Chapter Hypersensitivity超敏反应.docx

1、Chapter Hypersensitivity超敏反应Hypersensitivity超敏反应Definition:It is excessive immune response, which leads to undesirable consequences, such as tissue or organ damage, dysfunction, etc. Type: I, II, III and IV Hypersensitivity Ab mediated: Type I, II, III由抗体所介导的 T cell mediated: Type IV由T细胞介导的。Part I:

2、Type I hypersensitivity型超敏反应又称过敏反应，主要由特异性抗体IgE抗体介导产生的，主要特征是1反应发生快，消退亦快2常引起生理功能紊乱，几乎不发生严重组织细胞损伤3具有明显个体差异和遗传倾向v IgE mediated, immediate hypersensitivity / allergy;v Major features:1. React and disappear quickly on re-exposure to Ag;2. Dysfunction rather than severe tissue or cell damage occurs;3. Obvi

3、ous individual difference and genetic correlation.v Allergen变态原：An antigen that causes all allergy.变态原：凡经吸入或食入等途径进入体内后能引起IgE类抗体产生并导致变态反应的抗原性物质称为。v The General Components： Allergens IgE and its receptors the cells-mast cells basophils eosinophilsv Source of allergens some drugs & chemical materials i

4、nspiratory food some enzyme substancev IgE -IgE can bind FcRI on mast cells and basophils by its CH4 domain, cause anaphylaxis过敏反应。 the level in serum -normally: 0.10.4g/ml -for atopic individuals: 1g/ml atopic individual -allergens, IgE, excessive immune response the half-life-in the serum : 23 day

5、s -IgE had been bound to FcR: stable, weeks produced by B cell -at the lymph tissue in the lamina propria of the nasopharynx, tonsil, respiratory and gastrointestinal tract cytophil antibody Th2 dependent IgE的产生依赖细胞因子IL-4，Th2细胞受变应原刺激活化分泌IL-4等细胞因子可诱导变应原特异性B细胞增殖，分化成浆细胞，通过Ig类别转换等机制产生特异性IgE抗体。Th2细胞的活化可被

6、Th1细胞分泌的细胞因子IFN-以及DC和巨嗜细胞分泌的IL-2所抑制。因此提高Th1细胞活性，减少IL-4的水平，进而增加IgG抗体产生，降低IgE抗体的产生，将有助于过敏反应患者的治疗。v IgE receptors The high-affinity IgE receptor : FcRI the affinity: higher mainly on mast cells and basophils, fewer on eosinophils, LG, monocytes, platelets four chains:-ITAM one receptor interacts with b

7、oth CH3 of one IgE The low-affinity IgE receptor : FcRII The affinity: lower-CD23分子 on mast cells, B cell, activated T cell, Mo-M , FDC & Platelet bind to the CH3 of IgE sCD23 promotes production of IgE when sCD23 combines to CD21 on B cell atopic individual -High level of CD23 on lymphocyte & M -Hi

8、gh level of sCD23 in serumv Mast cells Express high affinity IgE Fc receptor FcR,granules contain mediators. Distribution: connective tissues, mucosa, skin. Anaphylaxis is triggered by clustering of IgE receptors(FcR)on mast cells and basophils through cross-linking.v Basophils derived from the bone

9、 marrow Distribution-circulate in the blood -should be recruited into tissues -the granulated cytoplasm stains with basic dyesmast cells and basophiles：作用：释放生物活性物质，介导型超敏反应。v Eosinophils derived from the bone marrow Distribution: -majority：throughout connective tissue of mucous membrane surfaces of t

10、he respiratory & gastrointestinal tracts -minor：circulate in the blood express FcR after the eosinophils are activated 作用：a.对型超敏反应产生负反馈调节作用 b.参与型超敏反应晚期反应。v Mechanisms of Type I HypersensitivitySensitization: allergen host specific B cell: IgE bind to mast cells and basophils via FcRIAllergic respons

