Lecture 16 - Type I hypersensitivity - ALLERGY Flashcards Preview

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1

What is an allergy?

What is atopy?

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

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

2

What do allergic reactions manifest as?

1. anaphylactic shock

2. Allergic Rhinitis

3. Bronchial Asthma

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?

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

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?

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

5

Basophils are circulating _____.

What are the 2 types of Mast cells?

Leukocytes

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

6

Describe the difference between the two types of mast cells.

Where are MCT cells found?

MCTC?

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

7

Tryptase along will cause degranulation. True or False?

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)

8

What are the important cytokines in IgE reactions?

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

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

1. Chitin

2. chitinase

10

What are the important cytokines in IgE reactions?

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

11

What 3 things do mast cells contain in large amounts?

1. histamine
2. Heparin
3. Proteases

12

What determines allergic reactions?

The immunodominant peptides of allergens are usually presented by what?

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)

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

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

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?

1. There is a direct relationship between IgE levels, allergy and the atopic state.

1. TIME of exposure
- very early in life + lack of exposure to antigens that incite Th1 and Th2 responses will increase IgE production and allergy

2. ROUTE
- mucosal surfaces facilitates allergy

3. 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


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?

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

16

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

FcεR

17

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

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.

18

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

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”.

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?

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.

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?

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


21

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

What releases this?

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)

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?

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***

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)

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.

24

What is the Late phase completely dependent on?

When does it occur?

What cytokines specifically? ( 7)

(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.

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)

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.

26

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

1. Major Basic Protein

2. Leukotrienes

3. Cationic proteins

27

The Clinical Manifestations of an Allergic Response are strongly dependent on
the _____ of the reaction.

What can immediate reactions result in?

1. SITE!!!

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

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?

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.

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?

1. “sets” normal Th1 and Th2 responses to subsequent environmental
antigen exposure.


2. T regulator cells that control IgE synthesis to
environmental antigens.

30

What is the relationship between asthma and obesity?

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.