Type I: IgE-Mediated Immediate Hypersensitivity

Localized and Systemic AnaphylaxisUpdated: 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.

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Immunology and MedicineTopics 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 447Cytokines, 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 toxinCatastrophe!Got the opposite of protection

Not phylaxis (protection)But ana-phylaxis (opposite of protection)

Notes on animal experimentationNotes 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 complexesGet deposition of AgAb Complexes in tissues and organsGet Inflammatory Damage

What if the antigen is an auto-antigen?Cannot be clearedGet chronic inflammatory responseRheumatoid Arthritis

Penicillin & HypersensitivityPenicillin 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

AllerIsStart Here, Tuesday Dec. 1, 2015

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 DanderAllergy1

Foreign SerumVaccines

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)

PositiveWheal and FlareReaction

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

Also with Anti-idiotype 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 Platelet Aggregation& Degranulation; 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* See Slide 42

Overview of Mast Cell Mediated Type I ImmediateHypersensitivity: 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 ImmediateHypersensitivity: 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 Influxa. 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 BiologyApplications 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.

0% 0% 0%0%0%

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!

Response Counter

Why do we get Type I Immediate Hypersensitivity Reactions in so many

different sites or even systemically?(Short answer slide)

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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 firstThen 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.