Hypersensitivity Rxns I

Front 1

WHAT are hypersensitivity rxns?

Back 1

-Characterized by immune reactions that damage tissues of the host (localized or systemic)

-A consequence of the immune reaction to an antigen in a previously sensitized host

Front 2

4 types of hypersensitivity rxns:
-what are they mediated by?

Back 2

(“Gell & Coombs Classification System”)

Type I – Immediate Hypersensitivity*
Type II – Antibody-Mediated*
Type III – Immune Complex*
*Ab-mediated

Type IV – Delayed Hypersensitivity (cell-mediated)

-All mediated by adaptive immunity

Front 3

Describe type I hypersensitivity rxns:

Back 3

Allergic Reactions:
- skin: “wheal and flare”
- allergic rhinitis and conjunctivitis (hayfever)
- allergic asthma
- urticaria (hives)
- angioedema
- ANAPHYLAXIS (respiratory distress, vascular shock)

Front 4

Key players in type I rxns: 3
key event?

Back 4

- Th2 cells
- IgE
- Mast cells

-Key event:
- Ag binds to IgE already on mast cells & basophils --> cross-linking of IgE receptors
-results in release of chemical mediators --> clinical effects.

Front 5

Two major steps that allow Type I rxns to happen?

Back 5

1. FIRST exposure to antigen (allergen) – aka “Pre-exposure (sensitization) phase”
-Production of specific IgE to a particular allergen
(IgE then binds to receptors on mast cells)

2. Re-exposure to allergen --> mast cell degranulation --> symptoms

Front 6

Describe the pre-sensitization step that is necessary for a type I rxn to happen:

Back 6

-This is humoral immunity development.
-Dendritic cells pick up allergen --> present to CD4 cells --> differentiation and activation to Th2 cells

-B cell recognition of allergen

-Th2 and B cell “dance” in peripheral lymphoid tissues (MHC presentation; CD40L and cytokine production by T cells --> B cell activation, proliferation)

-B cell -->* Plasma cell --> IgE
*requires Th2, IL-4

Front 7

What is a "primed" mast cell in a type I hypersensitivity rxn?

Back 7

Front 8

Describe the second step that is necessary for a type I hypersensitivity rxn to happen?
-what happens in the vasculature?
-what happens in the airways?
-what happens in the nasal passages?
-what happens in the GI tract?

Back 8

-Re-exposure to allergen, mast cell degranulation

+ blood flow, + vascular permeability
*Increased fluid, cells, & proteins in tissues --> edema
*Vasodilation --> hypotension

Airways: bronchoconstriction, mucus secretion --> congestion, wheezing, coughing, asphyxiation

Nasal passages: congestion, sneezing

G.I. tract: + fluid secretion, + periistalsis, NVD

Front 9

What are the 2 phases of a type I rxn?
timeline?

Back 9

immediate (5-30 mins to 60 mins)

late (not as acute, 2-24 hours later without additional antigen exposure; may last several days)

Front 10

What happens to FEV in a type I rxn?

Back 10

-Goes way down in the immediate phase
-Goes down again in the late phase.

Front 11

What causes the late phase rxn in a type I rxn?

Back 11

-The late phase reaction is due to cellular infiltration by eosinophils, neutrophils, basophils, monocytes, & CD4+ cells, and resulting tissue destruction.
*eosinophils especially important

Front 12

Back 12

Example of a late phase reaction (2-24 hours) in nasal mucosa: lots of eosinophils!

Mucosal edema
Mucus secretion
Leukocyte infiltration
Epithelial damage

Front 13

What is the role of mast cells in the immediate and late phases of a type I rxn?

Back 13

Degranulation of mast cells results in release of mediators:
-Some are pre-formed (immediate effects)
*histamine
*proteases
*chemotactic factors
*arachidonic acid & products
*PAF

-Others require synthesis (late phase effects)
*Secreted cytokines

Front 14

Most important pre-formed granule mediator in a type I rxn?
What all does it cause? 4

Back 14

Histamine

increased vascular permeability vasodilation
bronchoconstriction
secretion of mucous

Front 15

Role of proteases in a type I rxn?
are they pre-formed?

Back 15

-Preformed, released from mast cells early.

-generate kinins

-cleave complement components --> more chemotactic factors

-degrade blood vessel BM & microbial structures

Front 16

Role of chemotactic factors in a type I rxn?
are they pre-formed?

Back 16

-Preformed, released from mast cells early.

-attract neutrophils and eosinophils

Front 17

Discuss the lipid mediators involved in the immediate phase of a type I rxn: 4
-what do they do?

