cells and mediators of asthma Flashcards
Asthma context
> 300 million people estimated to have asthma worldwide, ≈500,000 deaths/year
5.5 million people being treated for asthma in the UK, 1500 deaths/year
50% of the 1 billion spent by the NHS on asthma is used to treat the <200,000 individuals with ‘severe asthma’
resistant asthma doesn’t work under common treatment like corticosteroids and B2 agonists
Overview of the mechanism responsible for allergic asthma sensitisation
An allergen is inhaled enters airway tissue activates antigen presenting cells APC engulfs & processes allergen. Presents antigen to naïve helper T cell Differentiates into Th1 and Th2
Th2 cell interacts with B cell displaying antigen
mature Th2 activates B cells through IL 4 and eosinophils through IL 5
B cell proliferates & produces IgE antibodies
Antibodies bind FcεRI (IgE) receptor on mast cells.
adaptive immune system reacts to inhaled allergens
IgE antibodies specific to stimulus antigen causing inflammation
allergen cross links that bind to the IgE can cause mast cells to degranulate
eosinophils release Inflammatory mediators
(ROS, enzymes, leukotrienes)
causes contraction of smooth muscle and mucus leading to obstruction and reduction in air flow
Additional mechanisms contributing to asthma pathophysiology & symptoms: The role of epithelial cells and innate lymphoid cells
Allergen inhaled, enters airway tissue Local tissue damage & antigen detection Airway epithelial cells Alarmins (TSLP, IL-25, IL-33) Antigen-presenting cell (e.g. dendritic cell)
Group 2 innate lymphoid cells
release IL5 andIL13
B cells interact with IgE
APCs also present to T cells
mature Th2 activates IL5 which activates eosinophils
epithelial cells in airways are either damaged by allergen, or certain conserved regions of allergens are recognised by PAMPS in epithelial cell membrane
as a result of damage/inflammation, from signal, epthelial cells release cytokines called alarmins
warns immune system to generate response
il 25 and 33
promotoes t cells and APCs
stimulate activity of group 2 innate lymphoid cells
leukocytes similar to Th2 cells in that they have particular markers on their surface similar to T cells (eg similar cytokine production) BUT they don’t have a t cell receptor
Additional mechanisms: Neurogenic inflammation, mucus secretion, and bronchoconstriction
a way pathology in the airways is generated is through activation of sensory neurones in CNS brain stem, this sends an efferent signal to the goblet cells/ mucus glands/SM in the airway, to change function in secondary way
neurogenic effects work on top of the normal bronchostriction and physiological basis
Inflammatory mediators and tissue injury causes epithelial shedding
and activates sensory nerves
this activates the CNS
lots of downstream effects:
cholinergic bronchial hyperactivity, including bronchoconstriction and mucus hypersecretion
Plasma leak and oedema
smooth muscle hypertrophy and hyperplasia
vasodilation and angiogenesis
LAMA drugs can work on this system by working on the parasympathetic ganglion to reduce bronchoconstriction and mucus secretion
How are the changes to airway function are relatively consistent between asthma patients, whereas the characteristics of the inflammation can vary considerably?
there is some variation between amount of cough, degree of remodelling, age of onset etc
BUT they are relatively consistent- usually the stimulus is what differs
Exposure to stimulus (allergens, cold air, NSAIDs) Immune system response Airway Inflammation Impaired airway function Symptoms: Wheeze, Cough, Dyspnoea, ↓FEV1/FVC
what differs:
*Relatively consistent - some variation still exists, e.g. age of onset, reversibility of obstruction, degree of remodelling and cough
different asthma patients have different immunolgocial responses eg. different numbers of T cells and esoinophils
graphs show severity of disease is not determined by eosinophils or t cells (no correlation) - can be normal or abnormal numbers in severe asthma
similar case for IgE
Asthma syndrome vs phenotypes vs endotypes
Characterised by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness and inflammation
Asthma subgroups defined by varying observable characteristics, e.g. early vs late onset, specific triggers
Asthma subgroups defined by distinct pathophysiological mechanisms e.g. T2 high vs. T2 low
6 types of asthma (type 2 high)
TYPE 2 HIGH
Early-onset allergic asthma
Cause = allergen sensitisation
↑IgE, ↑Th2, ↑Eosinophils
Steroid sensitive, treatable
Late-onset eosinophilic asthma
Cause = Staphylococcus enterotoxin-induced IgE
↑Eosinophils, ↑specific IgE
Severe from onset + frequent exacerbations. Steroid refractory
Aspirin-exacerbated respiratory disease
Cause = Dysregulated aracidonic acid metabolism
↑Eosinophils, ↑LTE4
Severe from onset + frequent exacerbation
6 types of asthma (type 2 low)
Obesity-associated asthma
Risk factors = middle age, female sex
↑IL-6, ↑Neutrophils
Steroid resistant
Smoking-associated asthma Cause = ↑oxidative stress ↑Neutrophils Severe w/ preserved lung function ‘asthma-COPD overlap syndrome’
Very-late onset asthma Onset after 50 years of age (or 65?) Cause = aging associated decline in airway and immune system function Th1/Th17 inflammation, ↑Neutrophils Steroid resistant
or 1 of 4: Aspirin-associated respiratory disease Cold air/exercise induced asthma Allergic broncho-pulmonary mycosis Allergic asthma
Why does it matter if there are underlying differences in inflammation?
Specific therapies are more effective for specific endotypes, ∴ potential for improved treatment strategy via personalised medicine (if method of accurate diagnosis/classification developed)
Impact on research – both for investigation of pathophysiology and development of novel treatments (e.g. need to choose whether one is researching broad spectrum treatments/general pathology or endotype specific)
How does the history of anti-IL-5 therapy illustrate the importance of understanding subgroups when researching asthma
When a general asthma patient population studied:
FEV1 was not reduced in general asthmatic patients but it did reduce eosinophils showing it was specific to severe eosinophilic asthma
this anti-IL-5 did not show significant effect in general group fo asthma patients compared to placebo
however when compared to specifically trying it on eosinophilic asthma, symptoms improved
shows how it’s important to know the type and category of asthma when investigating treatment
Asthma summary
The heterogeneity of asthma, a phenomenon that has been observed by clinicians for more than 100 years ago, is now widely understood and yielding a wealth of potential strategies for improving the effectiveness of treatment.
This approach will enable patients to be treated with therapies that target the specific pathological changes responsible for their symptoms/disease.
However, it first requires a clear and accurate framework for classifying patients that meaningfully differentiates them based on their varying physiology/sensitivity to individual treatments, as well as the identification of relevant biomarkers and the formulation of practical diagnostic systems.
