《医学免疫学英文版课件：Hypersensitivity (超敏反应)》由会员分享，可在线阅读，更多相关《医学免疫学英文版课件：Hypersensitivity (超敏反应)（88页珍藏版）》请在金锄头文库上搜索。
1、Hypersensitivity (超敏反应)Chapter 17oHypersensitivity Some immune responses can give rise to an excessive or inappropriate reaction, resulting in significant tissue damage or even death. oThe classification: type IIVRobin Coombs 1921 - 2006I I型型 - - 速发型速发型 （IgEIgE）II II型型 - - 细胞毒型（细胞毒型（IgGIgG，IgMIgM）II
2、IIII型型 - - 免疫复合物型（免疫复合物型（IgGIgG）IVIV型型 - - 迟发型（迟发型（T TDTHDTH）-Philip George Houthem Gell1914 - 2001Types of hypersensitivity diseases. In the four major types of hypersensitivity reactions, different immune effector mechanisms cause tissue injury and diseaseType I hypersensitivity (immediate hyperse
3、nsitivity)Allergy(变态反应变态反应)Anaphylaxis（过敏反应）（过敏反应）初次注射海葵毒素无明显反应再次注射海葵毒素导致狗死亡Richet和Porteir提出了过敏反应的概念，二人因此获1913年诺贝尔奖。AnaphylaxisCarl Prausnitz-Giles 1876-1963Carl Prausnitz-Giles 1876-1963Type I hypersensitivityPrausnitz-Kustner test - “reagin”1921Heinz Kustner (1897-1963)Kimishige Ishizaka（1925-）and
4、 Teruka IshizakaReagin = IgE19661.Characteristics of Type I hypersensitivity1. Rapid: react and disappear quickly on re-exposure to Ag2. Dysfunction: dysfunction rather than severe tissue and cell damage occurs3. Strong hereditary tendency: obvious individual difference and genetic correlation oMedi
5、ated by IgE antibodies oTypical examples include polymorphisms of the promoter region for IL-4 and polymorphism of the gene for IL-5, either of which can directly influence the IgE production to allergens.oatopy: An IgE-dependent allergy often arising from exposure to an unknown Ag. 特应症，特应性个体特应症，特应性
6、个体oAllergen is an antigen that gives rise to immediate hypersensitivity. protein or chemicals For example: pollen, house dust mite, animal hair, dander, some foods, foreign serum, drugs. oAllergin is a specific IgE that gives rise to immediate hypersensitivity.II. Components involved in type I hyper
7、sensitivityAllergen禾本科花粉豚草花粉长蠕孢子格链孢子IgEIgE分子及其受体分子及其受体 H2N NH2 HOOC COOHNH2NH2 COOH COOHFceRINH2NH2NH2 COOHFceRII IgE 分分 子子 及及 其其 两两 种种 Fc 受受 体体FcR（高亲和力）：（高亲和力）： 肥大细胞和嗜碱性粒细胞高表达肥大细胞和嗜碱性粒细胞高表达FcR（CD23）（低亲和力）（低亲和力） B、活化、活化T细胞、单核巨噬细胞、细胞、单核巨噬细胞、FDCITAMoThe majority of humans mount significant IgE respons
8、e only as a defense against parasitic infections. After an individual has been exposed to a parasite, serum IgE levels increase and remain high until the parasite is successfully cleared from the body.oAtopic individuals allow non-parasitic Ags to stimulate inappropriate IgE production, leading to t
9、ype I hypersensitivity.oMost allergic IgE response occur on mucous membrane surfaces in response to allergens that enter the body by either inhalation or ingestion. mast cells, basophils and eosinophilsoMast cells are found throughout connective tissue, particularly near blood and lymphatic vessels.
