1. Type I: IgE-Mediated Immediate Hypersensitivity Localized and Systemic Anaphylaxis Updated: November 18, 2014 Folder Title: IgEAllerNoTP Chapter 15, 7 th Edition, Kuby Immunology, pp 485 to 516

2. Immunology and Medicine Topics in Immunology and Medicine Planned for Coverage in BIO 447 Allergy – Hyper-sensitivity (Chapter 15) Immunity to Infectious diseases (Chapter 17) Vaccines (Chapter 17) Topics in Immunology and Medicine not Covered in BIO 447 Cytokines, Cytokine-based Diseases and Cytokine-Based Therapies (Chapters 4) Tolerance and Auto-immunity (Chapter 16) Transplantation Medicine (Chapter 17) Immune Deficiency Diseases e.g AIDS (Chapter 20) Genetics and the Immune Response – The MHC System (Chapter 8) In Biology of Cancer (BIO 501) Immunology and Cancer: In BIO 501, the Biology of Cancer Course (Chapter 21)

3. Portier and Richet: Discovery of Anaphylaxis (Early 20 th Century) Can We Treat Jellyfish Toxin poisoning the way we do for Diphtheria Toxin or Rabies Toxin ? Generate and antibody to the toxin? Make anti-toxin antibody in dogs: Inject Jellyfish toxin at sub-lethal levels into dogs. Give secondary booster injection with minute amount of toxin Catastrophe! Got the opposite of protection Not phylaxis (protection) But ana-phylaxis (opposite of protection) Notes on animal experimentation Notes on how Science and Medicine proceed

4. Some Definitions and Concepts "Hypersensitivity" - Suggests Heightened Response Includes in-appropriate ormis-regulated response "Allergy“: Generally refers to Type I Immediate Hypersensitivity; But also hear Types II and III "Allergy“ “Atopic” Allergy (Atopic Individual): Genetic misregulation of IgE production or response "Immediate"-Within minutes (Type I) or hours (Types II and III) "Delayed" - Takes two or more days "Phylaxis" - Protection "Anaphylaxis" - Opposite of Protection; Damaging Link to American College of Allergy, Asthma & Immunology http://www.acaai.org

5. Four Types of Hypersensitive (Allergic) Responses Also 15-1, 7th Edition

6. Antibody-mediated Hypersensitivity (Hyper123)

7. Note on Type III: Antigen-Antibody Mediated Allergy Excess antigen produces large amount of small antigen-antibody complexes because of excess antigen. Difficult for phagocytic cells to clear immmune complexes Get deposition of AgAb Complexes in tissues and organs Get Inflammatory Damage What if the antigen is an auto-antigen? Cannot be cleared Get chronic inflammatory response Rheumatoid Arthritis

8. Penicillin & Hypersensitivity Penicillin can induce all four types of Hypersensitive Reactions

9. Role of Mast Cells and IgE in Type One Allergy

10. Components of Immune System (MakeUp)

11. Resting Mast Cell

12. Roles of Mast Cells (MastDo) MastDo

13. IgE &Mast Cells (MastCell) See also: Figure 16-3 Immunology, 5th Ed p. 365

14. IgE Cross-Linking by Allergen (LinkIgE1) LinkIgE1

15. From Figure 15-1, 7 th Edition, p. 486

16. Sensitization of Mast Cells: Isotype-Switching to IgE Also Figure 15-2, 7 th Edition, p. 490

17. Initiation of Hypersensitivity (Start1)

18. What Determines Allergic Sensitivity? The Allergen (the immunogen) Dose of Allergen Route of Exposure or Administration Presence or absence of "adjuvants" (i.e. things that make allergy worse) Host Genetics AllerIs

19. Common Antigens Associated with Type I (Mast Cell & IgE or IgE-Receptor-Mediated) Hypersensitivity (Table 17.2 Kuby, 3rd Ed.) Proteins: Foreign Serum; Vaccines Plant Pollens: Rye Grass, Ragweed, Timothy, Birch Drugs: Penicillin, Sulfonamides, Salicylates, Anesthetics ACTH, Codeine, Morphine Foods: Nuts, Seafood, Eggs, Peas, Beans, Peanuts Insect Products: Bee, Wasp, or Ant Venom Mold Spores Animal Hair and Dander Allergy1

20. Foreign Serum Vaccines Also Table 15-1, 7 th Edition, p. 487

21. Type I Immediate Hypersensitivity: The Role of the Route of Exposure

22. IgE-Mediated Allergic Reactions (Allergy2)

23. Tissue & Mucosal Mast Cells (IgERoute)

24. Testing for and Measuring Type I Immediate Hypersensitivity

25. Atopic Urticaria ("Wheal and Flare" Reaction) Edematous - Swollen, Fluid-Influx "Wheal" Erythrematous - Reddened, Vasodilated, Blood-cell Influx "Flare" Manifestation of Type I Hypersensitivity in Skin: "Hives" Used for Skin Testing of Allergens (See Figure 15-10, Kuby, 6th Edition)

26. Positive Wheal and Flare Reaction

27. Mechanisms Generating Type I Mast-Cell and Basophil Immune Responses and Type I Allergy

30. Also with Anti- idiotype Antibody. (See 15-5b lower example)

31. IgE Specific Allergen Not Required

32. (IgE Not Required)

