Asthma and Allergy

Question 1

Describe 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 the cells and molecules of the mucosal immune system.
• In addition to innate defences - pattern recognition, antimicrobial peptides; the mucosal membranes are protected by adaptive immunity.

Question 2

Describe the anatomical features of the mucosal immune system.

Answer 2

• Intimate interaction 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

Describe the effector mechanisms of the mucosal immune system.

Answer 3

• Activated / memory T cells predominate even in the absence of infection.
• Multiple activated ‘natural’ effector/regulatory T cells are present.
• Secretory IgA antibodies.
• Presene of distinctive microbiota.

Question 4

Dscribe the immunoregulatory environment of the mucosal immune system.

Answer 4

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

Question 5

What is the class of antibody most associated with mucosal surfaces?

Answer 5

Secretory IgA

Question 6

What is dimeric IgA?

Answer 6

Two identical IgA molecules joined by a J chain, only dimeric IgA can cross the epithelial layers.

Question 7

Describe the action of IgA in mucosal surfaces.

Answer 7

Question 8

How is asthma mediated?

Answer 8

Asthma is an IgE mediated allergic reaction.

Question 9

What are the common stimuli of asthma?

What is their route of entry?

Answer 9

• Common stimulants:
  
  • Dander (cat)
  • Pollens
  • Dute-mite faeces
• Route of entry
  
  • Inhalation leading to contact with mucosal lining of the lower airways.

Question 10

What is the response provoked by an asthma attack?

Answer 10

• Bronchial constriction
• Increased mucous production
• Airway inflammation
• Bronchial hyperreactivity

Question 11

Describe the process which causes IgE production, and the progression of this in an individual.

Answer 11

• Individual must be exposed to allergen in a way that induces IgE production.
• The most common forms of allergic reaction in the developed world are to airborne allergens.
• Predisposition to developing allergies to many different allergens = ATOPY.
• Atopic individuals can have atopic eczema in childhood, that progresses through allergic rhinitis to asthma in adulthood - referred to as atopic march.

Question 12

Describe the characteristics of airborne allergens that may promote the priming of T_H2 cells that drive IgE responses.

Answer 12

• Protein, often with carbohydrate side chains - protein antigens indice T-cell responses.
• Low dose - Favors activation of IL-4-producing CD4 T cells.
• Low molecular weight - allergen can diffuse out of the particles into the mucosa.
• Highly soluble - Allergen can be readily eluted from particle. If the antigens are insoluble they cannot cross the mucous membrane.
• Stable - Allergen can survive in desiccated particle.
• Contains peptides that bind host MHC class II - required for T-cell priming.

Question 13

Describe the process of allergic reaction to a house dust mite.

Answer 13

• The allergen is an enzyme called Der p 1 found in HDM faeces.
  
  • Der p 1 cleaves occludin at tight junction and crosses epithelium - dendritic cells take up the Der p 1 allergen.
  • Dendritic cell travels via lymph to lymph nodes, processes Der p 1 and presents to T_H2 cells and activates specific B cell.
  • B cell proliferates into memory B and plasma cell secreting Der p 1 specific IgE that travels back via lympg to breeched site.
  • IgE binds onto sub mucosal mast cells that are primed to degranulate the next time Der p 1 is inhaled.

Question 14

What are the enzymes released by activated mast cells?

What are their effects?

Answer 14

• Examples of molecules:
  
  • Tryptase
  • Chymase
  • Cathepsin G
  • Carboxypeptidase
• Biological effects:
  
  • Remodel connective tissue matrix

Question 15

What are the toxic mediators released by activated mast cells?

What are their effects?

Answer 15

• Toxic mediators:
  
  • Histamine
  • Heparin
• Biological effects:
  
  • Toxic to parasites
  • Increase vascular permeability
  • Cause smooth muscle contraction
  • Anticoagulation

Question 16

What are the cytokines released by activated mast cells?

What are their effects?

