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Flashcards in IgE Deck (24):
1

What type of hypersensitivity disease:

ANTIBODY DIRECTED AGAINST TISSUE ANTIGENS - mediated by IgG.

TYPE II - ANTIBODY DIRECTED AGAINST TISSUE ANTIGENS - mediated by IgG

2

Which type of hypersensitivity is mediated by T cells?

TYPE IV - DELAYED HYPERSENSIVITY-mediated by T Cells

3

Which type of hypersensitivity reaction is commonly seen in clinic - diffuse rash all over body?

IV- reactive to drug reactions (in clinic mostly type IV- diffuse rash all over the body)

TYPE IV - DELAYED HYPERSENSIVITY-mediated by T Cells

4

Hypersensitivity reaction: anaphylaxis to a drug. What type? Immune reactant? What is the effector mechanism?

Type I

soluble antigen, mast cell activation

5

Hypersensitivity reaction: drug allergy to penicillin.

What type? Immune reactant? What is the effector mechanism?

Type II

IgG - cell or matrix associated antigen

effector mechanism- complement FcR cells (phagocytes, NK cells)

6

Hypersensitivity reaction: Atopic eczema. What type? Immune reactant? What is the effector mechanism?

Type I

soluble antigen, mast cell activation

7

Hypersensitivity reaction:

allergic contact dermatitis, tuberculin reaction

Type IV
Th1 cells
soluble antigen
macrophage activation

8

Hypersensitivity reaction:

chronic asthma, chronic allergic rhinitis

vs

allergic asthma

Chronic asthma:
soluble antigen
Th2 cells, soluble antigen
IgE production, eosinophil activation, mastocytosis

Allergic asthma:
Type I, IgE, soluble antigen, mast cell activation

9

Hypersensitivity reaction:

graft rejection, allergic contact dermatitis to poison ivy

CTL Type IV, cell associated antigen
effector mechanism: cytotoxicity

10

What is a genetic predisposition to develop IgE antibodies upon exposure to environmental allergens?

atopy

if both parents are atopic (then 50% chance of developing the allergy)

11

What denotes the ability to transfer reactivity to allergens by means of serum (the transfer agent formerly called was reagin and is now known as IgE.)?

atopy

12

Which cells express HIGH affinity FcεR?

Where are these cells expressed? Which circulate? Which are in tissues?

Mast cells and Basophils

Both contain histamine, TNF-α and leukotrienes in cytoplasm

Mast cells - tissue bound, compartmentalized as mucosal or connective tissue, contain potent vasoactive compounds and cytokines

Basophils- circulating

Degranulation releases the mediators

13

What are the two types of mast cells? Where expressed?

Tryptase staining identifies all mast cells and is the primary method for identifying tissue mast cells

Mast cells - tissue bound, compartmentalized as mucosal or connective tissue, contain potent vasoactive compounds and cytokines

2 Types of Mast Cells
MC -Tryptase (prominent mast cell type within the mucosa of the respiratory and gastrointestinal tracts and increase with mucosal inflammation)

MC- Tryptase and Chymase (cells are localized within connective tissues, such as the dermis, submucosa of the gastrointestinal tract, heart, conjunctivae, and perivascular tissues...skin)

14

How are these allergens presented? (What MHC class?)

Describe the sequence of an allergic response.

The immunodominant peptides of these allergens are usually preferentially presented in selected (Class II) D MHC loci by dendritic cells. The D genes, in concert with other non-MHC genes, promote IgE production over IgG responses by influencing the type of TLR activated, type of T-helper cell and cytokine milieu present during allergen presentation by APC.

Contact with an allergen is usually mucosal (respiratory or gastrointestinal), but can be cutaneous or systemic.

Uptake of allergen by antigen presenting cells (DC) via “allergic” TLR that induces the DC to produce IL-4 instead of IL-12

Presentation of the allergen as an immunodominant peptide in a Class II MHC groove. The nature of the peptide and possibly its unique presentation dictate a dominant IgE response.