Back 17

Products of activation of PL-A2 (PAF) & arachidonic acid metabolism

1) Leukotriene C4 & D4 ** increased vascular permeability, bronchial smooth muscle contraction; most vasoactive & spasmogenic agents known!

2) Leukotriene B4 -- chemotactic (neutrophils, eosinophils, monocytes)

3) Prostaglandin D2 -- intense bronchospasm, mucous secretion

4) PAF -- increased vascular permeability, vasodilation, platelet aggregation, histamine release, bronchospasm, chemotactic for neutrophils, eosinophils

Front 18

Discuss the cytokines involved in the late-phase of type I rxns: 6
-what do they do?

Back 18

1) TNF; upregulates adhesion molecules on endothelial cells; promotes influx of inflammatory cells into tissues.

2) IL-3*
3) IL-5*
4) GM-CSF*
*activate eosinophils, promote eosinophil survival

5) IL-4; promotes Th2 differentiation, which is important for B cell class switching to IgE

6) Chemokines e.g. MIP-1a (Macrophage Inflammatory Protein; chemotactic for monocytes)
-chemokines are cytokines that recruit inflammatory cells to sites of injury

Front 19

What cells are producing the cytokines involved in the late phase of a type I hypersensitivity rxn? 2
Which cytokines do they make?

Back 19

1. Mast cells produce IL-3 & IL-5

2. TH2 cells make IL-3, IL-5, & GM-CSF --> production & recruitment of eosinophils

*IL-5 is the most potent eosinophil-activating cytokine known!

Front 20

Why are eosinophils in a type I rxn damaging to us?

What do they secrete? 6

Back 20

-Eosinophils secrete a range of highly toxic granule proteins and other inflammatory mediators

-Proteins (toxic to parasites AND epithelial cells!):
*Major Basic Protein
*Eosinophil Cationic Protein

-Enzymes:
*Peroxidase (triggers granule release from mast cells)
*Collagenase

-Lipid mediators (Leukotrienes C4, PAF)

Front 21

Clinical Manifestations of Type I Hypersensitivity Reactions depend on:

Back 21

The dose and route of allergen administration determine the type of IgE-mediated allergic reaction that results.

Front 22

What are the 4 ways an allergen can be taken in, and what do they result in?

Back 22

-Intravenous --> anaphylaxis (bee sting, IV penicillin, etc)

-Ingestion --> food allergy (G.I. symptoms); risk of anaphylaxis

-Inhalation --> *upper airway: allergic rhinitis, conjunctivitis
*lower airway: allergic asthma;
*risk of anaphylaxis

-Subcutaneous --> wheal and flare; risk of anaphylaxis

Front 23

Discuss ingestion of allergens.
what 2 levels of rxn are there?

Back 23

Local reaction:
Ingestion of Ag -> mucosal IgE-coated mast cell degranulation -> contraction of intestinal smooth muscle (vomiting) -> outflow of fluid into gut -> diarrhea

Systemic reaction:
*If Ag diffuses into blood -> widespread dissemination -> urticaria (hives), laryngeal edema, bronchospasm, anaphylaxis

*Angioedema – Localized swelling of the deeper layers of skin and subcutaneous tissue

Front 24

what are we looking at here? 2

Back 24

angioedema and urticaria

Front 25

What other things could cause a mast cell to degranulate that would NOT constitute a type I hypersensitivity rxn? 5

Back 25

-Anaphylatoxins (C5a, C3a)
-Bacteria
-Chemicals (detergents, food additives)
-Locally produced neurotransmitters (acetylcholine)
-Physical conditions (cold, exercise, pressure)

*only if IgE and antigen mediate the degranulation do you call it a type I rxn

Front 26

When did we start food labeling for food allergies?

What 8 foods account for 90% of all food allergies?

Back 26

2006.

Milk
Egg
Peanut
Tree nuts (walnut, cashew, etc)
Fish
Shellfish
Soy
Wheat

Front 27

Discuss inhalation of allergens.
what does it result in?
where does the action occur?
what cells are the key players?
What mediators are responsible for this reaction?
How do we treat this condition?

Back 27

-Inhalation -> Allergic Rhinitis & Conjunctivitis (hayfever)

-In the upper airway: increased mucus & nasal inflammation -> nasal & conjunctival discharge

-Mucosal mast cells are key players!

-Histamine is key mediator
-Treat with Loratadine, Fexofenadine. Cetirizine, Flonase (antihistamines and a steroid nose spray)

Front 28

What happens if an allergen is inhaled into the lower airway?

Back 28

Allergic asthma.
Classic sx: wheezing, coughing, SOB.