Answer 16

• Cytokines:
  
  • IL-4, IL-13, IL-33
• Biological effects:
  
  • Stimulate and amplify T_H2 response
• Cytokines:
  
  • IL-3, IL-5, GM-CSF
• Biological effects:
  
  • Promote eosinophil production and activation
• Cytokines:
  
  • TNF-α (some stored preformed in granules)
• Biological effects:
  
  • Promotes inflammation, stimulates cytokine production by many cell types, activates endothelium

Question 17

What are the chemokines released by activated mast cells?

What are their effects?

Answer 17

• Chemokine:
  
  • CCL3
• Biological effects:
  
  • Attracts monocytes, macrophages and neutrophils

Question 18

What are the lipid mediators released by activated mast cells?

What are their effects?

Answer 18

• Lipid mediator:
  
  • Prostaglandins D₂, E₂
  • Leukotrienes C4, D4, E4
• Biological effects:
  
  • Smooth muscle contraction
  • Chemotaxis of eosinophils, basophils and T_H2 cells
  • Increase vascular permeability
  • Stimulate mucus secretion
  • Bronchoconstriction
• Lipid mediator:
  
  • Platelet-activating factor
• Biological effects:
  
  • Attracts leukocytes
  • Amplifies production of lipid mediators
  • Activates neutrophils, eosinophils, and platelets

Question 19

Describe basophil activation.

Answer 19

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

Question 20

Describe allergic asthma.

Answer 20

• A potentially serious disease triggered by activation of submucosal mast cells of the lower respiratory tract.
• Activation is by cross-linking of specific IgE on the mast cell surface and degranulation.
• Release of granule contents is instant - bronchial constriction and increased mucous secretion.
• Trapping air in the lungs and making breathing difficult.

Question 21

What are some of the allergen triggers of allergic asthma?

Answer 21

• Seasonal - plant allergens and fungal spored.
• Environmental enzymes - HDM, Der p 1, cat dander Fel d 1, cockroach Bla g 1.
• Allergic asthma normally requires management and treatment as can be life-threatening.
• Chronic allergen exposure can lead to chronic airway inflammation: continuous presence of pathogenic lymphocytes, eosinophils, neutrophils and basophils result in airway remodelling and permanent airway narrowing.

Question 22

What are asthma phenotypic subtypes - endotypes?

Answer 22

• Patients with asthma respond differently to different therapies - the underlaying submucosal cellular infiltrates, molecules and mediators are dictated by the original stimulus.
• Endotyping attempts to characterise underlying pathophysiology of individuals towards preparing personalised treatment regimens.

Question 23

What are the three main endotypes of allergic asthma?

Answer 23

1. Common allergic asthma IgE, T_H2, eosinophils, basophils predominate airway infiltrate.
2. Exercise-induced asthma.
3. Neutrophil predominant asthma T_H17 and neutrophils predominate airways.

Question 24

Describe the mechanism of moving from common allergic asthma to chronic severe asthma.

Answer 24

• Allergen + specific IgE on mast cells = initial episode.
• Amplifying cycle of inflammation: mast cell degranulation, release of mediators, attract eosinophils, basophils, neutrophils. T_H2, plasma cells promoting hypersensitivity and chronicity.

Question 25

Describe the proposed pathway to chronic asthma.

Answer 25

• Lower airway hyperreactivity to inhaled allergen.

1. ​Specific IgE allergic reaction to inhaled allergens - common asthma.
2. Persistent allergens can activate epithelium through TLRs and PAMP receptors.
3. Activated epithelium secretes IL-25 and IL-33.
4. Both can activate innate lymphoid cells (ILC type 2) in submucosal tissue.
5. ILC type 2 secrete IL-4, IL-5, IL-13 - all enhance T_H2 and IgE response.
6. Increased vascular permeability through mast cell granule release, activated epithelium up-regulates CCL5, CCL3 chemokines that attract macrophages, eosinophilsand basophils from blood submucosal layer.
7. Leading to hyper-reactivity driving IgE and other mediators of inflammation.

All results in irreversible airway damage and remodelling.