11、e: allergen once again enter the body bind with IgE (Fab) on mast cells and basophils cross-link of IgE cross-link of FcRI activation of mast cells degranulation release of mediators anaphylaxis symptomsBiochemical Mediators released by mast cells: Primary mediators(preformed): heparin, histamine, n

12、eutral protease, eosinophil and neutrophil chemotactic factors, provoke early phase(immediate).组胺与组胺受体1结合诱导血管扩张和通透性增强，刺激外分泌腺的分泌。 Secondary-mediators(newly-synthesized):leukotrienes,PGD2(Prostaglandin,D2）,PAF,CKs(cytokines), induce late phase reaction.1) Immediate reaction（early phase response）: in a

13、 few seconds to sustain保持 for a few hours majors mediators, e.g. histamine, prostaglandin main function changes：the permeability of blood vessel increased the smooth muscle rapidly contract2) late-phage reactions during 46 hours after stimulus of Ag to sustain for a few days or more long time locali

14、zed inflammation：the infiltration of cells,eosinophil(30%), neutrophil, Macrophage, Th2, basophilv Typical disease of anaphylaxis一）Systemic anaphylaxis全身过敏反应 -anaphylaxis shock (过敏性休克): fatal1. Anaphylaxis shock by drugs Drugs: penicillin、Xylocaine (利多卡因)、streptomycin (链霉素) etc.2. Anaphylaxis shock

15、by heterogeneous serum抗毒素血清，如破伤风和白喉抗毒素血清 anti-toxin : anti-tetanus, anti-diphtheria serum; venom (毒液) from bee or snake二）Localized anaphylaxis 局部过敏反应(atopy先天性过敏症)Typical diseases: asthma哮喘, hayfever花粉热, eczema, food allergyv Therapy of Type I Hypersensitivity1. Avoidance of allergen远离变应原Find allerge

16、n：best if possible, but often impractical, skin test.2. 急性脱敏治疗 (acute desensitization)Repeated injection of increasing doses (0.1ml、0.2ml、0.3ml) every 2030 mins；Appl: 外毒素所致疾病危及生命又对抗毒素血清过敏者。Fatal snake / bee bites but allergic to anti-toxin serum3. 慢性脱敏治疗 (chronic desensitization)采用微量( g、ng)，长时间反复多次皮

17、下注射 hyodermal injection of traces of allergensappl：已查明且难以避免接触的环境中抗原如尘土、花粉、螨虫、霉菌类等的病人。4. DrugsSuppress immune response: dexamethasone (DXM) antihistamines; adrenaline, etc. Immediate adrenaline injection of adrenaline can rescue anaphylatic shock.Part II: Type II hypersensitivity由IgG或IgM类抗体与细胞表面的抗原结合

18、，在补体、吞噬细胞及NK细胞等参与下，引起的以细胞溶解或组织损伤为主的病理性免疫反应。v Mechanisms of Type II Hypersensitivity：1. allergens - 常为细胞性抗原 (cell antigens)；2. Mediated by IgG or IgM；3. Tissue or cell damage caused by: Opsonic adherence: phagocytosis Complement: membrane damage ADCC: cell destructionv 靶细胞及其表面抗原：正常组织细胞，改变的自身组织细胞和被抗原或

19、抗原表位结合修饰的自身组织细胞，均可称为型超敏反应中被攻击的靶细胞。靶细胞表面的抗原主要包括：1正常存在于血细胞表面的同种异型抗原，ABO血型抗原，Rh抗原和HLA抗原2外源性抗原与正常组织细胞之间具有的共同抗原，如链球菌胞壁的成分与心脏瓣膜有共同抗原3感染和理化因素所致改变的自身抗原。4结合在自身组织细胞表面的药物抗原表位或抗原-抗体复合物。v allergens1. allogenic Ag：ABO、Rh、HLA etc. 2. Ag attached to cells (tissues) or hapten：Ag on microbes and drug molecules as hap

