Asthma - Dr. Monteil

Question 1

Asthma patients normally have what kind of cough?

Answer 1

Nocturnal cough

Question 2

What cells predominate in asthma?

Answer 2

Eosinophils and TH2 cells

Question 3

What cytokines are DIRECTLY released due to epithelial injury?

Answer 3

IL-25, IL-33, TSLP. They stimulate other cytokines to be released by stimulation of mast cells (mast cells also release chemotaxic factors) and other innate cells.

Activation of mast cells leads to an IL-4 rich environment.

TSLP stimulates DC cells and lead to TH2 differentiation.

Question 4

Mast cells are usually close to what structures?

Answer 4

Small blood vessels.

Question 5

How do eosinophils cause epithelial damage?

Answer 5

Mast cells release chemotaxic factors which recruits eosinophils. These eosinophils are activated and occupy the subepithelial space and get into the epithelium, where they cause damage.

Question 6

IL-13 is responsible for what?

Answer 6

Goblet cell hyperplasia and increased production of mucous.

Question 7

Endotype: Type 2 vs Non-type 2

Answer 7

Type 2: High IgE, Eosinophilia, High FeNO, Glucocorticoid sensitive

Non-type 2: Neutrophil, Pauci-Inflammatory, Less responsive to glucocorticoid Rx

Question 8

Immunotherapy does what?

Answer 8

Immunotherapy decreases the production of TH2 cells and increases the presence of TH1 cells.

Treg cells are increased and the production of IL-4, IL-5, IL-13 is decreased. Treg cells secrete inhibitory cytokines such as IL10, which decreases TH2 responses and IgE production.

There is a decrease in the amount of B cells that are producing IgE. They stop making IgE and start making other kinds of antibodies such as IgG4.

Question 9

Anaphylaxis

Answer 9

Low blood pressure, angioedema, & airway obstruction can be fatal (e.g. allergies to nuts, insect venom)

Question 10

Asthma

Answer 10

Reversible airway obstruction occurs in the bronchi

Question 11

Rhinitis

Answer 11

Discharge, sneezing, & nasal obstruction often coexist with allergic conjunctivitis

Question 12

Urticaria

Answer 12

Itchy edema of the cutaneous tissues is short lived. Lesion is identical to that induced by skin-prick testing.

Question 13

Angioedema

Answer 13

Short-lived, non-itchy edema of the subcutaneous tissues occurs. Some forms, such as lip-swelling, may be manifestations of food allergy.

Question 14

Atopic Eczema

Answer 14

Chronic, itchy inflammation of the skin occurs. Some cases are caused by food allergy

Question 15

Definition of Allergen

Answer 15

Allergens are substances that trigger allergic reactions in susceptible individuals

Characteristics:
Small particles or low-molecular weight glycoyslated substances with high solubility that penetrate body after being inhaled, eaten or administered

Question 16

How are mast cells and basophils activated?

Answer 16

By cross-linking of high affinity IgE receptors on their surfaces. This occurs when allergen simultaneously engages two or more allergen-specific IgE molecules attached to these receptors.

Question 17

What 3 biologic responses result from mast cell activation?

Answer 17

1. Secretion of preformed granules (e.g. histamine) by exocytosis (degranulation)
2. De novo synthesis and secretion of lipid mediators, e.g. leukotriene production from membrane phospholipid
3. Synthesis and secretion of cytokines e.g. IL4, IL5, IL6, IL13 and TNF

Question 18

What does histamine do?

Answer 18

Vasodilation and increased vascular permeability, especially of capacitance vessels.

Histamine induces the production of smooth muscle relaxants, nitric oxide and prostacyclin by vascular endothelial cells

Question 19

What mediates bronchial smooth muscle constriction?

Answer 19

Prostaglandin D2, leukotrienes, and platelet activating factor.

These mediators also increase intestinal smooth muscle hypermotility.

Question 20

What does tryptase do?

Answer 20

Cytokines and some of the other mast cell granule constituents such as tryptase are important in important in mediating inflammatory responses and tissue damage and possibly repair by fibrosis.

Question 21

How do eosinophils cause damage?

Answer 21

By releasing lytic enzymes can cause tissue damage.

IgE, mast cells and eosinophils are important components of man’s defense response against parasites

Question 22

What drug should be used for the immediate management of anaphylaxis?

Answer 22

Epinephrine. It causes bronchodilation and vasoconstriction, and it does this in a few minutes.

Question 23

What does diphenhyramine do?

Answer 23

It is an anti-histamine and will compete with any residual histamine, released from mast cells and basophils, for histamine receptors.

Question 24

Early phase vs. Late phase

Answer 24

Early phase response following mast cell degranulation is caused by preformed mediators such as histamine and de novo mediators such as leukotrienes. In our patient, the consequent

Late phase responses are thought to be mediated by inflammatory cells that come to the affected areas several hours after the initial stimulus. These cells are encouraged to these sites by chemotactic factor released in the first phase of response and by cytokines also released by the mast cells. The inflammatory cells themselves release mediators that induce a recrudescence of symptoms.

Question 25

Timing of the early vs. late response

Answer 25

In the immediate reaction (aka the early responses) the predominant changes are in the tissue vasculature. The release of preformed mediators, as histamine causes dilated blood vessels filled with red cells and leakage of plasma from venules into the surrounding tissues.

The wheal and flare reaction occurs within about 15 minutes and usually subsides within 1 hour.

The late phase reaction follows the immediate response but which typically starts 2-6 hours later. This is characterized histologically by the accumulation of inflammatory white cells, including neutrophils, eosinophils, basophils, and helper T cells. The inflammation is maximal at about 24 hours and then gradually subsides.

Question 26

Cytokine Gene Cluster

IL4, IL5, IL13

Answer 26

5q

Asthma

IL4 & IL13 promote IgE switching; IL5 promotes eosinophil growth & differentiation

Question 27

CD14

Answer 27

5q

Asthma

LPS receptor- with TLR4 may influence balance between Th1 & Th2 responses

Question 28

ADAM33

Answer 28

20q

Asthma

Metalloproteinases involved in airway remodeling

Question 29

Filaggrin

Answer 29

1q

Atopic Dermatitis

Important for epithelial barrier function; increases the risk of sensitization to allergens

Question 30

Most common in vivo test?

Answer 30

Skin prick test. In this test the skin is used as the surrogate for IgE-mediated mast cell degranulation in other tissues.

Wheal and flare reaction within 15 minutes.

Question 31

In vitro test for specific IgE?

Answer 31

One in vitro method of specific IgE identification is radioallergosorbent test (RAST).

The allergen is tethered to a solid phase. The patient’s serum is layered onto the solid-allergen complex and if allergen-specific IgE antibodies are present, they will bind with the allergen. After wash steps to removed unbound antibodies, the bound IgE antibodies are identified using radiolabeled anti-IgE antibody. The quantity of allergen-specific IgE is proportional to the amount of radiation measured.

Question 32

After administration of allergen immunotherapy, why must that patient wait 30 minutes?

Answer 32

anaphylaxis can follow this form of immunotherapy and most of these episodes occur within the first 30 minutes.