提呈給T使之致敏,TH1釋放細(xì)胞因子激活MΦ,后者釋放炎癥介質(zhì)引起炎癥反應(yīng);TC直接殺傷靶細(xì)胞,常見病例,過敏性休克蕁麻疹過敏性哮喘/花粉癥過敏性胃腸炎,溶血性貧血血細(xì)胞減少癥新生兒溶血移植物超級(jí)排斥反應(yīng)GRAVES’病,局部ARTHUS反應(yīng)血清病感染后腎小球腎炎類風(fēng)濕性關(guān)節(jié)炎,傳染性IV超敏反應(yīng)接觸性皮炎移植物排斥反應(yīng),,變應(yīng)原皮膚實(shí)驗(yàn),,變應(yīng)原皮膚試驗(yàn),,,,,,,,,,,,,,,,,,RH,,RH–,再孕,,,,,,,,,,,,,,,,,,,RH,,RH–,初孕,,胎兒紅細(xì)胞致敏母親,,新生兒溶血,健康新生兒,,新生兒溶血,母胎RH血型不符,母胎ABO血型不符,,,GOODPASTURE’SSYNDROME,VIRUSA2TYPEINFLUENZAVIRUS、ORGANICSOLVENT,LUNGTISSUEDAMAGE,,INHALE,,AUTOANTIBODY,GLOMERULEDAMAGE,,PRODUCE,THEREHAVECOMMONANTIGENINALVEOLUSWALLANDGLOMERULEBASEMENTMEMBRANEOFKIDNEY,CROSSREACTION,,,HORSESERUMINJECTTORABBITMANYTIMES,THEINJECTEDLOCALPLACEAPPEARINFLAMMATORYREACTION,SKININFLAME,BLEEDINGANDNECROSIS,,PRODUCE,,RABBITANTIHORSESERUMANTIBADY,ICAGGRADATION,,AFTER46TIMESINJECT,ICHORSESERUMRABBITABFORMED,,ARTHUSREACTION,ARTHUSLIKEREACTION,,ANINJECTIONHIGHDOSEOFAFOREIGNPROTEINHORSESERUM,PENICILLIN,ETC,INDUCINGFEVER,SYMPTOMSOFVASCULITISNEPHRITISANDARTHRITIS,JOINTTENDERNESS,URTICARIA,PROTEINURIA,,714DAYSLATER,,ANTIBODYFORTHEFOREIGNPROTEINFORMED,IC,,REACTION,REMNANTFOREIGNPROTEIN,,FORM,SERUMSICKNESS,SERUMSICKNESS,,STREPTOCOCCUSINFECT,DEPOSITATGLOMERULARBASEMENTMEMBRANEGLOMERULONEPHRITIS,,INDUCE,,ANTISTREPTOCOCCUSAB,IC,,23WEEKS,STREPTOCOCCALAGAB,,FORM,,POSTSTREPTOCOCCALGLOMERULONEPHRITIS,RFANTIBODYFORAUTODENATUREDIGG(IGM),ARTHROSISSYNOVIALMEMBRANE,,BIND,,AUTODENATUREDIGGINCIRCLE,CHRONICINFLAMMATIONOFTHEJOINT,,FORM,SOLUBLEAGABCOMPLEX,,REPEATEDLYDEPOSIT,RHEUMATOIDARTHRITIS,,,TUBERCULOSIS,TUBERCULINTEST,,①檢驗(yàn)卡介苗的接種效果②衡量免疫應(yīng)答狀態(tài)。,組織中的異物(硅、礦物質(zhì)、真菌、分枝桿菌、寄生蟲等)長期得不到徹底清除,引起巨噬細(xì)胞和上皮樣細(xì)胞的聚集。結(jié)節(jié)中心的外周有T細(xì)胞圍繞,并伴有一定程度的纖維化。,慢性肉芽腫,,接觸性皮炎,CONTACTDERMATITIS,,
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