Asthma and allergy

Question 1

What are mucosal membranes?

Answer 1

The skin and epithelial layers line organs/surfaces that are directly exposed to the external world. The thin epithelial layers are fairly delicate and are protected by cells and molecules of mucosal immune system. In addition to innate defences - pattern recognition, antimicrobial peptides, the mucosal membranes are protected by adaptive immunity
e.g. sinus, middle ear, trachea, lungs have mucosal tissue in respiratory tract

Question 2

What are the anatomical features of mucosal immune system?

Answer 2

• Intimate interactions between mucosal epithelia and lymphoid tissues
• Discrete compartments of diffuse lymphoid tissue and more organised structures such as Peyer’s patches, isolated lymphoid follicles and tonsils
• Specialised antigen uptake mechanisms e.g. M-cells in Peyer’s patches, adenoids and tonsils

Question 3

What are effector mechanisms for mucosal immune system?

Answer 3

• Activated/memory T-cells predominate even in absense of infection
• Multiple activated natural effector/regulatory T-cells present
• Secretory IgA antibodies
• Presence of distinctive microbiota

Question 4

What is immunoregulatory environment of mucosal membranes?

Answer 4

• Active downregulation of immune responses (e.g. to food and other innocuos antigens) predominates
• Inhibitory macrophages and tolerance inducing dendritic cells

Question 5

What happens in allergic asthma?

Answer 5

Allergen - cat dander, pollens, dust-mite faeces
Route of entry - inhalation leading to contact between allergen and mucosal surfaces of the lower respiratory tract
This causes bronchial constriction, increased mucous production, airway inflammation and bronchial hyper-reactivity

Question 6

Define atopy

Answer 6

Predisposition to developing allergies to many different allergens e.g. eczema/allergic rhinitis
Individual must be exposed to allergen in a way that causes IgE production in asthma

Question 7

What are the characteristics of airborne allergens that drive IgE responses?

Answer 7

Protein (often with carbohydrate side chains), low dose, low MW, highly soluble, stable, contains peptides that bind host to MHC class II

Question 8

What molecules are released by activated mast cells?

Answer 8

• Enzymes (tryptase, chymase, cathepsin G, carboxypeptidase)
• Toxic mediators (histamine, heparin)
• Cytokines (IL-4, IL-3, TNF-alpha etc)
• Chemokines - CCL3
• Lipid modulators - prostaglandins, leukotirenes, platelet-activating factor

Refer to slides for more info

Question 9

How are basophils activated?

Answer 9

Similar to mast cells except they have a lobate nucleus and are found in circulation and can enter tissues - they are mobile
They are coated with specific IgE like mast cells and degranulate to drive IgE allergic reactions
Mast cells are resident - activity is not amplified
Basophils attracted to site of inflammation e.g. by CCL3 and cross the more permeable endothelium and accumulate in submucosal tissues - amplified response including increased plasma cell activity

Question 10

What can chronic allergen exposure lead to?

Answer 10

Can lead to chronic airway inflammation, continuous presence of pathogenic lymphocytes, eosinophils, neutrophils and basophils resulting in airway remodelling and permanent airway narrowing

Question 11

What are endotypes and what are the 3 main types?

Answer 11

Endotyping attempts to characterise underlying pathophysiology of indivisuals towards preparing personalised treatment regimes

Three main types are:

• Common allergic asthma - IgE, TH2, eosinophils, basophils predominate airway infiltrate
• Exercise induced asthma
• Neutrophil predominant asthma TH17 and neutrophils predominate airways

Question 12

What is mechanism of common allergic asthma to chronic severe asthma?

Answer 12

Allergen and specific IgE on mast cells - initial episode
Amplifying cycle of inflammation - mast cell degranulation, release of mediators, attract eosinophils, basophils, neutrophils, TH2, plasma cells promoting hypersensitivity and chronicity

Question 13

Pathway to chronic asthma

Answer 13

Specific IgE allergic reaction - common asthma
Persistent allergens can activate epithelium - this activated epithelium secretes IL25 and IL33
Both of these can activate ILCs in submucosal tissue
ILC type 2 secrete IL4, IL5, IL14 - all enhance TH2 and IgE response
Increased vasc permeability through mast cell granule release, activated epithelium up-regulates chemokines that attract macrophages, eosinophils and basophils from blood submucosal layer
This leads to hyper-reactivity during IgE and other mediators of inflammation