Lecture 16 - Type I hypersensitivity - ALLERGY

Question 1

What is an allergy?

What is atopy?

Answer 1

ALLERGY - a disease induced by reaction to a usually innocuous antigen

Atopy – genetic predisposition to develop IgE antibodies upon exposure to environmental allergens

Question 2

What do allergic reactions manifest as?

Answer 2

1. anaphylactic shock
2. Allergic Rhinitis
3. Bronchial Asthma

Question 3

1. What is the role of IgE?
2. What is its structure?

What is interesting about its Fc Region?

3. What does it have high affinity for? Lower affinity?
4. Presence in serum?
5. Selective stimuli?

Answer 3

1. Central mediator of ALLERGY
2. standard Ig (2H, 3 L)
   - heavily GLYCOSYLATED
   - 2 Fc regions!
3. Fc has high affinity FcE receptors on Mast cells and basophils and APC’s (lower)
4. LOW SERUM level
5. selective stimuli for IgE:
   a) worms
   b) parasites
   c) biodegradable resistant antigens

Question 4

Mast Cells and Basophils:

1. Both express ____ affinity for FcεR and express it _____
2. Both contain what 3 things in cytoplasm?
3. _______ releases the mediators
4. Both develop from what?

Answer 4

1. HIGH, COSNTITUTIVELY
2. histamine,
   TNF-α and
   leukotrienes in cytoplasm
3. Degranulation
4. Both from HSC’s, but are distinct lineages and phenotypic markers

Question 5

Basophils are circulating _____.

What are the 2 types of Mast cells?

Answer 5

Leukocytes

1. Mucosal (GALT and BALT)
2. Connective tissue

Question 6

Describe the difference between the two types of mast cells.

Where are MCT cells found?

MCTC?

Answer 6

2 major subtypes based on presence of TRYPTASE or tryptase and mast cell - specific CHYMASE in different locations

1) mucosal: MCt
- respiratory & GI mucosa & increase with mucosal inflammation

2) Connective tissue: MCtc
localized in dermis, submucosa of GI, heart, conductive, and perivascular tissue

Question 7

Tryptase along will cause degranulation. True or False?

Answer 7

FALSE

-does not degranulate (if only tryptase)

• which is why people that snort cocaine
• do not get degranulation
  but get the amphetamine rush in the nostril (same with morphine)

Question 8

What are the important cytokines in IgE reactions?

Answer 8

Il-4, Il-13, IL-3, IL-5 GM - CSF, and TNF alpha

Question 9

One characteristic of many is that they contain ____- a polysaccharide not found in mammals.

This induces expression of ______- a possible inducer of allergenic antigen generation and release of vasoactive mediators

Answer 9

1. Chitin

2. chitinase

Question 10

What are the important cytokines in IgE reactions?

Answer 10

IL - 3,4,5,6,8,10,13
GM - CSF, and TNF alpha
- chemokines

Question 11

What 3 things do mast cells contain in large amounts?

Answer 11

1. histamine
2. Heparin
3. Proteases

Question 12

What determines allergic reactions?

The immunodominant peptides of allergens are usually presented by what?

Answer 12

GENES
- 50% of children of 2 atopic parents will be atopic
(15% of children of non-atopic parents will be atopic)

MHC - Class II (D loci by DC’s)

Question 13

What does the following statement hope to emphasize:

varying expression of IFN-γ via the T-Bet gene,

FcεR avidity via a maternal gene,

IgE synthesis and bronchial reactivity,

IL-13 synthesis

Answer 13

Multiplicity of genes must act in concert to produce an allergic reaction

Question 14

There is a direct relationship between Ige and what?

What 3 things are most important in context of antigen exposure?

What does decreased early exposure show?

Answer 14

1. There is a direct relationship between IgE levels, allergy and the atopic state.
2. TIME of exposure
   - very early in life + lack of exposure to antigens that incite Th1 and Th2 responses will increase IgE production and allergy
3. ROUTE
   - mucosal surfaces facilitates allergy
4. GENETICALLY PREDISPOSED PERSON (all of the above must couple with this)
   - decreased early exposure to infections in the genetically predisposed individual is associated with insufficient T regulator control of IgE

Question 15

Describe the sequence of an allergic response

A) Contact with an allergen is usually _____.

B) Allergen uptake by DC by allergen TLR -
induces the DC to produce _____ instead of IL-12

C) In what context is the allergen presented?

D) Allergic responses are dependent on ____activation.

E) What signal does this provide?

F) What are the 2 dominant cytokines?

G) Promotion of IgE class switching occurs by up regulation of _______ on mast cells and basophils that increase their production of what cytokines? .

H. What is the result?

Answer 15

A) usually mucosal
- but can be cutaneous or systemic.

