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Hypersensitivity (超敏反应) Qingqing Wang Institute of Immunology Zhejiang University School Of Medicine wqq@zju. edu. Hypersensitivity (超敏反应) Qingqing Wang Institute of Immunology Zhejiang University School Of Medicine [email protected] edu. cn

o Hypersensitivity Some immune responses can give rise to an excessive or inappropriate reaction, o Hypersensitivity Some immune responses can give rise to an excessive or inappropriate reaction, resulting in significant tissue damage or even death. o The classification: type I~IV

I型 ---- 速发型 (Ig. E) II型 ---- 细胞毒型(Ig. G, Ig. M) III型 ---- 免疫复合物型(Ig. I型 ---- 速发型 (Ig. E) II型 ---- 细胞毒型(Ig. G, Ig. M) III型 ---- 免疫复合物型(Ig. G) IV型 ---- 迟发型(TDTH) ----------------------- Robin Coombs Philip George Houthem Gell 1921 - 2006 1914 - 2001

Types of hypersensitivity diseases. In the four major types of hypersensitivity reactions, different immune Types of hypersensitivity diseases. In the four major types of hypersensitivity reactions, different immune effector mechanisms cause tissue injury and disease

Type I hypersensitivity (immediate hypersensitivity) Type I hypersensitivity (immediate hypersensitivity)

Richet和Porteir提出了过敏反应的概念, 二人因此获 1913年诺贝尔奖。 初次注射 海葵毒素 导致狗死亡 再次注射 海葵毒素 无明显反应 anaphylaxis Richet和Porteir提出了过敏反应的概念, 二人因此获 1913年诺贝尔奖。 初次注射 海葵毒素 导致狗死亡 再次注射 海葵毒素 无明显反应 anaphylaxis

Type I hypersensitivity Carl Prausnitz-Giles 1876 -1963 Type I hypersensitivity Carl Prausnitz-Giles 1876 -1963

1921 Prausnitz-Kustner test --- “reagin” 1921 Prausnitz-Kustner test --- “reagin”

1966 Reagin = Ig. E Kimishige Ishizaka(1925 -)and Teruka Ishizaka 1966 Reagin = Ig. E Kimishige Ishizaka(1925 -)and Teruka Ishizaka

1. Characteristics of Type I hypersensitivity 1. Rapid: react and disappear quickly on re-exposure 1. Characteristics of Type I hypersensitivity 1. Rapid: react and disappear quickly on re-exposure to Ag 2. Dysfunction: dysfunction rather than severe tissue and cell damage occurs 3. Strong hereditary tendency: obvious individual difference and genetic correlation

o Mediated by Ig. E antibodies o Typical examples include polymorphisms of the promoter o Mediated by Ig. E antibodies o Typical 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 Ig. E production to allergens. o ‘atopy’: An Ig. E-dependent allergy often arising from exposure to an unknown Ag.

II. Components involved in type I hypersensitivity o Allergen is an antigen that gives II. Components involved in type I hypersensitivity o Allergen 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. o Allergin is a specific Ig. E that gives rise to immediate hypersensitivity.

Allergen 格链孢子 禾本科花粉 长蠕孢子 豚草花粉 Allergen 格链孢子 禾本科花粉 长蠕孢子 豚草花粉

Ig. E分子及其受体 FcεRⅠ(高亲和力):αβγγ FcεRⅡ(CD 23)(低亲和力) Ig. E 分 子 及 其 两 种 Fc Ig. E分子及其受体 FcεRⅠ(高亲和力):αβγγ FcεRⅡ(CD 23)(低亲和力) Ig. E 分 子 及 其 两 种 Fc 受 体 NH 2 COOH H 2 N NH 2 COOH HOOC NH 2 COOH Fce. RI NH 2 Fce. RII

o The majority of humans mount significant Ig. E response only as a defense o The majority of humans mount significant Ig. E response only as a defense against parasitic infections. After an individual has been exposed to a parasite, serum Ig. E levels increase and remain high until the parasite is successfully cleared from the body. o Atopic individuals allow non-parasitic Ags to stimulate inappropriate Ig. E production, leading to type I hypersensitivity.

o Most allergic Ig. E response occur on mucous membrane surfaces in response to o Most allergic Ig. E response occur on mucous membrane surfaces in response to allergens that enter the body by either inhalation or ingestion.

