Atopic Asthma and the Immune System
The development of atopic asthma in an individual has both genetic and environmental
components. Genetic research currently implicates at least two key genes
in the predisposition to asthma. One major gene cluster located on chromosome
5 codes for a group of cytokines that mediate inflammatory immune responses
(IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, and GM-CSF). Gene linkage studies
have connected this gene cluster (particularly IL-4) with both IgE production
and manifestation of the asthmatic phenotype. Another potential "asthmatic"
gene, located on chromosome 11, involves a mutation in the ß chain
of Fcbeen linked with atopy (Holgate et al. 29; Bradding 305).
Environmental influences are also critical to the acquisition of atopic
asthma. Despite having a genetic predisposition for asthma, the actual expression
of asthmatic symptoms in an individual requires the initial sensitization
to an environmental allergen (Sporik et al. 502). Sensitization to allergens
may occur as early as in the developing fetus. Such intrauterine exposure
results from allergens passing directly across the placenta or via maternal
cells carrying allergens into the fetal bloodstream (Holgate et al. 30).
More definitive research has been done with regards to sensitization in
early childhood. One longitudinal study strongly correlates development
of atopic asthma with childhood sensitization to inhaled house-dust mite
allergen (Der p I). This allergen is present in large quantities in the
average house, particularly in mattresses and carpets, where very early
exposure (to a newborn) is likely to occur. Other aeroallergens, derived
from cat dander, cockroach, and grass pollen, have also been linked to early
sensitization (Sporik et al. 502-6; Utell and Looney 49).
One model for the development of asthma proposes that initial sensitization
to environmental allergens occurs in infancy or early childhood through
a "competition" between T lymphocyte subsets. Upon initial exposure
to an allergen, an individual's CD4+ T helper cells begin to differentiate
into Th1 or Th2 cells (Holt 44-5). Th1 cells mediate phagocytic immune responses
to intracellular microbes, while Th2 cells mediate IgE-dependent immune
responses to allergens (Abbas et al. 207-8). In addition to mediating immune
responses, each of these T cell subsets produces cytokines that inhibit
the proliferation of the other subset. Th1 cells produce high levels of
IFN-\ which inhibits Th2 cell growth. Th2 cells, conversely, produce IL-10
which inhibits Th1 cell growth, and IL-4 which promotes IgE production (a
vital component of atopy). In response to an allergen, these mutually antagonistic
cell populations will competitively grow, and one subset will become dominant
and differentiate into memory cells that will determine future responses
to the allergen. When the Th1 subset is dominant, the individual is able
to inhibit IgE production, which effectively protects against atopy. This
IgE suppression may also be enhanced by allergen-specific CD+8 T cells that
secrete IFN-\. However, if the Th2 subset is dominant, IgE production is
increased and the individual becomes atopic for the allergen (Holt 44-45;
Corrigan et al. 504).
Once sensitization to an allergen has occurred, all subsequent exposures
to that allergen will elicit a hypersensitive immune response, as seen in
asthma. The immune response begins with the binding, processing, and presentation
of the allergen by dendritic cells in the lungs. In non asthmatic individuals,
the bronchial epithelium provides a protective barrier against inhaled allergens
that prevents these particles from reaching the antigen presenting dendritic
cells beneath the epithelial layer. In asthmatic patients however, it has
been demonstrated that the bronchial epithelium is unusually permeable to
certain allergens, allowing access to the subepithelial dendritic cells.
Bronchial epithelial cells in asthmatic individuals have also been shown
to secrete GM-CSF, which enhances the proliferation and antigen-presenting
capabilities of dendritic cells. The result of these aberrations in the
bronchial epithelium is the increased presentation of allergen to hypersensitivity-mediating
T cells (Mori et al. 817-818).
The immune response to inhaled allergen is mediated by two major pathways,
each associated with a distinct phase in the asthmatic reaction (see Fig.1
at end of paper). Because both of these pathways are initiated by specific
Th2 cell recognition of processed allergen, the T cell is considered to
be the central orchestrator of all immune responses against the allergen
(Corrigan et al. 503; Kay, Corrigan, and Frew 107s). The initial response
to allergen exposure is called the early phase asthmatic response (occurring
4 to 6 minutes after exposure), and is mediated by the IgE antibody network.
Though such humoral immunity is directly controlled by B cells, antibody
production cannot occur without the critical second signal provided by T
cell help (Abbas et al. 189). Upon activation by allergen, the Th2 cell
secretes IL-4 which induces the isotype-switching and production of allergen-specific
IgE by B lymphocytes. IgE binds to the allergen, and this complex in turn
binds to certain high affinity IgE receptors (Fcal. 421).
After binding to the mast cell, these allergen-IgE complexes cross-link
with each other, which stimulates the mast cell to release its intracellular
granules (Sutton et al. 421). Such degranulation is also stimulated by histamine
releasing factors secreted by T cells (Wilson et al. 86). Mast cell granule
products, including histamine, leukotrienes, tryptase, prostoglandin, and
platelet-activating factor, are major contributors to the clinical manifestations
of asthma. These products produce the immediate bronchoconstriction, vasodilation
(resulting in bronchial edema), mucus secretion, and tissue destruction
that characterize an early phase asthmatic response. However, despite their
initial potency, these mast cell granule-mediated responses are short-lived
and comprise only the initial acute phase of the asthmatic process (Holgate
et al. 31; Redington et al. 23-31,36; McFadden and Gilbert 1929-30).
