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Chapter 16 Hypersensitivity Reaction I . Hypersensitivity reaction II. Type I Anaphylactic Reactions III. Type II Antibody-mediated cytotoxic hypersensitivity IV. Type III Immune complexmediated hypersensitivity V. Type IV T cell-mediated hypersensitivity 教学大纲 掌握超敏反应的概念、各型超敏反应的 特点及发生机制; 熟悉各型超敏反应引起的常见临床疾病。 了解I型超敏反应的防治原则 Hypersensitivity reaction 1. Concept 2. Types of Hypersensitivity Reaction 1. Concept Under some circumstances, immunity, rather than providing protection, produces damaging and sometimes fatal results. Such deleterious reactions are known collectively as hypersensitivity reactions, but it should be remembered that they differ from protective immune reactions only in that they are exaggerated or inappropriate and damaging to the host. The cellular and molecular mechanisms of the two types of reaction are virtually identical. 2. Types of Hypersensitivity Reaction Hypersensitivity reaction were divided into four classes, designated types I- IV, by Gell and Coombs Type I: Anaphylactic Reactions Type II: Antibody-mediated cytotoxic hypersensitivity Type III: Immune complex-mediated hypersensitivity Type IV: T cell-mediated hypersensitivity Type I: Anaphylactic Reactions 1. Concept of Type I 2. Characteristics of type I 3. Mechanism of type I a. Sensitization phase b. Activation phase c. Effect phase 4. Clinical aspects of type I 1. Concept of type I Anaphylactic reaction are mediated by IgE antibodies, which bind to receptors on mast cells and basophils. When cross-linked by antigen, the IgE antibodies trigger the mast cells (basophils) to release several pharmacologically active agents that are responsible for the characteristic symptoms of anaphylaxis. Reactions are rapid, occurring within minutes after challenge antigen. mediated by IgE IgE bind to FcR on mast cells and basophils release several pharmacologically active agents Reactions are rapid, occurring within minutes Allergens associated with Type I hypersensitivity Proteins :foreign serum Plant pollens Insect products :bee or wasp venom Mold spores , dust mites Animal hair and dander Foods : seafood , Eggs, milk Drugs :penicillin ,sulfonamides ,local anesthetics 2. Characteristics of type I a. Anaphylactic reaction are rapid, occurring within minutes after challenge, exposure to same antigen. Its reaction has its peak within 10-15 minutes; then it fades without leaving any residual damage, if it isn’t fatal. b. IgE antibodies-mediated and IgG4(a little), without IgA, IgM, IgG1,2,3 and complements. 2. Characteristics of type I C .The mast cells and basophils are the main effectors of type I reaction, and many pharmacologically active agents released by the mast cells and basophiles. d. The symptoms of anaphylaxis seen in systemic reactions. This would induce a typical wheal and flare reaction consisting of blood vessel dilation and increase in permeability and induce difficulty in breathing because of constriction of bronchiolar muscles, uterine cramps, or involuntary urination and defecation. e. The different individual have distinct difference. (individual difference) Characteristics without leaving any residual damage IgE , IgG4 mast cells and basophils release vasoactive mediators individual difference 3. Mechanism of type I Sensitization phase b. Activation phase c. Effect phase - preformed mediators - Newly synthesized mediators a. Mechanism: Allergen TCR MHC-II B cell Th cell CD4 Bm IL-4 Allergen Plasma cell IgE mast cell mast cell FcR Sensitized Degranulation Smooth muscle cell, Small blood vessel, Mucous gland, Blood platelets,Sensory nerve endings, Eosinophil, And so on. Principal mediators involved in type I hypersensitivity Mediator Activities primary 1. Histamine: Increased vascular permeability; Smooth muscle contraction. 2. Serotonin: Increased vascular permeability; Smooth muscle contraction. 3. Eosinophil chemotactic factor: (ECF-A) Eosinophil chemotaxis 4. Neutrophil chemotactic factor: (NCF-A) Neutrophil chemotaxis 5. Proteases: bronchial mucous secretion Degradation of blood-vessel basement Principal mediators involved in type I hypersensitivity Mediator Activities Secondary 1. Platelet-activating Platelet aggregation and degranulation. Factor:(PAF) Contraction of pulmonary smooth muscles. 2. Leukotrienes: Increased vascular permeability; ( SRS-A) Contraction of pulmonary smooth muscles. 