Transcript IgEAllerNoTP - Prof. Thomas P. Fondy, Biographical Information

Type I: IgE-Mediated
Immediate Hypersensitivity
Localized and Systemic Anaphylaxis
Updated: November 29, 2016
Folder Title: IgEAllerNoTP
Chapter 15, 7th Edition,
Kuby Immunology, pp 485 to 516
Immunology and Medicine
(See Presentation Called “ImmunMed”)
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 an antibody to the toxin?
Make anti-toxin antibody in dogs:
Inject Jellyfish toxin at sub-lethal levels into dogs.
Then give a 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
Turning Point Quiz Question
Please put away all devices and notes other than
the NXT device.
To here: Thursday Nov 17, 2016
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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)
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
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
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(Short answer slide)
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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 are produced by Mast Cell/Basophil
Immune Responses to generate Type I Hypersensitivity
Primary Mediators
Secondary Mediators
How Do We Control Type I Immediate Hypersensitivity?
Preventing degranulation and type I allergy
Counteracting the effects of Type I allergy mediators
Desensitization by Isotype Switching
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
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(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
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
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.
Comparing Types I, II, and III Hypersensitivity
Types I, II, and III Hypersensitivity are all triggered by
Antibody Responses
Type IV Hypersensitivity (“Delayed Type Hypersensitivity”) is
Cell Mediated (by T-Cells)
Types II and III Antibody-mediated Hypersensitivity are
covered in the next Presentation: “AgAbHype”
Antibody-mediated Hypersensitivity (Hyper123)
Penicillin & Hypersensitivity
Penicillin can induce all four types of Hypersensitive Reactions
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
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)
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I am having a hard time but I
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I’m following very well.
This is not hard to follow. Please
move on!
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