Asthma Flashcards
How does asthma progress?
In normal individuals, there is a steadily declining lung function as you age after peak around 25 YO in males.
Asthmatic individuals can have decreass excarcebated by viruses and allergen exposure..
What is extrinsic asthma?
Atopic - allergy.
Young onset.
Hyper responsive.
IgE-mediated sensitivity primarily to inhaled allergens and resulting in bronchoconstriction
V. similar inflammatory profile to intrinsic asthma
What is intrinsic asthma?
Non-atopic = non-allergic.
Tends to develop in middle age +
Airflow block can be more severe
Hyper responsive.
No identifiable external cause is found.
Usually normal serum IgE levels.
What are the generics of allergy?
“changed reactivity”.
- innappropriate immune response to non-harmful allergen.
Allergy used interchangeably with Type 1 immediate hypersensitivity.
= IgE mediated mast cell degranulation.
Allergens are antigens elicit an allergic resppknse.
What is anaphylaxis? causes?
Acute severeallergic reaction resulting in respiratory COLLAPSE.
60% caused by medication - half of these due to antibiotics.
How can you develop allergy?
Strong genetic influence with many gene loci implicated - family history strongly contributes to risk of allergic asthma.
The allergenic potential - physiochemical characteristics of the allergen, surface etc..
Dosing regimen - Intermitten exposure for prolonged periods can trigger development of allergic response e.g dog hair.
Driven by Th2 cells and cytokines particularly IL-4, IL-5, IL-10, IL-13
= increased Th2:Th1 cytokine ratio, not necessarily cell no’s.
How does Th2:Th1 balance impact asthma?
Allergic asthma associated with an increase in Th2:Th1 cytokine ratio.
- therefore, elevated IL-4, IL-5, IL10, Il-13 compared to Th1 cytokines like IL-2 and IFN-y.
Th1 = Il-2 + IFN-y.
Th1 cytokines suppress Th2 production.
Th2 = IL-4, IL-5, IL-10, IL13.
What factors favour Th2 phenotype vs Th1?
Th2 favoured by widespread antibiotic use, Urban environments, house-dust mites sensitisisation.
Th1 phenotype - older siblings, exposure to day care, rural environments..
BUT
also strong genetic component to this balance in cytokines.
How do Th2 cytokines influence allergic asthma?
Increased Th2 cytokine production leads to elevated Il-4 and Il-13.
Il-4 and Il-13 can stimulate activated B cells to release IgE antibodies.
= stimulates class switching to IgE antibodies.
IgE fixes onto FcR on surface of tissue mast cells.
Cross-lining IgE by allergen bound to FcR1 on mast cell surfaces triggers mast cell degranulation.
What are IgE antibodies?
Stimulated class switching to IgE of activated B cells by Th2 cytokines Il-4 and Il-13.
IgE binds with high affinity (logKd = -10), to FcR1 on tissue mast cells + basophils.
IgE is relatively rare in plasma…
Mast cell degranulation is triggered by cross-linking of IgE by antigen bound to FcR1 on mast cell surface.
What is the time course of allergic asthma development?
Dosing regimen of intermittent exposure for prolonged periods.
Onset of allergic asthma in youth.
Initial sensititisation can take months/years, during this period very few/no symptoms.
Th2 cell selection + expansion, with B cell production of IgE and mast cell priming.
Sensitisation increases over years BUT: Once IgE fixed on mast cell FcR1 - allergen rexposure will trigger immediate mast cell degranulation through cross-linking bound IgE.
What are the consequences of Mast cell degranulation?
Granular products are released:
Heparins, histamine, TNF, proteases…
= inflammatory mediators.
Release of leukotrienes and prostaglandins.
in the Lungs, Mast cells contain little histamine, but skin mast cells contain high histamine.
What is the role of eosinophils in allergy?
In normal individuals, eosinophils make up less than 1% of WBCs.
In allergic asthmatics, can rise up to 5%!!!!
whilst mast cells involved in acute phase of asthmatic response, Eosinophils seem to involve in Late phase asthmatic response.
Eosinophils migrate to site of inflammation due to release of IL-5 and chemokines like eotaxin.
In tissue, they release proteases and ROS, leukotrienes and prostaglandins.
Why aren’t anti-histamines useful in asthma?
NONE or little use in asthma.
Histamine content of mucosal lung mast cells is low relative to histamine content of connective tissue mast cells in the skin.
E.G cetirizine, loratidine.
EXCEPT Ketotifen - H1 antagonist with additional effects such as PDE inhibition (vasodilation) and anti-leukotriene effect.
- can be used in asthma.
What are Chromones?
Effective for approx 50% of patients with allgeric, irritant + exercise induced asthma.
- against early + late phase asthma.
DSCG and Nedocromil.
- Mast cell stabilisers to inhibit degranulation in lung mast cells.
Require prolonged prophylaxis.
WELL TOLERATED
Inhibit eosinpphil chemotaxis.
Inhibit sensory nerve fibre excitation + neural reflex = by inhibiting NKA, BK and SO2 induced bronchoconstriction.