10、oSome tissues, including skin and mucous membrane surfaces of the respiratory and gastrointestinal tracts, contain high concentrations of mast cells.oBasophils and eosinophils are granulocytes that circulate in the blood of most vertebrates.oMast cellsoBasophilsoEosinophils Mediators released by eos
11、inophil: eosinophil cationic protein（阳离子蛋白）（阳离子蛋白） eosinophil peroxidase （过氧化物酶）（过氧化物酶） LTs（白三烯）（白三烯）, PAF（血小板活化因子）（血小板活化因子）, etc.They express Fc RI Their granulated cytoplasm contain pharmacologically active mediators III. Pathogenic mechanisms Th1 (IFN- , IL-12)oallergenbodyB cell Th2 (IL-4) Fc Ig
12、Emasts cell or basophils (Fc RI ) Ag cross-linking IgE on Fc R signal transduction occurring through the chain of Fc RI the mediators are degranulation synthesized and releasedRe-exposureThe sequence of events in immediate hypersensitivityThe activation of mast cellsC, D: light micrographsE, F: elec
13、tron micrographsBiochemical events in mast cell activation. Cross-linking of IgE on a mast cell by an allergen initiates multiple signaling pathways from the signaling chains of the Fc RI, including the phosphorylation of ITAMs. These signaling pathways stimulate the release of mast cell granule con
14、tents (amines, proteases), the synthesis of arachidonic acid metabolites (PG, LT), and the synthesis of various cytokines.IgE Antibody Binds To Mast Cells & Basophils To Arm Them For Mediator Release静息肥大细胞激活后 5 分钟激活后 60 分钟Mediators（介质）（介质）oThe preformed mediators include: histamine(组胺), kinnogenase(
15、激肽原酶), eosinophil chemotactic factor of anaphylaxis (ECF-A) oThe mediators newly synthesized include: prostaglands (PG,前列腺素), leukotrienes (LTs, 白三烯), platelet activating factor (PAF, 血小板活化因子), cytokines (IL-4, IL-13) phospholipid phospholipase A2 arachidonic acid (花生四烯酸) cyclooxygenase 5-lipooxygen
16、ase postaglandins leukotrienesArachidonic Acid Metabolites1. cyclooxygenase products: prostaglandins (PG) PGD22. lipooxygenation products: leukotrienes (LTs) LTB4, LTC4, LTD4, LTE4. LTB4 is a potent chemoattractant. LTC4, LTD4 and LTE4 induce smooth muscle contraction, bronchoconstriction, and secre
17、tion in the airways and the reaction in the skin. platelet activating factor (PAF) PAF is synthesized and released, along with histamine and leukotrienes, by mast cells and platelets. 花生四烯酸代谢产物花生四烯酸代谢产物Immediate phaseoThe immediate phase of the inflammatory response is due to preformed mediators (es
18、pecially histamine) stored in the mast cell granules and also to certain rapidly synthesized arachidonate derivatives. It reaches maximal intensity within about 15 minutes after antigen re-exposure.oThis phase is characterized grossly by erythema, localized edema in the form of a wheal, and pruritus
19、 (itching).oMicroscopic examination at this stage reveals only vasodilatation血 管 舒 张 and edema水 肿 . The granule contents, however, also induce local expression of the VCAM-1, as well as secretion of chemokines, which recruit subsequent inflammatory cells to the site.Late phaseoManifestation of the l
20、ate phase are due in part to presynthesized TNF- and in part to other mediators (principally PAF, LT, IL-4, etc.) whose synthesis begins after the mast cell degranulates.oThe effects of these mediators become apparent about 6 hours after antigen contact and are marked by an infiltration of eosinophi
21、ls and neutrophils.oClinical features of the late phase include erythema红斑, induration硬结, warmth, pruritus瘙痒, and a burning sensation at the affected site. Fibrin deposition纤维素沉积 probably occurs transiently. TNF- not only functions in the short term as a leukocyte chemokine but also can stimulate lo
22、cal angiogenesis, fibroblast proliferation, and scar formation during prolonged hypersensitivity reactions.IV. Type I hypersensitivity- associated diseasesoThe clinical manifestations of type I hypersensitivity can range from serious life-threatening conditions, such as systemic anaphylaxis and asth
23、ma, to hay fever (枯草热枯草热) and eczema（湿疹）（湿疹）, which are merely annoying.Clinical manifestations of immediate hypersensitivity reactionsoSystemic anaphylaxis is a shock-like and often fatal state whose onset occurs within minutes of a type I hypersensitivity reaction. If not treated quickly, these re
24、actions can be fatal.oAllergens: penicillin, antitoxin, etc.1. Systemic anaphylaxis (shock)2. Localized anaphylaxis (atopy)oAllergic rhinitis It is the most common atopic disorders. It results from the reaction of airborne allergens with sensitized mast cells in the conjunctivae and nasal mucosa to
25、induce the release of pharmacologically active mediators from the mast cells. These mediators then cause localized vasodilation and increased capillary permeability. The symptoms include watery exudation of the conjunctivae, nasal mucosa, and upper respiratory tract, as well as sneezing and coughing