20、tens 3. heterophilic Ag (异嗜性抗原)：same Ag structure shared by streptococcus and Heart valves or glomerular basement membrane v mechanisms causing tissue/ cell damage1.classical pathways of Complement activation cascade有补体受体IgG或IgM）+ Ag（on cells）activate complementMAC cell damage。 2. Opsonization：-IgG

21、+ Ag on cells bind to FcR(M) phagocytosis。-IgG（or IgM）+ Ag on cells C3b bind to CR (on phagocytes)phagocytosis of the Ag expressing cells。3. ADCCIgG + Ag on cells bind to FcR(on NK cells) killing of the Ag expressing cells。 v Type II associated diseases (常见疾病)(一）Transfusion reaction (输血反应) ABO血型不符的输

22、血: mismatched blood transfusion cause complement-mediated hemolysis.ABO blood group: isohemagglutinins (IgM)Prevention: Blood type test: cross-matching between donor and recipient blood(二）Heamolytic diseases of newbornRh incompatibility:Rh blood groupsRh- mother has the first Rh+baby, mother sensiti

23、zed by babys erythrocytes,anti-Rh IgGMother has the second Rh+ baby,IgG enter the fetus through placenta,destruction of fetal RBC(三）Autoantibodies Stimulate -Host Target Cell Receptors and Alter FunctionMyasthenia gravis 重症肌无力 an auto-Ab reacts with the acetylcholine receptor at the neuromuscular ju

24、nction Anti-acetylcholine receptors to block the binding of the neurotransmitter to stop neural stimulation of the muscle (antagonism) severe muscle weakness difficulty in chewing, swallowing & breathing(四）Drug-Induced Hemolytic Anemia Blood cell lysis,anemia(5）Graves disease 甲状腺功能亢进病患体内可产生针对甲状腺细胞表面

25、甲状腺激素受体的自身抗体，这种抗体与甲状腺细胞表面TSH受体结合，反而刺激甲状腺细胞合成分泌甲状腺素，引起甲状腺功能亢进。Part : Type hypersensitivity概念：由中等大小可溶性免疫复合物（immune complex，IC）沉积于局部或全身多处毛细血管基底膜后，通过激活补体和在一些效应细胞(如血小板、嗜碱性性粒细胞、中性粒细胞等)参与作用下，引起的以充血水肿、局部坏死和中性粒细胞浸润为主要特征的炎症反应和组织损伤。一、发生机制（一）可溶性免疫复合物的形成与沉积1.中等大小免疫复合物（immune complex,IC）的形成 ： 抗原+抗体抗体抗原复合物 大分子的IC易

26、被吞噬细胞清除 小分子的IC不沉淀、易被滤过排出 中等大小IC存在于循环，可能沉淀2.导致中等大小可溶性免疫复合物的沉积的因素：(1)血管通透性增加(2）血管内高压及形成涡流免疫复合物易于沉积血压较高的毛细血管迂回处(例如：肾小球基底膜和关节滑膜)3. 导致免疫复合物的清除能力降低的因素 -补体功能障碍或补体缺陷 IC量过大，吞噬细胞功能异常或缺陷。(二）免疫复合物沉积引起的组织损伤1.补体的作用 免疫复合物激活补体经典途径 C3a、C5a 与相应受体(肥大细胞或嗜碱性粒细胞)结合释放组胺等炎性介质局部毛细血管通透性增加，渗出更多，出现水肿 免疫复合物激活补体经典途径 C3a、C5a 趋化中性