 • mast cells, basophils and eosinophils o Mast cells are found throughout connective • mast cells, basophils and eosinophils o Mast cells are found throughout connective tissue, particularly near blood and lymphatic vessels. o Some tissues, including skin and mucous membrane surfaces of the respiratory and gastrointestinal tracts, contain high concentrations of mast cells. o Basophils and eosinophils are granulocytes that circulate in the blood of most vertebrates.

o Mast cells o Basophils o Eosinophils They express Fc RI Their granulated cytoplasm o Mast cells o Basophils o Eosinophils They express Fc RI Their granulated cytoplasm contain pharmacologically active mediators Mediators released by eosinophil: eosinophil cationic protein eosinophil peroxidase LTs, PAF, etc.

III. Pathogenic mechanisms Th 1 (IFN- , IL-12) o allergen→body→B cell← Th 2 (IL-4) III. Pathogenic mechanisms Th 1 (IFN- , IL-12) o allergen→body→B cell← Th 2 (IL-4) ↓ Fc Ig. E→masts cell or basophils (Fc RI ) ↓ Ag cross-linking Ig. E on Fc R ↓ signal transduction occurring through the chain of Fc RI ↓ the mediators are ← degranulation synthesized and released Re-exposure

The sequence of events in immediate hypersensitivity The sequence of events in immediate hypersensitivity

The activation of mast cells C, D: light micrographs E, F: electron micrographs The activation of mast cells C, D: light micrographs E, F: electron micrographs

Biochemical events in mast cell activation. Cross-linking of Ig. E on a mast cell Biochemical events in mast cell activation. Cross-linking of Ig. E 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 contents (amines, proteases), the synthesis of arachidonic acid metabolites (PG, LT), and the synthesis of various cytokines.

Ig. E Antibody Binds To Mast Cells & Basophils To Arm Them For Mediator Ig. E 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 静息肥大细胞 激活后 5 分钟 激活后 60 分钟

Mediators o. The preformed mediators include: histamine, kinnogenase, eosinophil chemotactic factor of anaphylaxis (ECF-A) Mediators o. The preformed mediators include: histamine, kinnogenase, eosinophil chemotactic factor of anaphylaxis (ECF-A) o. The mediators newly synthesized include: prostaglands (PG), leukotrienes (LTs, 白三烯), platelet activating factor (PAF), cytokines (IL-4, IL-13) phospholipid ↓phospholipase A 2 arachidonic acid (花生四烯酸) cyclooxygenase ↓ ↓ 5 -lipooxygenase postaglandins leukotrienes

 • Arachidonic Acid Metabolites 1. cyclooxygenase products: prostaglandins (PG) PGD 2 2. lipooxygenation • Arachidonic Acid Metabolites 1. cyclooxygenase products: prostaglandins (PG) PGD 2 2. lipooxygenation products: leukotrienes (LTs) LTB 4, LTC 4, LTD 4, LTE 4. LTB 4 is a potent chemoattractant. LTC 4, LTD 4 and LTE 4 induce smooth muscle contraction, bronchoconstriction, and secretion 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.

Immediate phase o. The immediate phase of the inflammatory response is due to preformed Immediate phase o. The immediate phase of the inflammatory response is due to preformed mediators (especially 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. o. This phase is characterized grossly by erythema, localized edema in the form of a wheal, and pruritus (itching). o. Microscopic examination at this stage reveals only vasodilatation and edema. 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 phase o Manifestation of the late phase are due in part to presynthesized Late phase o Manifestation of the late 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. o The effects of these mediators become apparent about 6 hours after antigen contact and are marked by an infiltration of eosinophils and neutrophils. o Clinical features of the late phase include erythema, induration, warmth, pruritus, and a burning sensation at the affected site. Fibrin deposition probably occurs transiently. TNF- not only functions in the short term as a leukocyte chemokine but also can stimulate local angiogenesis, fibroblast proliferation, and scar formation during prolonged hypersensitivity reactions.

