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

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

3. Robin Coombs 1921 - 2006 I 型 ---- 速发型 （ IgE ） II 型 ---- 细胞毒型（ IgG ， IgM ） III 型 ---- 免疫复和物型（ IgG ） IV 型 ---- 迟发型（ T DTH ） -------------------------------------------- -- Philip George Houthem Gell 1914 - 2001

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

5. Type I hypersensitivity (immediate hypersensitivity)

6. 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。 anaphylaxis

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

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

10. Kimishige Ishizaka （ 1925- ） and Teruka Ishizaka Reagin = IgE 1966

11. 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

12.  Mediated by IgE antibodies  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 IgE production to allergens.  ‘atopy’: An IgE-dependent allergy often arising from exposure to an unknown Ag.

13.  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.  Allergin is a specific IgE that gives rise to immediate hypersensitivity. II. Components involved in type I hypersensitivity

14. Allergen 禾本科花粉 豚草花粉 长蠕孢子格链孢子

15. IgE 分子及其受体 H 2 N NH 2 HOOC COOH NH 2 COOH Fc  RI NH 2 COOH Fc  RII IgE 分 子 及 其 两 种 Fc 受 体 FcεR Ⅰ（高亲和力）： αβγγ FcεR Ⅱ（ CD23 ）（低亲和力）

16.  The majority of humans mount significant IgE response 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.  Atopic individuals allow non-parasitic Ags to stimulate inappropriate IgE production, leading to type I hypersensitivity.

17.  Most allergic IgE response occur on mucous membrane surfaces in response to allergens that enter the body by either inhalation or ingestion.

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

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

20. III. Pathogenic mechanisms Th1 (IFN- , IL-12)  allergen → body → B cell ← Th2 (IL-4) ↓ Fc IgE → masts 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 released Re-exposure

21. The sequence of events in immediate hypersensitivity

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

23. Biochemical 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 contents (amines, proteases), the synthesis of arachidonic acid metabolites (PG, LT), and the synthesis of various cytokines.

24. IgE Antibody Binds To Mast Cells & Basophils To Arm Them For Mediator Release

25. 静息肥大细胞 激活后 5 分钟 激活后 60 分钟

27. Mediators  The preformed mediators include: histamine, kinnogenase, eosinophil chemotactic factor of anaphylaxis (ECF-A)  The mediators newly synthesized include: prostaglands (PG), leukotrienes (LTs, 白三烯 ), platelet activating factor (PAF), cytokines (IL-4, IL-13) phospholipid ↓ phospholipase A2 arachidonic acid ( 花生四烯酸 ) cyclooxygenase ↓ ↓ 5-lipooxygenase postaglandins leukotrienes

28. Arachidonic Acid Metabolites 1. cyclooxygenase products: prostaglandins (PG) PGD2 2. lipooxygenation products: leukotrienes (LTs) LTB4, LTC4, LTD4, LTE4. LTB4 is a potent chemoattractant. LTC4, LTD4 and LTE4 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.

29. Immediate phase  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.  This phase is characterized grossly by erythema, localized edema in the form of a wheal, and pruritus (itching).  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.

30. Late phase  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.  The effects of these mediators become apparent about 6 hours after antigen contact and are marked by an infiltration of eosinophils and neutrophils.  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.

31. IV. Type I hypersensitivity- associated diseases  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.

32. Clinical manifestations of immediate hypersensitivity reactions

33.  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.  Allergens: penicillin, antitoxin, etc. 1. Systemic anaphylaxis (shock)

34. 2. Localized anaphylaxis (atopy)  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.

35. Bronchial asthma  In some cases, airborne or blood-borne allergens, such as pollens, dust, fumes, insect products, or viral antigens, trigger an asthmatic attack.  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.

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

37. 荨麻疹

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

39. 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.

40. 2) For specific allergens  Gradually increasing quantities of Ag are injected subcutaneously.  This 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.  The response to treatment includes an increase in IgG antibodies, a decrease in IgE antibodies in the serum.

41. Type II hypersensitivity (cytotoxic type)  Type 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.  The antibodies damage cells and tissues by activating complement, and by binding and activating effector cells carrying Fc  R.

42. I. Pathogenic mechanisms Ags on the surface of target cells ↓ body → IgG, IgM ↓ 1. damage the target cell 1) activation of complement 2) opsonization: FcR, C3bR 3) ADCC: NK cells, M  2. target cell dysfunction

44. NK cell opsonization

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

46. II. Clinical disease 1. Transfusion reactions A 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 血细胞溶解

47. 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.

50. 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。

51. 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.

52. Human antibody-mediated diseases

53. 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.

54. 5. Graves ’ disease The patients produce antibodies to thyrotropin (thyroid stimulating hormone, TSH) receptor. The end result is overproduction of thyroid hormone and hyperthyroidism.

56. Type III hypersensitivity (immune complex type) Immune complexes (IC) deposit in basement membranes of small blood vessels in various organs.

57. I. Pathogenic mechanisms Ag → body → IgG, IgM, IgA ↓ immune complexes (IC) ↓ soluble IC ↓ ICs are deposited from the circulation into vascular basement membranes ① ↓ ② ↓ FcR activation of complement plat. and basophils ↓ C3a, C5a → mast cell → release of vasoactive amines ↓ basophils ③ Neutrophils vasodilation ↓ lysosomal edema enzymes → damage the tissue aggravate

59. IC are capable of triggering a variety of inflammatory processes  ICs interact with the complement system to generate C3a and C5a. These complement fragments stimulate the release of vasoactive amines and are chemotactic factors for mast cells and basophils, eosinophils and neutrophils.  ICs interact directly with basophils and platelets (via FcR) to induce the release of vasoactive amines.  Neutrophils exocytose their lysosomal enzymes onto the site of IC deposition and damage the underlying tissue.

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

61. II. Clinical diseases 1. 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.

62. Nicolas Arthus 1862-1945

63. 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。

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

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

67. 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 抗原形成复和物，沉积于肾小球基底膜处

68. Human immune complex disease

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

70. 自身抗体与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 ， SLE

71. SLE

72. Type IV hypersensitivity (Delayed type hypersensitivity)  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.  This reaction is independent of antibody and complement.

73. I. Pathogenic mechanisms Ag-MHC Antigen → APC → T 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 inducing the inflammatory perforin and granzymes response or by the FasL-Fas pathway (primarily M  and T cells)

74. Mechanisms of T cell-mediated tissue injury

75. 

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

77. 结核菌素试验

78. 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)

79. 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.

80. 2. Contact dermatitis  Langerhans cells and keratinocytes acting as APCs have key roles in contact hypersensitivity.  Keratinocytes produce a range of cytokines.  A 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.

81. 接触橡胶接触羽毛

82.  Many important sensitizing allergens are organic chemicals, and some are metals such as nickel, chromate. It is assumed that they function as haptens.  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.

83. T cell-mediated diseases

84. Comparison of 4 types of hypersensitivity

85. Thanks for your attention!  Thank you very much for your support and cooperation in my teaching  If you have any question and suggestion, please feel free to contact me: wqq@zju.edu.cn