26、.lBronchial asthmaoIn some cases, airborne or blood-borne allergens, such as pollens, dust, fumes, insect products, or viral antigens, trigger an asthmatic attack.oAsthma is triggered by degranulation of mast cells with release of mediators, but instead of occurring in nasal mucosa, the reaction dev
27、elops in the lower respiratory tract. The resulting contraction of bronchial smooth muscles leads to bronchoconstriction. Anaphylaxis to foodsoVarious foods can induce localized anaphylaxis in allergic individuals. Allergen crosslinking of IgE on mast cells along the upper and lower gastrointestinal
28、 tract can induce localized smooth muscle contraction and vasodilation.oVomiting and diarrhea are the most common symptoms of food allergies.荨麻疹 Atopic dermatitis 特应性皮炎，湿疹特应性皮炎，湿疹oAtopic dermatitis is an inflammatory disease of skin that is frequently associated with a family history of atopy.oThe d
29、isease is observed most frequently in young children, often developing during infancy.oThe reaction is characterized by infiltration of neutrophils, eosinophils, macrophages, lymphocytes, and basophils.oThe localized late-phase response also may be mediated by cytokines released from mast cells.V. I
30、mmunoprophylaxis & immunotherapy1. Skin test to identify allergen and avoid the offending allergen2. Hyposensitization or desensitization with allergens1) For antitoxin: stimulation with small dose of Ag provokes a minimal amount of mediators release, and the latter are rapidly resolved.2) For speci
31、fic allergensoGradually increasing quantities of Ag are injected subcutaneously.oThis is a form of immunotherapy aimed at stimulating the production of IgG blocking antibody that binds the offending antigen and prevents its combining to IgE.oThe response to treatment includes an increase in IgG anti
32、bodies, a decrease in IgE antibodies in the serum.Type II hypersensitivity(cytotoxic type)oType II hypersensitivity reactions are mediated by IgG and IgM antibody binding to specific cells or tissues. The damage caused is thus restricted to the specific cells or tissues bearing the antigen.oThe anti
33、bodies damage cells and tissues by activating complement, and by binding and activating effector cells carrying Fc R.I. Pathogenic mechanisms Ags on the surface of target cells bodyIgG, IgM 1. damage the target cell 1) activation of complement 2) opsonization: FcR, C3bR 3) ADCC: NK cells, M 2. targe
34、t cell dysfunctionNK cellopsonizationEffector mechanisms of Ab-mediated diseasesGraves diseaseIn myasthenia gravis the Abs against Ach receptor inhibit neuromuscular transmission and cause paralysisII. Clinical disease1. Transfusion reactionsA型血A型血抗原A型血输入B型血体内B型血体内存在抗A抗体补体抗原抗体反应输血活化血细胞溶解2. Hemolytic
35、 disease of the newbornMainly occurs when an Rh- mother gives birth to an Rh+ infant.Prevention: The administration of anti-Rh Ab to an Rh- mother within 72 hours of delivering an Rh+ infant will prevent sensitization and problems with subsequent pregnancies. 母体内的IgG与胎儿体内的Rh抗原结合，导致胎儿出生后发生新生儿溶血症。3. A
36、utoimmune hemolytic disease Some drugs or viruses stimulate Ab formation by changing the erythrocyte surface components to form new epitopes. The resulting Abs can cross react with epitopes on unmodified RBCs.Human antibody-mediated diseases4. Drug-induced reaction to blood components These diseases
37、 have been associated with many different chemotherapeutics, such as penicillin, the sulfonamides. These drugs stimulate Ab formation by forming new epitopes with serum proteins, which then adsorb nonspecifically to the red blood cell surface so that its new epitopes are expressed.5. Graves disease
38、The patients produce antibodies to thyrotropin (thyroid stimulating hormone, TSH) receptor. The end result is overproduction of thyroid hormone and hyperthyroidism.Type III hypersensitivity(immune complex type)Immune complexes (IC) deposit in basement membranes of small blood vessels in various orga
39、ns.I. Pathogenic mechanisms AgbodyIgG, IgM, IgA immune complexes (IC) soluble IC ICs are deposited from the circulation into vascular basement membranes FcRactivation of complement plat. and basophils C3a, C5a mast cell release of vasoactive amines basophils Neutrophils vasodilation lysosomal edema
40、enzymesdamage the tissueaggravateDeposition of IC in tissuesoAn increase in vascular permeability通透性通透性 In general, complement, mast cells, basophils and platelets must all be considered as potential producers of vasoactive amines.oLocal high blood pressure and turbulence涡流涡流 The blood pressure in t
41、he glomerular capillaries is approximately four times that of most other capillaries.IC are capable of triggering a variety of inflammatory processesoICs interact with the complement system to generate C3a and C5a. These complement fragments stimulate the release of vasoactive amines and are chemota