B) IL-4

C) immunodominant peptide in a Class II
MHC groove.

D) Th-2

E) Th-2 cell then provides the critical IL-4 signal to an allergen specific B-cell.

F) IL-4 and IL-13,
dominate the cytokine profile.

G) CD-23 (FcεRII
receptor) on mast cells and basophils that increase their production of IL-4
and IL-13.
-This is strongly influenced by gene influenced polymorphisms.

H) results in IgE synthesis

Question 16

ONLY FcR
THAT CAN
BE OCCUPIED
BY ANTIBODY 
WITHOUT
ANTIGEN IS what?

Answer 16

FcεR

Question 17

What 4 things can skew the cytokines to activate during Type I hypersensitivity?

Answer 17

1. Presentation of this antigen by a DC in the absence of Th1-TLR binding
   or by an “allergic” TLR
2. Ensuing absence of the Th1 initiator cytokine IL-12 or presence of IL-4
   then leads to presentation to a Th2 by default.
3. Early release of IL-4 from mast cells or basophils- commonly caused by
   innate immune responses of these cells to parasites
4. ANY situation where IL-4 is the dominant cytokine at the time of antigen
   appearance.

Question 18

How does arming of Fcε Receptor Cells by Allergen Specific IgE occur?

Answer 18

The allergen specific IgE then binds to the high affinity IgE Fc receptors on
mast cells and basophils. The FcεR is the ONLY FcR that can be occupied
by antibody not previously complexed with antigen. These cells are now
“armed”.

Question 19

How does Activation of Armed Fcε on Receptor Cells occur?

1. Subsequent exposure to the same allergen then does what?
2. What happens next?
3. What causes degranulation?

Answer 19

1. cross-links the IgE previously
   bound to FcεR receptors.
2. The cross-linked Fcε receptors then aggregate and signal transduction occurs.
3. Signal transduction activates calcium influx into armed mast cells and basophils
   which then DEGRANULATE, releasing potent vasoactive, inflammatory and
   fibrogenic mediators.

Question 20

Describe the EARLY phase of Allergic Reaction.

1. What is the time frame?
2. What is this MAINLY dependent on?
3. What 3 important things are synthesized and released?
4. What is activated?

What happens if NO previous exposure?

Answer 20

1. Immediate Reaction - defined as an allergic reaction occurring within 15
   minutes of allergen exposure.
2. **This portion of the reaction is completely
   dependent on previous exposure and sensitization.
3. Prostaglandin and leukotriene synthesis and release
4. COMPLEMENT is activated

CANNOT HAPPEN IF NO PREVIOUS EXPOSURE***** need to have a specific IgE

Question 21

What does direct complement activation in the IMMEDIATE reaction depend on for activation?

What releases this?

Answer 21

1. TRYPTASE
2. released from mast cells
   cleavage.

(Elevated tryptase levels can serve as a serum marker for
massive mast cell activation that occurs in anaphylaxis)

Question 22

What does direct complement activation in the IMMEDIATE reaction depend on for activation?

What releases this?

What can serve as a marker for massive mast cell activation in anaphylaxis?

Answer 22

1. TRYPTASE
2. released from mast cells
   cleavage.

Elevated tryptase levels can serve as a serum marker for
massive mast cell activation that occurs in anaphylaxis***

Question 23

The Late Phase:

A. The late phase is characterized by infiltration of the site of the response by
activated ______.

B. IL-3, IL-5 and GM-CSF regulate _____.

C. IL-5 stimulates their release from bone marrow and augments the chemotactic
effect of a specific chemokine called ______.

D. IL-5 increases____

E. Eosinophils produce several unique inflammatory enhancers, the major ones
being what? (3)

Answer 23

A) eosinophils

• neutrophils
• additional mast cells
• basophils and
• lymphocytes.

B) growth and marrow release of EOSINOPHILS.

C) eotaxin

D) FcεR display and thereby augments the IgE reaction

E) major basic protein

• leukotrienes
• cationic proteins.

Question 24

What is the Late phase completely dependent on?

When does it occur?

What cytokines specifically? ( 7)

Answer 24

(also known as slow-reacting phase)

occurring within HOURS of allergen contact.

• This phase is completely dependent upon T-cell
  ACTIVATION and the presence of cytokines IL3, 4, 5, 13, TNF-α, GM-CSF and IL-10.

Question 25

The Late Phase: A. The late phase is characterized by infiltration of the site of the response by activated ______. B. IL-3, IL-5 and GM-CSF regulate _____. C. IL-5 stimulates their release from bone marrow and augments the chemotactic effect of a specific chemokine called ______. D. IL-5 increases____ E. Eosinophils produce several unique inflammatory enhancers, the major ones being what? (3)

Answer 25

A) eosinophils - neutrophils - additional mast cells - basophils and - lymphocytes. B) growth and marrow release of EOSINOPHILS. C) eotaxin D) FcεR display and thereby augments the IgE reaction E) major basic protein - leukotrienes - cationic proteins.