27、粒细胞至免疫复合物沉积部位2.中性粒细胞的作用 中性粒细胞 吞噬免疫复合物 释放溶酶体酶(包括蛋白水解酶、胶原酶和弹力纤维酶) 水解，损伤周围组织。3.血小板的作用 肥大细胞及嗜碱性粒细胞活化 释放血小板活化因子 激活血小板 1促凝血，形成血栓 局部缺血、坏死2释放血管活性胺 血管通透性进一步加重水肿组织损伤特点： 血管扩张、渗出； 中性粒细胞浸润； 出血坏死及血栓为特征的血管炎。二临床常见疾病(一)局部免疫复合物病(二）全身免疫复合物病1.血清病 抗毒素血清(大量) 机体 产生抗体与抗原(局部尚未被完全排除)结合 局部红肿、全身皮疹、发热、关节肿痛、淋巴结肿大、肾损伤等症状及体征。2.链球菌

28、感染后肾小球肾炎（免疫复合物型肾炎）溶血性链球菌（可溶性抗原）机体 产生抗体 形成免疫复合物 沉积于肾小球基底膜肾小球肾炎。(一般发生在A族溶血性链球菌感染后2-3周，此时体内产生大量抗链球菌抗体。)3.系统性红斑狼疮 细胞核物质(如DNA、RNA、核内可溶性蛋白)抗原 抗核抗体 沉积于全身各个部位 引起损伤。诊断：血液检查抗核抗体，抗体滴度升高，检查SLE特异性的抗体ds-DNA，ds-DNA升高，血清中C3水平降低，正常是100-200 mg/dl.4.类风湿性关节炎 变性IgG(抗原) 抗变性IgG的抗体(IgM类，称为类风湿因子)形成免疫复合物 沉积于全身小关节滑膜处 小关节红肿、变形

29、僵直、失去运动功能。(一些病毒感染或其病原体的代谢产物，使体内的IgG分子发生了变性，从而刺激机体产生抗变性IgG的自身抗体，主要以IgM为主，称为类风湿因子。当自身变性IgG与类风湿因子结合形成的免疫复合物反复沉积于小关节滑膜时即可引起风湿性关节炎）Part : Type hypersensitivity-是效应T细胞同特异性抗原作用后，引起的以单个核细胞浸润和组织损伤为主要特征的炎症反应。特点：1参与的效应T细胞 - CD4+Th1(主要)和CD8+CTL细胞；2以单个核细胞侵润为主要特征的炎症反应；3发生较慢，在接触相同抗原后2472小时后发生炎症反应。4无抗体和补体参与。5与效应T细胞

30、和吞噬细胞及其产生的细胞因子或细胞毒性介质有关。一、发生机制（一）抗原与相关细胞：胞内寄生菌，病毒，寄生虫和化学物质（二）T细胞介导炎症反应和组织损伤1. CD4+Th1细胞介导的炎症反应和组织损伤：效应T细胞识别抗原后活化，释放多种细胞因子，其中MCP-1可趋化单个核细胞到达抗原部位；TNF-和LT-可使局部血管内皮细胞黏附分子的表达增加，促进巨噬细胞和淋巴细胞至抗原存在部位聚集，并可直接对靶细胞及其周围组织细胞产生细胞毒作用，引起组织损伤。IFN-和TNF-可使巨噬细胞活化，并释放促炎症细胞因子IL-1，TNF-加重炎症反应。 2. CD8+CTL细胞介导的细胞毒作用：CTL释放穿孔素和颗粒酶等介质，使靶细胞溶解或凋亡。二、临床常见IV超敏反应1.感染性迟发型超敏反应性疾病：如结核、麻风及某些原虫感染等。结核杆菌侵入巨噬细胞巨噬细胞活化细菌被杀死；细菌抵抗杀伤 形成肉芽肿。 肉芽肿中心：由巨噬细胞融合形成的巨细胞构成，在缺氧和巨噬细胞的细胞毒作用下，形成干酪样坏死。 2.接触性皮炎 半抗原（小分子）+ 蛋白质（体内）朗格汉斯细胞摄取、处理、递呈Th1细胞 皮肤炎症反应（红肿、皮疹、水疱）。小 结