3. Prostaglandins: Vasodilation; Contraction of pulmonary smooth muscles. Platelet aggregation. 4. Bradykinin: Increased vascular permeability; Smooth-muscles contraction. 4. Clinical aspects of type I a. Anaphylactic shock ( drug anaphylactic reaction) b. Anaphylactic reaction of respiratory system ( bronchial asthma ) c. Allergic dermatitis (eczema) d. Intestinal allergy 初次接触 花粉 B细胞产生 特异性IgE 再次接触 花粉 IgE结合于肥大 细胞的FcεRⅠ 脱颗粒 花粉症 penicillin degrade 青霉噻唑酸及青霉烯酸 (hapten) protein (carrier) hapten-carrier complex clinical symptoms (mechanism) sensitive state Release bioactive mediators Activation phase Type-I hypersensitivity The common allergy Many organ are be affected by “allergy” The nasopharynx Rhinorrhea Many organ are be affected by “allergy” The nasopharynx Nasal polyp Many organ are be affected by “allergy” The nasopharynx Tonsillitis Many organ are be affected by “allergy” The skin Urticaria hives Many organ are be affected by “allergy” The skin Eczema(湿疹) Many organ are be affected by “allergy” The eye Conjunctivitis (结膜炎) Ⅰ型超敏反应的防治原则 Hyposensitization III. Type II: Antibody-mediated cytotoxic hypersensitivity 1. Concept of type II 2. Characteristics of type II 3. Mechanism of type II 4. Clinical aspects of type II 1. Concept of type II A type II hypersensitivity reaction (cytotoxic reaction) occur when IgM or IgG antibodies bind to antigen on the surface of cells and activate the complement cascade, leading to cell damage through complement-mediated lyses or Ab-dependent cell-mediated cytotoxicity (ADCC). cytotoxic reaction IgM or IgG bind with Ag Mechanism of damage complement activation and ADCC Several antigens of type II Allogenic antigen Forssman Ag autoantigen Foreign antigen or hapten 2. Characteristics of type II a. IgM and IgG antibodies-mediated b. In type II hypersensitivity binding of the appropriate antibody directly to an antigen on the surface of a cell produces damage to that cell through a variety of mechanisms. 2. Characteristics of type II c. The mechanisms of type II hypersensitivity involve either the complete complement sequence and eventual lyses of the cell or opsonic effects mediated by receptors for Fc or C3b, which lead to phagocytosis and destruction of the cell by macrophages, neutrophils and NK cells (ADCC). 3. Mechanism of type II Cell-surface Ag Fc 1. NK IgG Target cell 3. Cytotoxic action (ADCC) CR 2. Antibody C Phagocyte Target cell Complement mediated lyses opsonization 4. Clinical aspects of type II a. Transfusion reactions b. Rh incompatibility reaction* c. Drug-induced reaction d. Autoimmune type II hypersensitivity -- Autoimmune haemolytic anemia -- Goodpasture’s syndrome -- Anti-receptor auto-antibody disease -- Anti-hormone auto-antibody disease Haemolytic disease of the newborn First birth postborn subsequent pregnancy RhD mother RhD red cells Bcell Anti-Rh IgG Anti-RhD lysis RhD fetus RhD fetus 免疫性血细胞减少症 自身免疫性溶血性贫血 + 药物 自身抗体 药物过敏性血细胞减少症 毒 性 甲 状 腺 肿 的 发 病 机 制 Type III Immune complex-mediated hypersensitivity 1. Concept of type III 2. Characteristics of type III 3. Mechanism of type III 4. Clinical aspects of type III Systemic lupus erythematosus 1. Concept of type III A type III hypersensitivity -Immune complex reaction--occur when complexes of antigen and IgM or IgG antibody accumulate in the circulation or in tissue and activate complement. Neutrophils are attracted to the site of activation, and damage results from the release of lytic enzymes from their granules. Reaction occur within hours of challenge with antigen. 2. Characteristics of type III a. IgM and IgG-mediated b. When antigen and antibody meet at the appropriate concentrations, they form insoluble antigen-antibody complexes(IC). 2. Characteristics of type III c. IC can activate the complement cascade. Release C3a and C5a causes a local increase in vessel permeability and permits the release of serum (edema) and chemotactic attraction of neutrophils. The neutrophils release degradative lysosomal enzymes that produce tissue damage. 2. Characteristics of type III d. IC accumulate in or near vessel walls and deposit in such tissues as kidney , joints, or skins. If the site of reaction is a vessel wall, the outcome is hemorrhage and necrosis; If the site is a glomerular basement membrane, loss of integrity and release of protein and red blood cells into the urine results; and if the site is a joint meniscus, destruction of synovial membrane and cartilage occurs. 