Allergic responses are dependent on Th-2 activation.
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.

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

F. The accelerated production of Th-2 cytokines, especially IL-4 and IL-13, dominate the cytokine profile.

G. Promotion of IgE class switching occurs by up regulation of 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. IL-4 from Th-2, Basophils and mast cells activate ε germ-line transcription in B-cells and results in IgE synthesis.

15

What might decreased early exposure to infections in the genetically predisposed individual be associated with?

Timing is important: decreased early exposure to infections in the genetically predisposed individual is associated with insufficient T regulator control of IgE

16

What is unique about the binding of FcεR?

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”.

importance of relative binding strength of IgE to mast cells, eosino. and basophils. thats why once its bound there always in mast cell surface so can bind allergen anytime in the future. (slide 14)

17

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”.

Describe the activation of armed FcεR on receptor cells.

Subsequent exposure to the same allergen then cross-links the IgE previously bound to FcεR receptors.

The cross-linked Fcε receptors then aggregate and signal transduction occurs.

Signal transduction activates calcium influx into armed mast cells and basophils which then degranulate, releasing potent vasoactive, inflammatory and fibrogenic mediators.

18

Describe temporal sequence of activation: early vs late.

EARLY
WITHIN 15 MINUTES
PROSTAGLANDINS & LEUKOTRIENE RELEASE
DIRECT COMPLEMENT ACTIVATION
CANNOT HAPPEN IF NO PREVIOUS EXPOSURE (HAVE to have encountered allergen before, before you develop IgE specific to that allergen)

LATE
COMPLETELY DEPENDENT ON Th2 ACTIVATION
AND CYTOKINES IL3,4,5,13,AND 10
EOTAXIN
CHARACTERIZED BY EOSINOPHILS

19

What might elevated serum tryptase levels indicate?

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

20

Late phase (also known as slow-reacting phase) is defined as occuring within hours of allergen contact. This phase is completely dependent upon what type of cell activation and presence of which cytokines?

Describe the action of each.

The Late Phase (also known as slow-reacting phase) and defined as 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-alpha, GM-CSF and IL-10.

The late phase is characterized by infiltration of the site of the response by activated eosinophils, neutrophils, additional mast cells, basophils and lymphocytes.

IL-3, IL-5 and GM-CSF regulate growth and marrow release of eosinophils.

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

IL-5 increases FcER display and thereby augments the IgE reaction

Eosinophils produce several unique inflammatory enhancers, the major ones being major basic protein, leukotrienes and cationic proteins.

21

What is resultant dermal microvascular hyperpermeability? Produces pruritic edematous plaques called wheals.

Urticaria (hives) is a common disorder of the skin characterized by localized mast cell degranulation and resultant dermal microvascular hyperpermeability. This produces pruritic edematous plaques called wheals. Angioedema is closely related to urticaria and is characterized by edema of the deeper dermis and the subcutaneous fat. Urticaria most often occurs between ages 20 and 40, but all age groups are susceptible. Individual lesions develop and fade within hours (usually less than 24 hours), and episodes may last for days or persist for months. Sites of predilection for urticarial eruptions include any area exposed to pressure, such as the trunk, distal extremities, and ears. Persistent episodes of urticaria may herald an underlying disease (e.g., collagen vascular disorders, Hodgkin lymphoma), but in the majority of cases no underlying cause is identified and presumed autoimmune.

22

Describe in vivo vs in vitro allergen testing.

In-vivo - Skin Testing
In-vitro - RAST - (CAP RAST/CAP FEIA (fluorenzymeimmunoassay) )

In vitro assays for allergy can be very misleading - mostly use to support diagnosis

23

Hypersensitivity for latex?

Type 4 and type I
(immediate reaction- I)

24

What promotes IgE class switching?

Promotion of IgE class switching occurs by up regulation of 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.