Type I: IgE-Mediated Immediate Hypersensitivity Localized and Systemic Anaphylaxis Updated: December 01, 2015 Folder Title: IgEAllerNoTP Chapter 15, 7th Edition, Kuby Immunology, pp 485 to 516 This is a Turning Point Slide to Open the System to Accept Your Transmitted Questions. No need to answer. Rank 1 2 3 4 5 6 Responses 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) Portier and Richet: Discovery of Anaphylaxis (Early 20th 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 Some Definitions and Concepts "Hypersensitivity" - Suggests Heightened Response Includes in-appropriate or mis-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 Four Types of Hypersensitive (Allergic) Responses Also 15-1, 7th Edition Antibody-mediated Hypersensitivity (Hyper123) 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 Penicillin & Hypersensitivity Penicillin can induce all four types of Hypersensitive Reactions Role of Mast Cells and IgE in Type One Allergy Components of Immune System (MakeUp) Resting Mast Cell Roles of Mast Cells (MastDo) MastDo IgE &Mast Cells (MastCell) See also: Figure 16-3 Immunology, 5th Ed p. 365 IgE Cross-Linking by Allergen (LinkIgE1) LinkIgE1 From Figure 15-1, 7th Edition, p. 486 Sensitization of Mast Cells: Isotype-Switching to IgE Also Figure 15-2, 7th Edition, p. 490 Initiation of Hypersensitivity (Start1) Turning Point Quiz Question Please put away all devices and notes other than the NXT device. 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 Start Here, Tuesday Dec. 1, 2015 AllerIs 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 Foreign Serum Vaccines Also Table 15-1, 7th Edition, p. 487 Type I Immediate Hypersensitivity: The Role of the Route of Exposure IgE-Mediated Allergic Reactions (Allergy2) Tissue & Mucosal Mast Cells (IgERoute) Testing for and Measuring Type I Immediate Hypersensitivity 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) Positive Wheal and Flare Reaction Mechanisms Generating Type I Mast-Cell and Basophil Immune Responses and Type I Allergy Also with Antiidiotype Antibody. (See 15-5b lower example) IgE Specific Allergen Not Required (IgE Not Required) Turning Point Quiz Question Please put away all devices and notes other than the NXT device. Non-IgE Antibody-related Initiators of Type I Hypersensitivity Complement Activation Products: C3a, C4a, C5a "Anaphylotoxins" Various Drugs: ACTH, Codeine, Morphine, Penicillin NonIgE Underlying Mechanism of Type I Allergy: Calcium influx into Mast Cell. Triggering of degranulation Bound IgE and Allergen Not Required To here: Nov. 15, 2014 Topics in Type I Immediate Hypersensitivity That we Need to Address: Mediators that cause Mast Cell/Basophil Immune Responses and Type I Hypersensitivity How Do We Control Type I Immediate Hypersensitivity? Why do we have Type I Mast Cell Degranulation Responses Anyway? Mediators of Type I Hypersensitivity: Stored in Mast Cell Granules (See Table 16-3, Immunology, 5th Edition, p. 370) Primary Mediators of Type I Hypersensitivity Histamine, Heparin and Serotonin Increased vascular permeability; Smooth Muscle Contraction Chemotactic Factors for Eosinophils and Neutrophils Attract Eosinophils & Neutrophils Proteases Degrade Basement membranes of blood vessels; Activate bronchial mucous secretions; Activate Complement Secondary Mediators of Type I Hypersensitivity: Synthesized and Released After Mast Cell Activation (See Table 16-3, Immunology, 5th Edition, p. 370) Platelet Activating Factor Prostaglandins Leukotrienes (SRS-A)* Platelet Aggregation& Degranulation; Smooth muscle contraction Vasodilation; Smooth muscle contraction Increased vascular permeability; Pulmonary smooth muscle contraction (*SRS-A : Slow Reacting Substance of Anaphylaxis) Bradykinin Increased vascular permeability; Smooth muscle contraction Cytokines: (IL1 & TNF-a; Others*) * See Slide 42 Systemic Anaphylaxis; Altered Cell adhesion 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) 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??? Approaches to Control of Type I Hypersensitivity Reponses 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 How Can we Prevent or Over-ride This IgE mediated Immediate Type I Hypersensitivity? Desensitization to Type I (IgE-Mediated)Immediate Hypersensitivity: Isotype-Switching from IgE to IgG Association of Economic Status with Type I Immediate Hypersensitivity Allergy: The Role of Environmental Multicellular Agents Why is IgE Causing All This Trouble? ADCC-Mediated anti-parasitic Attack 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.) 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. Turning Point Quiz Question Please put away all devices and notes other than the NXT device. Stop Here Dec. 1, 2015 Signal Transduction Mechanisms Underlying Type I Hypersensitivity and Managing the Pathology Signal Transduction in Biology Applications to Therapeutic Intervention This is to introduce the concept of intra-cellular signal transduction triggered by extra-cellular signals and cell surface receptors. Details will not be asked. Major concept being illustrated is important Turning Point Quiz Question Please put away all devices and notes other than the NXT device. 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. 2. 3. 4. 5. I am totally lost I am having a hard time but I follow some of it. I’m doing OK. I follow some of it. I’ll figure the rest out later. I’m following very well. This is not hard to follow. Please move on! Response Counter 0% 1. 0% 0% 2. 3. 0% 4. 0% 5. Why do we get Type I Immediate Hypersensitivity Reactions in so many different sites or even systemically? (Short answer slide) Rank 1 2 3 4 5 6 Responses 0% 0% 1 2 0% 0% 3 4 0% 0% 5 6 Meanings and Concepts Associated with Type I and Type IV Hypersensitivity Atopic Allergy (Atopic Individual): Genetic misregulation of IgE production or response (Type I) Type IV Delayed Type T-Cell-Mediated Hypersensitivity 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 An Example of Signal Transduction: Type I Allergy Signal Transduction Cascade. (Details not to be memorized. Concept of Signal Transducxtion is Illustrated This shows time course of responses. Methylation and decline (Solid blue line) happens first Then cyclic AMP formation and break-down (Solid black line) Then Calcium uptake (Dashed blue line) Then histamine release (Dashed black line) Treatment depends on these time courses.