IV. Type I hypersensitivityassociated diseases o The clinical manifestations of type I hypersensitivity can IV. Type I hypersensitivityassociated diseases o The clinical manifestations of type I hypersensitivity can range from serious life-threatening conditions, such as systemic anaphylaxis and asthma, to hay fever (枯草热) and eczema(湿疹), which are merely annoying.

Clinical manifestations of immediate hypersensitivity reactions Clinical manifestations of immediate hypersensitivity reactions

1. Systemic anaphylaxis (shock) o Systemic anaphylaxis is a shock-like and often fatal state 1. Systemic anaphylaxis (shock) o Systemic 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 reactions can be fatal. o Allergens: penicillin, antitoxin, etc.

2. Localized anaphylaxis (atopy) o Allergic rhinitis(过敏性鼻炎) It is the most common atopic disorders. 2. Localized anaphylaxis (atopy) o Allergic rhinitis(过敏性鼻炎) 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 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.

l Bronchial asthma o In some cases, airborne or blood-borne allergens, such as pollens, l Bronchial asthma o In some cases, airborne or blood-borne allergens, such as pollens, dust, fumes, insect products, or viral antigens, trigger an asthmatic attack. o Asthma is triggered by degranulation of mast cells with release of mediators, but instead of occurring in nasal mucosa, the reaction develops in the lower respiratory tract. The resulting contraction of bronchial smooth muscles leads to bronchoconstriction.

 • Anaphylaxis to foods o Various foods can induce localized anaphylaxis in allergic • Anaphylaxis to foods o Various foods can induce localized anaphylaxis in allergic individuals. Allergen crosslinking of Ig. E on mast cells along the upper and lower gastrointestinal tract can induce localized smooth muscle contraction and vasodilation. o Vomiting and diarrhea are the most common symptoms of food allergies.

荨麻疹 荨麻疹

 • Atopic dermatitis(特应性皮炎,湿疹) o Atopic dermatitis is an inflammatory disease of skin that • Atopic dermatitis(特应性皮炎,湿疹) o Atopic dermatitis is an inflammatory disease of skin that is frequently associated with a family history of atopy. o The disease is observed most frequently in young children, often developing during infancy. o The reaction is characterized by infiltration of neutrophils, eosinophils, macrophages, lymphocytes, and basophils. o The localized late-phase response also may be mediated by cytokines released from mast cells.

V. Immunoprophylaxis & immunotherapy 1. Skin test to identify allergen and avoid the offending V. Immunoprophylaxis & immunotherapy 1. Skin test to identify allergen and avoid the offending allergen 2. Hyposensitization or desensitization with allergens 1) For antitoxin: stimulation with small dose of Ag provokes a minimal amount of mediators release, and the latter are rapidly resolved.

2) For specific allergens o Gradually increasing quantities of Ag are injected subcutaneously. o 2) For specific allergens o Gradually increasing quantities of Ag are injected subcutaneously. o This is a form of immunotherapy aimed at stimulating the production of Ig. G blocking antibody that binds the offending antigen and prevents its combining to Ig. E. o The response to treatment includes an increase in Ig. G antibodies, a decrease in Ig. E antibodies in the serum.

Type II hypersensitivity (cytotoxic type) o Type II hypersensitivity reactions are mediated by Ig. Type II hypersensitivity (cytotoxic type) o Type II hypersensitivity reactions are mediated by Ig. G and Ig. M antibody binding to specific cells or tissues. The damage caused is thus restricted to the specific cells or tissues bearing the antigen. o The antibodies 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 ↓ body→Ig. G, Ig. I. Pathogenic mechanisms Ags on the surface of target cells ↓ body→Ig. G, Ig. M ↓ 1. damage the target cell 1) activation of complement 2) opsonization: Fc. R, C 3 b. R 3) ADCC: NK cells, M 2. target cell dysfunction

