Asthma and Allergy Flashcards
Describe mucosal membranes.
- 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.
Describe the anatomical features of the mucosal immune system.
- 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.
Describe the effector mechanisms of the mucosal immune system.
- 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.
Dscribe the immunoregulatory environment of the mucosal immune system.
- Active downregulation of immune responses (e.g. to food and other innocuous antigens) predominates.
- Inhibitory macrophages and tolerance-inducing dendritic cells.
What is the class of antibody most associated with mucosal surfaces?
Secretory IgA
What is dimeric IgA?
Two identical IgA molecules joined by a J chain, only dimeric IgA can cross the epithelial layers.
Describe the action of IgA in mucosal surfaces.
How is asthma mediated?
Asthma is an IgE mediated allergic reaction.
What are the common stimuli of asthma?
What is their route of entry?
- Common stimulants:
- Dander (cat)
- Pollens
- Dute-mite faeces
- Route of entry
- Inhalation leading to contact with mucosal lining of the lower airways.
What is the response provoked by an asthma attack?
- Bronchial constriction
- Increased mucous production
- Airway inflammation
- Bronchial hyperreactivity
Describe the process which causes IgE production, and the progression of this in an individual.
- 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.
Describe the characteristics of airborne allergens that may promote the priming of TH2 cells that drive IgE responses.
- 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.
Describe the process of allergic reaction to a house dust mite.
- 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 TH2 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.
What are the enzymes released by activated mast cells?
What are their effects?
- Examples of molecules:
- Tryptase
- Chymase
- Cathepsin G
- Carboxypeptidase
- Biological effects:
- Remodel connective tissue matrix
What are the toxic mediators released by activated mast cells?
What are their effects?
- Toxic mediators:
- Histamine
- Heparin
- Biological effects:
- Toxic to parasites
- Increase vascular permeability
- Cause smooth muscle contraction
- Anticoagulation
What are the cytokines released by activated mast cells?
What are their effects?
- Cytokines:
- IL-4, IL-13, IL-33
- Biological effects:
- Stimulate and amplify TH2 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
What are the chemokines released by activated mast cells?
What are their effects?
- Chemokine:
- CCL3
- Biological effects:
- Attracts monocytes, macrophages and neutrophils
What are the lipid mediators released by activated mast cells?
What are their effects?
- Lipid mediator:
- Prostaglandins D2, E2
- Leukotrienes C4, D4, E4
- Biological effects:
- Smooth muscle contraction
- Chemotaxis of eosinophils, basophils and TH2 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
Describe basophil activation.
- 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.
Describe allergic asthma.
- 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.
What are some of the allergen triggers of allergic asthma?
- 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.
What are asthma phenotypic subtypes - endotypes?
- 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.
What are the three main endotypes of allergic asthma?
- Common allergic asthma IgE, TH2, eosinophils, basophils predominate airway infiltrate.
- Exercise-induced asthma.
- Neutrophil predominant asthma TH17 and neutrophils predominate airways.
Describe the mechanism of moving from common allergic asthma to chronic severe asthma.
- Allergen + 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.
Describe the proposed pathway to chronic asthma.
- Lower airway hyperreactivity to inhaled allergen.
- Specific IgE allergic reaction to inhaled allergens - common asthma.
- Persistent allergens can activate epithelium through TLRs and PAMP receptors.
- Activated epithelium secretes IL-25 and IL-33.
- Both can activate innate lymphoid cells (ILC type 2) in submucosal tissue.
- ILC type 2 secrete IL-4, IL-5, IL-13 - all enhance TH2 and IgE response.
- Increased vascular permeability through mast cell granule release, activated epithelium up-regulates CCL5, CCL3 chemokines that attract macrophages, eosinophilsand basophils from blood submucosal layer.
- Leading to hyper-reactivity driving IgE and other mediators of inflammation.
All results in irreversible airway damage and remodelling.