Question 26

What are the 3 major unique inflammatory enhancers produced by EOSINOPHILS?

Answer 26

1. Major Basic Protein 2. Leukotrienes 3. Cationic proteins

Question 27

The Clinical Manifestations of an Allergic Response are strongly dependent on the _____ of the reaction. What can immediate reactions result in?

Answer 27

1. SITE!!! 2. Immediate reactions can range from anaphylaxis with laryngeal and bronchiolar constriction and generalized increase in vascular permeability. They can be fatal.

Question 28

______ occurs when allergen binds to cells in the nasal submucosa and incites a chronic allergic inflammatory reaction driven by continuous aeroallergen exposure. What happens when IgE armed mast cells are activated in the skin? How does bronchial asthma occur?

Answer 28

1. Allergic rhinitis 2. Urticaria(hives), which can be severely pruritic, are skin lesions that occur when IgE armed mast cells are activated in the skin. 3. Acute and chronic bronchial asthma occurs when IgE armed cells are recruited to SUBMUCOSAL sites of the pulmonary bronchi.

Question 29

There is increasingly compelling evidence that early exposure to childhood illnesses does what? The lack of early exposure to environmental and infectious antigens is associated with a lack of what?

Answer 29

1. “sets” normal Th1 and Th2 responses to subsequent environmental antigen exposure. 2. T regulator cells that control IgE synthesis to environmental antigens.

Question 30

What is the relationship between asthma and obesity?

Answer 30

There is a strong correlation between asthma and obesity also but the causal link is unknown. The adipocyte tissue is an organ of sorts and has its own cytokine systems, i.e. leptin, among others, being pro-inflammatory and this may be an underlying factor.

Question 31

What is the most important aspect at arriving at a correct diagnosis for IgE allergic reactions? How else can allergic responses be detected?

Answer 31

A careful clinical history is the most important factor in arriving at the correct diagnosis!!!! (TEST) 1. Skin testing and measuring specific IgE: a) RAST b) In vitro assays (BUT ONLY USED IN DIAGNOSTIC ADJUNCTS TO AN APPROPRIATE CLINICAL SETTING) c) skin testing and RAST can be positive, but the patient may NOT have the clinical symptoms

Question 32

What are 4 types of treatment options of Allergic Reactions?

Answer 32

1. Allergen avoidance 2. Anti-IgE therapy - use of monoclonal anti-IgE antibody to bind to site on circulating IgE that binds to cell bound IgE receptor 3. Allergen Immunotherapy - promote either Th1 or TH2 response - subcutaneous, sublingual, or oral route 4. Vaccines

Question 33

How does Anti-IgE therapy done? What does it decrease?

Answer 33

Anti-IgE therapy-use of an anti-IgE monoclonal antibody that has been engineered to bind to the site on circulating IgE that binds to the cellbound IgE receptor. Anti-IgE therapy results in decrease in eosinophilic inflammation and IgE-bearing cells. Withdrawal of this therapy results in return on asthma symptoms and this correlates with increasing serum IgE.

Question 34

Why does the delayed reason occur?

Answer 34

Most likely due to recruitment of Eosinophils

Question 35

What happens during allergic anaphylactic shock? Tx?

Answer 35

HYPOVOLEMIA (drop in BP) - increase in HR TX: with epinephrine injection

Question 36

What factors of the environment increase allergen sensitivity? What about T cells? What are the 3 triggers?

Answer 36

1. RIGHT ALLERGEN AT THE RIGHT TIME 2. SMALL FAMILY 3. HYPERHYGIENE 4. ANTIBIOTICS EARLY Treg deficiency!!! 3 triggers: 1. Re-exposure 2. Viruses 3. Pollutants

Question 37

What is the in vivo and in vitro allergen testing?

Answer 37

1. Vivo - Skin testing | 2. Vitro - RAST

Question 38

What are the steps for RAST?

Answer 38

1. Allergen in solid phase 2. Patient IgE serum - patients serum added to cellulose disc with covalently bound ALLERGENS 3. IgE binds allergen 4. After washing, radio-labeled Anti-IgE added - radioactivity is counter with a gamma counter

Question 39

What is sublingual Immunotherapy (SLIT)?

Answer 39

Oral tablets of allergen that need to be taken everyday Ex: Grastek - Timothy grass Oralair - Kentucky blue, orchard, perennial rye, sweet vernal and timothy grass Ragwitek - Ragweed