NK cell opsonization NK cell opsonization

Effector mechanisms of Ab-mediated diseases Graves’ disease In myasthenia gravis the Abs against Ach Effector mechanisms of Ab-mediated diseases Graves’ disease In myasthenia gravis the Abs against Ach receptor inhibit neuromuscular transmission and cause paralysis

II. Clinical disease 1. Transfusion reactions A型血输入B型血体内存在抗A抗体 抗原 抗体 反应 A型血抗原 活 化 A型血 II. Clinical disease 1. Transfusion reactions A型血输入B型血体内存在抗A抗体 抗原 抗体 反应 A型血抗原 活 化 A型血 输血 血细胞溶解 补体

2. Hemolytic disease of the newborn Mainly occurs when an Rh- mother gives birth 2. Hemolytic disease of the newborn Mainly 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Ig. G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。 母体内的Ig. G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. Autoimmune hemolytic disease Some drugs or viruses stimulate Ab formation by changing the 3. Autoimmune 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 diseases Human antibody-mediated diseases

4. Drug-induced reaction to blood components These diseases have been associated with many different 4. Drug-induced reaction to blood components These diseases 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 The patients produce antibodies to thyrotropin (thyroid stimulating hormone, TSH) receptor. 5. Graves’ disease 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 Type III hypersensitivity (immune complex type) Immune complexes (IC) deposit in basement membranes of small blood vessels in various organs.

I. Pathogenic mechanisms Ag→body→Ig. G, Ig. M, Ig. A ↓ immune complexes (IC) ↓ I. Pathogenic mechanisms Ag→body→Ig. G, Ig. M, Ig. A ↓ immune complexes (IC) ↓ soluble IC ↓ ICs are deposited from the circulation into vascular basement membranes ①↓ ② ↓Fc. R activation of complement plat. and basophils ↓ C 3 a, C 5 a →mast cell → release of vasoactive amines ↓ basophils ③ Neutrophils vasodilation aggravate ↓ lysosomal edema enzymes→damage the tissue

IC are capable of triggering a variety of inflammatory processes o ICs interact with IC are capable of triggering a variety of inflammatory processes o ICs interact with the complement system to generate C 3 a and C 5 a. These complement fragments stimulate the release of vasoactive amines and are chemotactic factors for mast cells and basophils, eosinophils and neutrophils. o ICs interact directly with basophils and platelets (via Fc. R) to induce the release of vasoactive amines. o Neutrophils exocytose their lysosomal enzymes onto the site of IC deposition and damage the underlying tissue.

Deposition of IC in tissues o An increase in vascular permeability In general, complement, Deposition of IC in tissues o An increase in vascular permeability In general, complement, mast cells, basophils and platelets must all be considered as potential producers of vasoactive amines. o Local high blood pressure and turbulence The blood pressure in the glomerular capillaries is approximately four times that of most other capillaries.

II. Clinical diseases 1. Arthus reaction An animal is immunized repeatedly until it has II. Clinical diseases 1. Arthus reaction An animal is immunized repeatedly until it has appreciable levels of serum Ab (mainly Ig. G). Following subcutaneous or intradermal injection of the antigen a reaction develops at the injection site, sometimes with marked edema and hemorrhage.

Nicolas Arthus 1862 -1945 Nicolas Arthus 1862 -1945

Arthus’s 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。 Arthus’s 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。

基底膜 1 2 内皮细胞 免疫复合物沉淀 抗原 抗体 复合物 中性粒细胞 补体 C 3 a C 基底膜 1 2 内皮细胞 免疫复合物沉淀 抗原 抗体 复合物 中性粒细胞 补体 C 3 a C 5 a 血小板凝聚 肥大细胞 C 5 a 趋化 微血栓形成 血管活性胺 活性 血管壁 酶

2. Serum sickness is a complication of serum therapy, in which massive doses of 2. Serum sickness is a complication of serum therapy, in which massive doses of anti-serum are given in conditions such as snake bite.