42、ctic factors for mast cells and basophils, eosinophils and neutrophils.oICs interact directly with basophils and platelets (via FcR) to induce the release of vasoactive amines.oNeutrophils exocytose their lysosomal enzymes onto the site of IC deposition and damage the underlying tissue.II. Clinical
43、diseases1. Arthus reaction An animal is immunized repeatedly until it has appreciable levels of serum Ab (mainly IgG). Following subcutaneous or intradermal injection of the antigen a reaction develops at the injection site, sometimes with marked edema and hemorrhage.Nicolas Arthus 1862-1945Nicolas
44、Arthus 1862-1945Arthuss reaction （1903）经抗原反复免疫之后,注射抗原的皮下出现局部红肿、出血和坏死等剧烈炎症反应。C3aC5a 肥大细胞 血小板补体抗体抗原内皮细胞 复合物血管活性胺C5a 中性粒细胞 血小板凝聚 免疫复合物沉淀趋化活性酶微血栓形成基底膜血管壁122. Serum sickness血清病血清病 Serum sickness is a complication of serum therapy, in which massive doses of anti-serum are given in conditions such as snake
45、 bite. Serum sickness（血清病）Clemens Pirquet 1874-1929Clemens Pirquet 1874-19293. Postinfectious glomerulonephritis常见于A族溶血性链球菌感染后2-3周。抗体与链球菌可溶性抗原形成复和物，沉积于肾小球基底膜处Human immune complex disease4. Rheumatoid arthritis类风湿性关节炎类风湿性关节炎oRheumatoid factor (RF): an immunoglobulin (mainly IgM but also IgG and IgA)
46、with antibody specificity for the Fc portion of IgG.oThe joint synovial fluid contains IC consisting of RF-IgG-complement.oMany patients with rheumatoid arthritis also have antinuclear antibodies.5. Systemic lupus erythematosus (SLE) 系统性红斑狼疮系统性红斑狼疮oantinuclear antibodiesohypergammaglobulinemia 自身抗体与
47、可溶性自身抗原形成免疫复和物，沉积于皮下、关节和肾小球基底膜等处。RA，SLESLEType IV hypersensitivity(Delayed type hypersensitivity) 迟发型迟发型oDelayed type hypersensitivity is initiated by sensitized T cells reacting with specific antigens. The reactions are manifest as inflammation at the site of antigen exposure, which usually peaks 2
48、4-72 hours after exposure.oThis reaction is independent of antibody and complement.I. Pathogenic mechanisms Ag-MHC AntigenAPCT cells co-stimulating factors sensitized T cell effector and memory cells CD4+T cell (Th1 type) CD8+T cell (CTL) release of cytokines killing target cells by the release of i
49、nducing the inflammatory perforin and granzymesresponse or by the FasL-Fas pathway(primarily M and T cells)Mechanisms of T cell-mediated tissue injury o II. Clinical diseases1. Infectious DTH In the infective process, intracellular parasitical bacteria (Mycobacterium tuberculosis结核结核, Mycobacterium
50、leprae麻风麻风, Brucella布鲁氏菌布鲁氏菌), viruses and fungi cause T cell-mediated immune responses, which are referred to as infectious delayed type hypersensitivity.肉芽肿样超敏反应：致病因子持续存在于巨噬细胞内肉芽肿样超敏反应：致病因子持续存在于巨噬细胞内干酪样坏死干酪样坏死结核菌素试验结核菌素试验Tuberculin-type hypersensitivityThe tuberculin skin test (OT) reaction princi
51、pally involves M tuberculinbodyT cells are activated IFN- M TNF , IL-1 endothelial cells in dermal blood vessels express CAM: E-selectin, ICAM-1, VCAM-1 recruiting monocytes and T cells (Monocytes constitute 80-90% of the total cellular infiltrate)Tuberculin-like delayed type hypersensitivity reacti
52、on are used practically in two ways.1) To confirm past infection with M. tuberculosis, but not necessarily active disease.2) To be a general measure of cell-mediated immunity. 2. Contact dermatitisoLangerhans cells and keratinocytes acting as APCs have key roles in contact hypersensitivity.oKeratino
53、cytes produce a range of cytokines.oA contact hypersensitivity reaction has two stages: sensitization and elicitation. Sensitization produces a population of memory T cells and elicitation involves recruitment of CD4+ lymphocytes and macrophages.接触橡胶接触羽毛oMany important sensitizing allergens are orga
54、nic chemicals, and some are metals such as nickel, chromate. It is assumed that they function as haptens.oWhen allergen again penetrates the skin, these memory cells rapidly evolve into effectors that mediate a delayed-type hypersensitivity reaction at the site of penetration.T cell-mediated disease
55、sComparison of 4 types of hypersensitivityREVIEW QUESTIONSoWhat types of antigens may induce immune responses that cause hypersensitivity reactions? oWhat is the sequence of events in a typical immediate hypersensitivity reaction? What are some examples of immediate hypersensitivity disorders?oWhat
56、are some examples of diseases caused by IgG or IgM antibodies or immune complexes, what is their pathogenesis, and what are their principal clinical and pathologic manifestations?oWhat are some examples of diseases caused by T cells, what is their pathogenesis, and what are their principal clinical and pathologic manifestations?Thanks for your attention!oThank you very much for your support and cooperation in my teachingoIf you have any question and suggestion, please feel free to contact me: HAPPY NEW YEAR!HAPPY NEW YEAR!Enjoy your study!
