Case 47: Allergic Asthma Flashcards
what type of hypersensitivity reaction if asthma?
type I
what are type I hypersensitivity reactions?
type I reactions
involve the activation of helper CD4+ TH2 cells, IgE antibody formation, mast-cell
sensitization, and the recruitment of eosinophils
allergen-specific IgE antibodies
formed in sensitized individuals bind to and occupy high-affinity Fcε receptors
(FcεRI) on the surfaces of tissue mast cells and basophils
when the
antigen is encountered again, it cross-links these bound IgE molecules, which triggers
the immediate release of mast-cell granule contents, in particular histamine
and various enzymes that increase blood flow and vascular permeability
what is the late phase reaction of type I hypersensitivity?
happens within 12 hours of contact with antigen,
AA metabolism in the mast cell generates prostaglandins and leukotrienes,
which further increase blood flow and vascular permeability
IL-3, IL-4 and IL-5 and TNFα are
produced by both activated mast cells and helper T cells, and these further prolong
the allergic reaction
these mediators and cytokines cause an influx of monocytes, more T cells, and eosinophils into the site of allergen entry
what happens during the acute response in allergic asthma?
TH2-mediated chronic inflammation in the airways
in sensitized
individuals, cross-linking of specific IgE on the surface of mast
cells by inhaled allergen triggers them to secrete inflammatory
mediators, causing bronchial smooth muscle contraction and
an influx of inflammatory cells, including eosinophils and TH2
activated mast cells and TH2 cells secrete cytokines
that also augment eosinophil activation, which causes further
tissue injury and influx of inflammatory cells. The end result is
chronic inflammation, which may then cause irreversible damage
to the airways
inflammatory mediators cause increased mucus secretion and smooth muscle contraction = airway obstruction
what are the main symptoms of asthma?
wheezing and coughing
both are due to the forced expiration of
air through airways that have become temporarily narrowed by the constriction
of smooth muscle as a result of the allergic reaction
as a consequence of the narrowed
airways, air gets trapped in the lung, and the lung volume is increased during
an attack of asthma
once someone has allergy asthma, why can it be triggered by other stuff too?
once asthma is established, an asthma attack can be triggered not only by the allergen
but by viral infection, cold air, exercise, or pollutants
this is due to a general
hyperirritability or hyperresponsiveness of the airways, leading to constriction in
response to nonspecific stimuli, thus reducing the air flow.
what can airway irritability be correlated too?
Airway irritability correlates positively with eosinophilia and serum IgE levels
what are the classes of drugs used to treat asthma?
corticosteroids
leukotriene antagonists
anti-IgE antibodies
anticholinergics
β2-adrenergic agonists
what do corticosteroids do for asthma?
inhibit the transcription of allergic and pro-inflammatory cytokines and can also
activate the transcription of anti-inflammatory cytokines
this leads to a decrease
in the numbers of mast cells, eosinophils, and T lymphocytes in the bronchial
mucosa
what does anti-IgE therapy do for asthma?
it’s a monoclonal antibody directed against the IgE that forms complexes
with free IgE and prevents its binding to the receptor FcεRI on the surfaces
of mast cells and basophils
results in a decrease in circulating free IgE and the
downregulation of FcεRI expression on the cell surfaces
what do β2-agonists do to treat asthma?
bind to the β2-adrenergic receptor, which is expressed on the surface
of bronchial smooth muscle cells
β2-agonists relax smooth muscle, thus rapidly
relieving airway constriction
helpful in treating the immediate phase of
the allergic reaction in the lungs
Explain the basis of Frank’s chest tightness and the radiograph findings.
During inspiration, the negative pressure on the airways causes their diameter to
increase, allowing an inflow of air.
During expiration, the positive expiratory pressure
tends to narrow the airways.
This narrowing is exaggerated when the airway is
inflamed and bronchial smooth muscle is constricted, as in asthma.
This causes air to
be trapped in the lungs, with an increase in residual lung volume at the end of expiration.
Breathing at high residual lung volume means more work for the muscles and
increased expenditure of energy; this results in the sensation of tightness in the chest.
The high residual lung volume is also the cause of the hyperinflated chest observed
on the chest radiograph.
The peribronchial inflammation in asthma causes bronchial
marking around the airways.
Explain the failure of Frank’s asthma to improve despite the frequent use of
bronchodilators, and his response to steroid therapy.
Chronic allergic asthma is not simply due to constriction of the smooth muscles
that surround the airway: it is largely due to the inflammatory reaction in the airway,
which consists of cellular infiltration, increased secretion of mucus, and swelling
of the bronchial tissues.
This explains the failure of bronchodilators, which dilate
smooth muscles, to maintain an open airway and their failure to completely reverse
the decreased air flow during Frank’s acute attacks.
Steroids are therefore given to
combat the inflammatory reaction of the late-phase response.
Eosinophilia is often detected in the blood and in the nasal and bronchial
secretions of patients with allergic rhinitis and asthma. What is the basis for this
finding?