33. Non-IgE Antibody-related Initiators of Type I Hypersensitivity Complement Activation Products: C3a, C4a, C5a "Anaphylotoxins" Various Drugs: ACTH, Codeine, Morphine, Penicillin NonIgE

34. Underlying Mechanism of Type I Allergy: Calcium influx into Mast Cell. Triggering of degranulation Bound IgE and Allergen Not Required

35. Mediators that cause Mast Cell/Basophil Immune Responses and Type I Hypersensitivity

36. Mediators of Type I Hypersensitivity : Stored in Mast Cell Granules (See Table 16-3, Immunology, 5th Edition, p. 370) Histamine and Increased vascular permeability; Serotonin Smooth Muscle Contraction Eosinophil and Neutrophil Attract Eosinophils & Neutrophils Chemotactic Factors Proteases Degrade Basement membranes of blood vessels; Activate bronchial mucous secretions; Activate Complement PrimeMed

37. Mediators of Type I Hypersensitivity: Synthesized or Released After Mast Cell Activation (See Table 16-3, Immunology, 5th Edition, p. 370) Platelet Activating Platelet Aggregation& Degranulation; Factor Smooth muscle contraction Prostaglandins Vasodilation; Smooth muscle contraction Leukotrienes (SRS-A)* Increased vascular permeability; Pulmonary smooth muscle contraction (*SRS-A : Slow Reacting Substance of Anaphylaxis) Bradykinin Increased vascular permeability; Smooth muscle contraction Cytokines: Systemic Anaphylaxis IL1 & TNF-a; Others Altered cell adhesion LaterMed

39. Overview of Mast Cell Mediated Type I Immediate Hypersensitivity: Triggering of Sensitized Cells and Release of Early and Late Mediators (From Roitt, Brostoff, and Male, Immunology, 4th Ed., Fig 22.14) IgEOView

40. Overview of Mast Cell Mediated Type I Immediate Hypersensitivity: Triggering of Sensitized Cells and Release of Early and Late Mediators: How Do We Treat This??? IgEOView

41. Approaches to Control of Type I Hypersensitivity Reponses

42. To Treat Type I Immediate Hypersensitivity Based on the Underlying Mechanisms: 1.Block Effects of Primary Mediators on Target Cells (e.g. respiratory smooth muscles or vascular endothelium) : Antihistamines; Cortisone 2.Block Calcium Ion Influx: Cromolyn 3.Block the Effects of Calcium Ion Influx a. Keep cyclic AMP (cAMP) from Falling Theophylline b. Increase production of cAMP: Adrenaline Why Basic Biological Mechanisms Matter in Medicine

44. How Can We Prevent or Over-ride This IgE- Mediated Immediate Hypersensitivity?

45. Desensitization to Type I (IgE-Mediated)Immediate Hypersensitivity: Isotype-Switching from IgE to IgG

46. Association of Economic Status with Type I Immediate Hypersensitivity Allergy: The Role of Environmental Multicellular Agents

47. Why is IgE Causing All This Trouble? ADCC-Mediated anti-parasitic Attack

48. Here is a question no reasonable Prof would ask in an Exam in Immunobiology: “List all of the primary and secondary mediators of Type I hypersensitivity that you can remember”. (If you need to know that kind of thing, search it on your favorite information source. That’s safer anyway, especially if you are trying to treat a patient.)

49. Here are questions that get to the heart of understanding and that really matter in the real world of medicine: (You can’t look something up if you don’t know enough to realize that the question exists and matters) “What is the fundamental difference between primary mediators of hyper-sensitivity and secondary mediators?” In terms of therapy, why does it matter whether something is a primary mediator or a secondary mediator of Type I immediate hypersensitivity? Give an example of a primary mediator of Type I hypersensitivity.

50. Signal Transduction Mechanisms Underlying Type I Hypersensitivity and Managing the Pathology Signal Transduction in Biology Applications to Therapeutic Intervention

51. An Example of Signal Transduction: Type I Allergy Signal Transduction Cascade. (Details not to be memorized. Concept of Signal Transducxtion is Illustrated

53. How Well Are You Following What is Being Presented at the Moment? (This is being set to “Anonymous”. Your name will not be linked to your response) 1.I am totally lost 2.I am having a hard time but I follow some of it. 3.I’m doing OK. I follow some of it. I’ll figure the rest out later. 4.I’m following very well. 5.This is not hard to follow. Please move on!

54. Meanings and Concepts Associated with Type I (and Type IV) Hypersensitivity Atopic Allergy (Atopic Individual): Genetic misregulation of IgE production or response Atopic Dermatitis (Allergic Eczema): Skin reaction from TH2-Type Helper T-Cells, IL4 production, and Eosinophil Influx Erythrematous (reddened, inflamed) White-cell Influx and Exudate (pus) Contact Dermatitis: Delayed-type (Type IV) Hypersensitivity TH1-Type Helper T-cells, Cytokines, Macrophage Influx e.g. Rubber-sensitivity, Poison Ivy, Poison Oak Dermal

55. Turning Point Quiz Question Please put away all devices and notes other than the NXT device.