3. Mechanism of type III a. Immune complexes production and deposition The amounts of antibodies and deposition Immune complexes size and deposition The sites of deposition of the complexes b. The mechanisms of damage 3. Mechanism of type III Antigen+antibody Platelets Immune complexes Complement Microthrombi Vasoactive Anaphylatoxins amines Mast cell Vasoactive amines Macrophages lysis Attract Neutrophils Activation and release of IL-1 and reactive Oxygen intermediates Release granular Increased vascular permeability contents Vasodilation Immune complex deposit Activating complement Mediate mast-cell and basophil Activating platelet C3a. C5a.C567 chemotaxis Releasing vasoactive Neutrophil infiltrating microthrombosis Capillary permeability Releasing lysosomal Tissue Ischemic ,necrosis Local congestion, edema vasculitis 4. Clinical aspects of type III a. Arthus’ reaction b. Serum sickness c. Infection-associated syndrome - glomerulonephritis - Rheumatic fever - Rheumatoid arthritis - Other infectious diseases Arthus’ reaction Inject Ag intradermally or subcutaneously into an animal, produce specific Ab ,form localized IC IC mediate acute Arthus reaction within 4-8h Localized tissue and vascular damage :edema , erythema , tissue necrosis Serum sickness 返回 Serum sickness Inject foreign protein (horse serum ) , leads to Ab response ,Ab binds with circulating Ag to form IC IC activate complement and phagocyte , cause fever; deposited in small vessels , lead to vascular nephritis and arthritis. Clinical symptoms: fever , joint tenderness , urticaria , proteinuria Systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Auto-antibodies to a vast array of tissue antigens , such as DNA , histones , RBCs ,platelet ,leukocyte , and clotting factors. Hemolytic anemia , thrombocytopenia IC deposit in small blood vessel, cause vasculitis and glomerulonephritis . Rheumatoid Arthritis Auto-antibodies (rheumatoid factor) , reactive with determinants in the Fc region of IgG. Auto-Ab bind with circulating IgG ,form complexes that are deposited in joints. Activate complement ,lead to chronic inflammation of the joints. Rheumatoid Arthritis Type IV: T cell-mediated hypersensitivity 1. Concept of type IV 2. Characteristics of type IV 3. Mechanism of type IV 4. Clinical aspects of type IV Poison ivy / poison oak reaction active hapten molecule Contact dermatitis reaction to mango sap Contact dermatitis reaction to leather 1. Concept of type IV called delayed-type hypersensitivity(DTH)--is mediated by T cells rather than by antibody. Upon activation, the T cells release cytokines that cause accumulation and activation of macrophages, which, in turn release lysosomal enzymes that cause local damage. This type of reaction has a delayed onset and may occur 1-2days after challenge with antigen. 2. Characteristics of type IV a. DTH, when activated by contact with an antigen presented by APC, T cells release soluble mediators, cytokines, some of which attract and activate other mononuclear cells such as monocytes, macrophages, and lymphocytes. b. This type of reaction has a delayed onset and may occur 1-2 days after challenge with Ag. 2. Characteristics of type IV c. The reaction reveals that the mononuclear infiltrates appear as a perivascular region before extensively invading the site of deposition of antigen. Later reaction show a more complexes pattern, with the arrival of lymphocytes and the formation of granuloma in persistent lesions. d. The reaction have not apparent individual difference. 3. Mechanism of type IV antigen T cell Inflammatory mediators cytokines Activated macrophages 4. Clinical aspects of type IV Dermatitis a. Contact Sensitivity ( skin inflammatory reaction) b. Allograft Rejection (HVGR) c. Graft Versus Host Reaction (GVHR) d. Infectious Disease Mycobacterium tuberculosis (传染性变态反应) OT test AID-DTH insulin-Dependent diabetes mellitus (IDDM) Multiple Sclerosis (MS) 多发性硬化症 Hashimoto’s Thyroiditis 桥本甲状腺炎 Inflammatory Bowel Disease (IBD) 炎性肠病 Crohn’s disease ulcerative colitis Ⅰ、Ⅲ、Ⅳ型超敏反应皮肤实验 1:15分钟出现1cm的界限清晰的风团 2:5-12小时出现超过5cm的红肿、出血、坏死 3:24-48小时出现的1cm的红肿、硬结 Granuloma in a leprosy patient Questions Describe the types and features of hypersensitivity . Which kind of hypersensitivity reaction disease can penicillin cause? Describe their developmental mechanism.