Cells and mediators of asthma Flashcards
The lancet: “progress in understanding asthma and its underlying mechanisms is slow; treatment can be difficult and response unpredictable; and prevention or cure is still a pipedream”
MAD
Define asthma
• Asthma is a chronic inflammatory disease of the bronchial airways characterized by episodes of:
– Wheeze
– Chest tightness
– Dyspnoea
– Cough
– Exhibits variability (worse at night/early morning)
• Improves with treatment (beta-2 agonist)
what is the prevalence of asthma like?
- Recent increase in prevalence worldwide
- Commonest chronic respiratory disease in UK
- UK prevalence 10-15%
describe what asthma mortality is like?
1000 asthma deaths per year
Over the past 25 years, haven’t been able to bring this down
briefly go over the pathophysiology of asthma
• Condition of intermittent airway obstruction caused by:
– Chronic airway inflammation (eosinophils, lymphocytes, mast cells all release inflammatory markers)
– Airway Hyper-responsiveness →Smooth muscle contraction
– ↑ Mucus production
If above not adequately controlled, then →
– Airway remodelling and fixed airway changes:
As eosinophils etc release fibrogenic factors= around the outside of the airway they lay down increased airway smooth muscle= becomes thicker.
They also release a layer of fibrotic deposition therefore airway narrowing will not be reversible anymore–> airways get smaller and smaller.
Takes about 10 years.
distinguish asthma from COPD
Asthma: reversible airways obstruction
COPD: irreversible airways obstruction
Distinguish intrinsic asthma from extrinsic asthma
• Extrinsic – Clear atopic component – Elevated IgE in blood – Can start at an early age – Tends to be allergic to things e.g. house dust mite, cat etc
• Intrinsic
– No atopy (normal IgE)
– Develops later in life
– More severe and difficult to treat
what is atopy (“out of place”)?
- Atopy is the hereditary predisposition to produce IgE antibodies against common environmental allergens
- The atopic diseases are allergic rhinitis, asthma and atopic eczema
- Allergic tissue reactions (in atopic subjects) are characterised by infiltration of Th2 cells
- Allergy is an exaggerated immunological response to a foreign substance (allergen) which is either inhaled, swallowed, injected, or comes in contact with the skin or eye.
- Common allergens include grass, weed and tree pollens, house dust mite, fungal spores, animal products and certain foods.
what is anaphylaxis?
what is prophylaxis?
Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death–> can occur by continuous, repeated exposure to allergen.
therefore, prophylaxis is protection–> prevention beforehand (immune beforehand)
Give an example of anaphylaxis
- When you have anaphylaxis to something, it’s not on the first exposure–> you have to be sensitised beforehand
- EXAMPLE: skin surface (e.g. mucosa of nose)–> allergen will be broken into little bits= come through the mucosa surface= picked up by dendritic cells or antigen presenting cells= go to the lymph node= Th2 cells will “sample” it over time Th2 cells produce IgE= remembers the presented allergen= IgE circulates and sits in mast cells ready to recognise the same bit of protein it was sensitised to
- mast cells may sit in your nose (hayfever), lungs (Asthma), skin or bowel
- HAPPENS ONLY TO THOSE WITH THE ALLERGY)
INFLAMMATION IN ASTHMA:
If you were to meet the allergen for the second time–> the allergen goes onto the mast cells= cross-links the mast cells= degranulates= releases lots of lots of mediators e.g. histamine that causes the anaphylactic reaction.
People with asthma: there is an acute phase response (which may be associated with the mast cells) and then there is a chronic phase response
- There are many downstream mediators that affect glands, blood vessels and nerves
mad
what is one thing that is changing in terms of our research approach towards asthma?
- Over the years (1980-2010), so many cells have been associated with asthma then not associated
- our thoughts on asthma and the cells involved in it are always changing!
- Eosinophils are thought to be the main mediators right now BUT most people that have died from asthma have neutrophils in the airways (so we should look more into them?)
Pathways leading to acute and chronic allergic reactions
Will first have an acute allergic reaction (mast cells degranulate + Fev1 drops) and if no treatment given–> the Fev1 will recover spontaneously–> will be fine for a while–> hours 4-8: have a late asthmatic response where FEV1 drops due to chronic allergic reaction.
Acute allergic reaction:
- wheezing
- urticaria
- sneezing, rhinorrhea, conjunctivitis
Chronic allergic reaction:
- further wheezing
- sustained blockage of the nose
- eczema
describe T cell imbalance in atopy
- When you are born, T-cells are differentiated and become Th1 and Th2 cells.
- Most of us should be Th1-dependent; when younger, exposed to lots of bacteria etc.
- HOWEVER NOW: it is thought that asthma is so predominant these days is due to the hygiene hypothesis–>
- Too clean= don’t get exposed to bacteria etc= Th cells switch to Th2 cells= start reacting against things we shouldn’t.
- One theory: switching to Th2 cells instead of Th1 cells.
what are the Th2 lymphocytes in asthma like?
• Th2 lymphocytes produce interleukins that have important drivers towards allergic disease
- Produce IL-4, IL-13, IL-5
- IL-4 and IL-13 drive the production of IgE in cells
- IL-5 is the most important interleukin for eosinophil from development to maturation to stopping death of the eosinophils.
• THEREFORE, Th2 lymphocytes make IgE and eosinophil more prevalent.