Allergic individuals have a tendency to respond to allergens with an immune
response skewed to the production of TH2 cells rather than TH1.
The cells produce
the interleukins IL-4 and IL-13, cytokines that induce IgE production in humans.
TH2 cells also make IL-5, which is essential for eosinophil maturation.
Furthermore,
activated T cells and bronchial epithelial cells secrete CCL11 (formerly known as
eotaxin), which attracts eosinophils in the airways.
The production of IL-4 and IL-5
by TH2 cells responding to allergens in atopic individuals explains the frequent association
of IgE antibody response and eosinophilia in these patients.
What is the basis of the wheal-and-flare reaction that appeared 20 minutes
after Frank had had a skin test for hypersensitivity to ragweed pollen?
IgE-mediated hypersensitivity to an allergen is tested for by injecting a small amount
of the allergen intradermally.
In allergic individuals, this is followed within 10–20 minutes
by a wheal-and-flare reaction at the site of injection which subsides
within an hour.
The wheal-and-flare reaction is due mainly to the release of
histamine by mast cells in the skin.
This increases the permeability of blood vessels
and the leakage of their contents into the tissues, resulting in the swollen wheal; dilation
of the fine blood vessels around the area produces the diffuse red ‘flare’ seen
around the wheal. This reaction is almost completely inhibited by antagonists of the
histamine type 1 receptor, the major histamine receptor expressed in the skin.
Frank called 24 hours after his skin test to report that redness and swelling
had recurred at several of the skin test sites. Explain this observation.
The recurrence of the redness and swelling at the site of previous immediate allergic
reactions represents the late-phase response characterized by a cellular infiltrate.
Frank developed wheezing on several occasions after taking the nonsteroidal
anti-inflammatory drugs (NSAIDs) aspirin and ibuprofen (Motrin). Explain the basis
for these symptoms.
NSAIDs such as aspirin and ibuprofen
can induce wheezing in certain patients
This is classically seen in patients with
Sampter’s triad: asthma, nasal polyps, and NSAID sensitivity.
NSAIDs inhibit the enzyme cyclooxygenase (COX).
Normally, the actions of COX lead to the synthesis
of prostaglandins from arachidonic acid. COX inhibition leads to shunting of the
arachidonic acid precursor away from prostaglandin synthesis and into the leukotriene
synthesis pathway
The increased leukotriene biosynthesis
leads to bronchial smooth muscle constriction and cell proliferation, plasma leakage,
mucus hypersecretion, and eosinophil migration, culminating in symptoms of
wheezing and asthma exacerbation.
Leukotriene E4 levels can be measured in the
urine. In patients with aspirin sensitivity, E4 levels are higher at baseline and rise an
additional fivefold after aspirin ingestion before returning to baseline as the aspirininduced
wheezing resolves.
How would the immunotherapy that Frank received help to alleviate his
allergies?
Repeated administration of relatively high doses of allergen by subcutaneous injection
is thought to favor antigen presentation by antigen-presenting cells that produce
IL-12.
This results in the induction of TH1 cells rather than TH2 cells.
The presence
of TH1 cells tends to lead to an IgG antibody response rather than an IgE response
because the TH1 cells produce IFN-γ, which prevents further isotype switching to
IgE.
The IgG antibody competes with the IgE antibody for antigen.
Furthermore,
IgG bound to allergen inhibits mast-cell activation (via FcεRI) and B-cell activation
(via surface immunoglobulin) by allergen because of inhibitory signals delivered
subsequent to the binding of Fcg receptors on these cells.
This is thought to be one
mechanism damping down the allergic response.
Another is no further boosting of
IgE production because IL-4 and IL-13 are not secreted. Existing IgE levels themselves
may not fall by much, because IFN-γ does not affect B cells that have already
switched to IgE production.
Although atopic children are repeatedly immunized with protein antigens such
as tetanus toxoid, they almost never develop allergic reactions to these antigens.
Explain.
Most human allergy is caused by a limited number of inhaled protein allergens that
elicit a TH2 response in genetically predisposed individuals. These allergens are
relatively small, highly soluble protein molecules that are presented to the immune
system by the mucosal route at very low doses. It has been estimated that the maximum
exposure to ragweed pollen allergens is less than 1 μg per year. It seems that
transmucosal presentation of very low doses of allergens favors the activation of
IL-4-producing TH2 cells and is particularly efficient at inducing IgE responses. The
dominant antigen-presenting cell type in the respiratory mucosa expresses high levels
of co-stimulatory B7.2 molecules. Expression of B7.2 on antigen-presenting cells
is thought to favor the development of TH2 cells. In contrast, injection of antigen
subcutaneously in large doses, as occurs on vaccination, results in antigen uptake in
the local lymph nodes by a variety of antigen-presenting cells and favors the development
of TH1 cells, which inhibit antibody switching to IgE.
