Asthma / Hay fever - molecular mechanisms (similarities versus differences) dr. R. Lutter 11:00-12:45 HG-12A00 Socioeconomical impact of Asthma; Clinical aspects of Asthma AMC, Longziekten Therapeutic intervention, incl. desensitization therap

23 important questions on Asthma / Hay fever - molecular mechanisms (similarities versus differences) dr. R. Lutter 11:00-12:45 HG-12A00 Socioeconomical impact of Asthma; Clinical aspects of Asthma AMC, Longziekten Therapeutic intervention, incl. desensitization therap

Astma Bronchiale Functional definition:

Variable bronchoconstriction
Apple-tabwhite-space Spirometric measurement (FEV1)
Apple-tabwhite-space Peak flow measurement

Bronchial hyperreactivity (permanent)
Apple-tabwhite-space Metacholine threshold 
Apple-tabwhite-space Histamin threshold
Apple-tabwhite-space (AMP, Mannitol, Exercise, Hyperventilation)

Astma bronchiale definition by pathology:

Chronic bronchial inflammation, characterized by:
Eosinophils
Lymphocytes (possible neutrophils, mast cells)
thickening of the basal membrane
Epithelial damage*
Hypertrophic airway smooth muscle cells
Hypertrophic mucus glands

Based on function and pathology, airway narrowing in asthma by:


1) Contraction of bronchial smooth muscle cells  (can arise and disappear quickly)
2) Inflammation “products”: edema, mucus  (slow process)
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Astma bronchiale definition by etiology:

Exact etiology still unknown

Probably different phenotypes (different mechanisms can underlay similar dysfunctions and similar complaints)

known etiological factors:
Inhalation-allergy / immunological mechanisms / changes in airway epithelium
Genetic I Apple-tabwhite-space : bronchial hyperreactivity
Genetic IIApple-tabwhite-space : inhalation allergy

Which forms of asthma are there?

Allergic asthma (ca. 80%)*
Non-allergic asthma (ca. 20%)*

Occupational asthma
Allergic (90%)
Irritant-induced (10%)

Name pro and cons in the following statement: Is asthma a purely allergic/immunologic disorder?

Pro:
strong (epidemiological) association at young age between inhalation-allergy and onset of asthma
occupational allergy often leads to occupational asthma

Con:
Irritant induced asthma (allergy is not required)
Non-allergic astma (asthma without evidence of allergy)
Allergic asthma can continue to exist without further exposure to antigen


What percentage of the Dutch populations suffers from allergic rhinitis?

20-25%


What percentage of patients with allergic asthma suffers from allergic rhinitis?

>90%

What type of hypersensitivity is asthma? classical view

Type I Allergy: Immediate hypersensitivity 
Central role for IgE and mast cell. Mediators are histamin, leukotrienes etc

What is the recent model for allergic asthma?

Th2 lymfocyt als inducer van IgE en als effector cel
Bi-phasic: 
Early allergic response (EAR); Th2 (IL-4) Bcel (IgE) mast cell
Late allergic response (LAR) TH2 (IL13,4,5-> steroid sensitive) eosinophil (inflammation BHR)

What are the 'but's in  the recent model for allergic asthma?

This model explains the contraction of airway smooth muscle cells (“early response”) and the allergic /asthmatic inflammation (“late response”) upon exposure to allergen.

Structural changes like hypertrophy of bronchial muscles remain unexplained. 

Asthma symptoms without previous exposure to allergen remain unexplained (“aspecific stimulants - irritants”).

New vision on the onset of asthma:

direct mast cell-muscle interaction as cause of structural muscle changes

What is the concept of Holtzman regarding asthma?

Holtzman: repetitive, early infections with respiratory viruses cause functional alterations of airway epithelium /mucosa. 

What is the concept of Davies regarding asthma?

Davies: the (allergic) inflammatory environment causes the mucosa to respond in an other way to stimuli; epithelial mesenchymal trophic unit (EMTU)
- EGFR on epithelial cells
- Arginase
- mRNA degradation

What can you say about the elevated levels of IL-17 present in asthma and COPD? And mRNA degration?

 IL-17 is critical for host defense against a wide range of pathogens, including bacteria, fungi, viruses, and through the recruitment of neutrophils and direct effects on structural cells.

IL-17 levels are elevated in asthma and COPD and correlate with the presence of neutrophils and severity of loss of lung function. 

IL-17 markedly amplifies epithelial IL-6 and IL-8 responses to TNF-α in human structural lung epithelial cells.

IL-6 and IL-8 mRNA decay measurements

IL-17 in presence of TNF-α loads more stabilizing AU-bp  on IL-8 mRNA

Name the two main Differences between rhinitis and asthma

Nose: allergic effect predominantly result from vasodilatation and increased permeability of the vascular endothelium (histamine is the most important mediator)

Lungs: smooth muscle cells (not present in the nose!) > clinical symptoms predominantly result from contraction of bronchial muscles

The treatment of asthma is based on two main symptoms:

Muscle activity:  
beta-2-mimetics
anti-cholinergic agents
leukotrienes antagonists
(bronchial thermoplastic treatment)

Immunological mechanisms/inflammation:
general: Apple-tabwhite-space corticosteroids
                        leukotrienes antagonists
(general:Apple-tabwhite-space hyposensitization (immunotherapy)
(IgE: Apple-tabwhite-space  anti-IgE)
(cytokines:Apple-tabwhite-space anti-IL5)


What are considered the cornerstones of therapy for asthma?

Inhalation corticosteroids (ICS) are extremely effective and the cornerstones of therapy

Beta-2-mimetics only when needed or combined with ICS

Leukotrienes-antagonists possible as addition


NO therapeutic role anymore for antihistaminics and cromones

How does the Mechanism hyposensitization: 1. “blocking antibodies” work?


Blocking effect of other antibody isotypes 

IgE and IgG4 are both Th2 regulated and often are concurrently produced

More IgG after relatively high allergen exposure and also during hyposensitization

Hyposensitization is effective in case of hay fever (allergic rhinitis). Why?

Hay fever is often monoallergy

Few side effects

Allergic rhinitis strongly depends on IgE

Remains effective for years after completing the therapy

Why is Hyposensitization in case of astma not so effective?

Asthma often involves multiple allergens

higher chance of side effects

less dependent on IgE

What is the Mechanism of anti-IgE therapy?

 Free IgE down
 mast cell-bound IgE down
 IgE production by B-lymfocytes down
 mast cell Fc receptor density down

How do bronchial inflammation and remodeling cause the complaints that are typical for asthma?


Specific bronchial reactions to allergens:
are predominantly determined by the aspecific bronchial hyperreactivity (changes in bronchial muscle activity) and not by the level of spIgE

Aspecific bronchial hyperreactivity:
the arise of bronchoconstriction after exposure to several non-sensitizing allergic stimuli

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