Serum sickness(血清病) Clemens Pirquet 1874 -1929 Serum sickness(血清病) Clemens Pirquet 1874 -1929

3. 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 抗原形成复合物,沉积于肾小球基底膜处 3. 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 抗原形成复合物,沉积于肾小球基底膜处

Human immune complex disease Human immune complex disease

4. Rheumatoid arthritis o Rheumatoid factor (RF): an immunoglobulin (mainly Ig. M but also 4. Rheumatoid arthritis o Rheumatoid factor (RF): an immunoglobulin (mainly Ig. M but also Ig. G and Ig. A) with antibody specificity for the Fc portion of Ig. G. o The joint synovial fluid contains IC consisting of RFIg. G-complement. o Many patients with rheumatoid arthritis also have antinuclear antibodies. 5. Systemic lupus erythematosus (SLE) o antinuclear antibodies o hypergammaglobulinemia

RA,SLE 自身抗体与可溶性自身抗原形成免疫复合物, 沉积于皮下、关节和肾小球基底膜等处。 RA,SLE 自身抗体与可溶性自身抗原形成免疫复合物, 沉积于皮下、关节和肾小球基底膜等处。

SLE SLE

Type IV hypersensitivity (Delayed type hypersensitivity) o Delayed type hypersensitivity is initiated by sensitized Type IV hypersensitivity (Delayed type hypersensitivity) o Delayed 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 24 -72 hours after exposure. o This reaction is independent of antibody and complement.

II. Clinical diseases 1. Infectious DTH In the infective process, intracellular parasitical bacteria (Mycobacterium II. Clinical diseases 1. Infectious DTH In the infective process, intracellular parasitical bacteria (Mycobacterium tuberculosis, Mycobacterium leprae, Brucella), viruses and fungi cause T cellmediated immune responses, which are referred to as infectious delayed type hypersensitivity.

I. Pathogenic mechanisms Ag-MHC Antigen→APC→T cells co-stimulating factors ↓ sensitized T cell ↓ effector I. Pathogenic mechanisms Ag-MHC Antigen→APC→T cells co-stimulating factors ↓ sensitized T cell ↓ effector and memory cells ↓ ↓ CD 4+T cell (Th 1 type) CD 8+T cell (CTL) ↓ release of cytokines ↓ inducing the inflammatory response (primarily M and T cells) ↓ killing target cells by the release of perforin and granzymes or by the Fas. L-Fas pathway

Mechanisms of T cell-mediated tissue injury Mechanisms of T cell-mediated tissue injury

o o

II. Clinical diseases 1. Infectious DTH In the infective process, intracellular parasitical bacteria (Mycobacterium II. Clinical diseases 1. Infectious DTH In the infective process, intracellular parasitical bacteria (Mycobacterium tuberculosis结核, Mycobacterium leprae麻风, Brucella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 干酪样坏死

结核菌素试验 结核菌素试验

Tuberculin-type hypersensitivity The tuberculin skin test (OT) reaction principally involves M tuberculin→body→T cells are Tuberculin-type hypersensitivity The tuberculin skin test (OT) reaction principally involves M tuberculin→body→T 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 reaction are used practically in two ways. 1) To confirm Tuberculin-like delayed type hypersensitivity reaction 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 dermatitis o Langerhans cells and keratinocytes acting as APCs have key roles 2. Contact dermatitis o Langerhans cells and keratinocytes acting as APCs have key roles in contact hypersensitivity. o Keratinocytes produce a range of cytokines. o A contact hypersensitivity reaction has two stages: sensitization and elicitation. Sensitization produces a population of memory T cells and elicitation involves recruitment of CD 4+ lymphocytes and macrophages.

接触羽毛 接触橡胶 接触羽毛 接触橡胶

o Many important sensitizing allergens are organic chemicals, and some are metals such as o Many important sensitizing allergens are organic chemicals, and some are metals such as nickel, chromate. It is assumed that they function as haptens. o When 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 diseases T cell-mediated diseases

Comparison of 4 types of hypersensitivity Comparison of 4 types of hypersensitivity

Thanks for your attention! o Thank you very much for your support and cooperation Thanks for your attention! o Thank you very much for your support and cooperation in my teaching o If you have any question and suggestion, please feel free to contact: [email protected] edu. cn