Front 29

What are the chronic changes in allergic asthma?

Back 29

-Asthma is a chronic inflammatory process characterized by reversible narrowing of airways (bronchoconstriction) in response to various stimuli.

Front 30

Mediators and Treatment of Asthma:
4 categories

Back 30

1) Mast cell “stabilizers”: Cromolyn (prevention)

2) Brochodilators: Epinephrine, Theophylline

3) Blocking inflammation: Corticosteroids

4) Leukotriene inhibitors: Montelukast (Singulair)

Front 31

What types of Ag can trigger allergic asthma?

Back 31

-Allergens are Ags that favor the production of IgE.

-Most are SMALL, highly SOLUBLE proteins that are carried on particles (pollen grains, mite feces).

-On contact with mucosa , allergens diffuse into the mucosa.

-Presenting an Ag transmucosally & at very low doses is a particularly efficient way of inducing TH2-driven IgE responses.

-Many allergens are enzymes.

Front 32

Common airborne allergens? 5

Back 32

Dust mites
Pollen
Molds
Pet dander
Cockroaches

Front 33

Discuss the House Dust Mite and why it is gross:

Back 33

-This is the allergen in people who are allergic to dust.

-Der p 1 is the major allergen in the feces of the house dust mite (Dermatophagoides pteronyssimus).

-Der p 1 is a cysteine protease.

Front 34

Back 34

House dust mite. Its crap is an allergen.

Front 35

Discuss subcutaneous intake of allergens.

Back 35

-Leakage of plasma fluid and proteins results in wheal.
-Less leakage in periphery, but still vasodilation--> flare.

*think mosquito bite.

Front 36

Back 36

-Wheal and flare caused by subcutaneous intake of allergen.

Front 37

what are we looking at here?
what's the timeline on the immediate and late phase?

Back 37

-“Wheal and Flare” Reaction
-Subcutaneous injection (skin testing) with intracutaneous injection of house dust mite antigen (HDM) and saline.

*Immediate = 1-2 minutes (lasts up to 30 minutes)
*Late phase = approximately 8 hours later

Front 38

How might you determine what someone is allergic to?

Back 38

1. History (consider possibility of cross-reactivity!)
2. Skin testing
3. Radioallergosorbent (RAST) Test

Front 39

What's the basis of allergy skin testing?
What can you use as a control?

Back 39

-Relies on the “Wheal and Flare” Reaction
-Histamine control

Front 40

RAST Test:

Back 40

A measure of specific serum IgE antibodies to specific antigens.

Front 41

What does it mean if someone is “atopic”?

Back 41

-Atopic individuals are prone to produce IgE antibodies in response to various antigens, and have strong immediate hypersensitivity responses

-Genetic tendency to have hypersensitivity reactions to allergens.

Front 42

What's the atopic triad?

Back 42

*Allergic rhinitis (hayfever)
*Asthma
*Atopic dermatitis (chronic eczema) or urticaria/hives

Front 43

Discuss the hygiene hypothesis explanation of allergies:

Back 43

“Numerous factors including alterations in the number and type of infections early in life, the widespread use of antibiotics, adoption of the Western lifestyle, and repeated exposure to allergens, may affect the balance between Th1 and Th2-type cytokine responses and increase the likelihood that the immune response will be dominated by Th2 cells and thus will ultimately lead to the expression of allergic diseases such as asthma.”

ANSWER: WE ARE WEAK AND SOFT

Front 44

What's the technical name for the strategy employed with allergy shots?

What's the basis behind it?
Does it work?

Back 44

-Desensitization or “Immunotherapy"

-Small but increasing quantities of antigen are administered subcutaneously 1-2x weekly for several months followed by monthly (typically for 3-5 years).

-Often results in a decrease in IgE titers, and an increase in IgG titers.

-Mechanism isn’t known. Possibilities include:
A change in predominant phenotype from Th2 to Th1, or induction of T cell tolerance

-Successful at preventing acute anaphylaxis due to protein antigens (bee venom). Also used to treat seasonal allergies and allergies to indoor allergens (dust mites, pet dander).

Front 45

What's the risk of skin testing or desensitization therapy?

Back 45

Anaphylaxis.

Front 46

Discuss Omalizumab (Xolair).
What's it do?
What's it useful for?
Pros/Cons?

Back 46

-A humanized monoclonal antibody currently FDA-approved only for severe allergic asthma.
-Shots of "anti IgE" to bind IgE and block it from binding to mast cells.
-Useful for extreme allergic rxns.
-Pros: it's effective
-Cons: expensive