IgE cross-linking also stimulates mast cells to secrete various inflammatory
cytokines (see Fig.2), including IL-4, IL-5, and TNF-ÿ (all originally
thought to be exclusively produced by T cells). IL-4 further amplifies the
IgE-mediated pathway, and along with TNF-ÿ, increases the expression
of certain vascular endothelial (and epithelial) cell adhesion molecules
(E-selectin, ICAM-1, VCAM-1) that recruit eosinophils, T cells, and other
inflammatory cells. IL-5 also aids in recruiting and activating eosinophils.
This mast cell cytokine production mediates the beginning of the late phase
asthmatic response (4 to 6 hours after exposure), which is marked by the
initial recruitment of inflammatory cells to the site of allergen exposure
before Th2 cells ever arrive. (Drazen et al. 1-2; Holgate 30-31; Okayama
et al. 1796-1797,1806; Redington et al. 36, 42-43).
The bronchial epithelium also plays a role in the IgE-mediated response
to allergen. It has been demonstrated that bronchial epithelial cells in
many asthmatics express a low-affinity IgE receptor (Fcexpression of pro-inflammatory
adhesion molecules (Campbell et al. 506-8). Furthermore, such direct IgE
binding to the bronchial epithelium stimulates these cells to produce IL-8,
which serves as a powerful eosinophil attractant when complexed with IgA
(Holgate et al. 32).
The second pathway in an asthmatic immune response is the direct Th2 cell-mediated
eosinophil recruitment and infiltration of the lungs in the late phase asthmatic
response. This recruitment phase is begun by IgE-activated mast cells (as
described above) and is greatly enhanced by the eventual arrival of Th2
cells to the site of allergen exposure (Holgate et al. 31; Makino et al.
19). In addition to IL-4, Th2 cells secrete IL-3, IL-5, and GM-CSF, all
of which result in the migration of eosinophils to the region of allergen
exposure. As seen in mast cells, these cytokines promote the expression
of certain adhesion molecules by local endothelial cells to increase eosinophil
binding, and also function in eosinophil activation, differentiation, and
survival (Drazen et al. 1-2; Redington et al. 31-2; Corrigan et al. 502-6).
The bronchial epithelium has also been shown to secrete IL-8, GM-CSF, and
RANTES, which all act as eosinophil attractants and activators (Davies et
al. 428-29; Wang, Devalia, et al. 27-28).
Eosinophils recruited to the site of allergen exposure become the major
effector cells of the late phase asthmatic response. The effects of eosinophil
action are manifold. The most significant result of the eosinophil response
in asthma is the damage and death of the bronchial epithelium, which is
directly correlated with increased airway hyperresponsiveness. This toxic
effect is mediated by several eosinophil granule products, including major
basic protein, eosinophil cationic protein, and eosinophil peroxidase. Eosinophils
also release certain chemical mediators, such as platelet activating factor
and leukotriene-4, which increase bronchoconstriction, vasodilation, and
bronchial hyperresponsiveness. Furthermore, eosinophils secrete several
cytokines (IL-3, IL-5, GM-CSF) that are thought to function in a self-promoting
autocrine manner (Makino 17-19; Corrigan 502-3; Kay and Corrigan 58; Drazen
et al. 2). Because of their late entrance into the immune response and the
significant damage caused to bronchial epithelium, eosinophil effector mechanisms
are responsible for the long-term bronchial inflammation and chronic symptoms
of asthma (Corrigan et al. 505).
It is apparent from these immunological effects and from personal experience
that asthma is a serious, and potentially life-threatening disease, whose
management is a major goal of medicine. One of the most effective and widely
used clinical treatments for atopic asthma is inhaled corticosteroids. These
drugs function as anti-inflammatory agents, aimed at reducing the edema,
leukocyte infiltration, and bronchial hyperresponsiveness that are characteristic
of the late-phase asthmatic response. The anti-inflammatory action of corticosteroids
takes several forms. The major anti-inflammatory effect is the inhibition
of the cytokines responsible for mediating asthmatic atopy, particularly
those cytokines that recruit asthmatic effector cells. Inhaled corticosteroids
inhibit cytokine production primarily at the molecular level. Proposed mechanisms
for this molecular intervention include inhibition of cytokine gene transcription,
breakdown of cytokine mRNA, and inhibition of cytokine receptor synthesis
(Wang, Devalia, et al. 35). Corticosteroids also alleviate asthma by acting
as vasocontrictors, which decrease airway edema and mucus secretion (Hanania
et al. 196). Finally, these drugs may actually promote the repair of damaged
epithelium, including regeneration of epithelial cilia (Duddridge et al.
489).
The specific inhaled corticosteroid that I use to control my asthma is called beclomethasone dipropionate (BDP) (sold as Vanceril). This particular steroid inhibits the production of several pro-inflammatory cytokines by bronchial epithelial cells. Several studies have shown that IL-8, GM-CSF, and RANTES expression by bronchial epithelia are all down-regulated during treatment with BDP. Since these cytokines regulate eosinophil chemotaxis and activation, BDP treatment results in significantly decreased numbers of activated eosinophils in the bronchial epithelium and decreased bronchial hyperresponsiveness (Wang, Trigg, et al. 1025,1032; Davies et al. 428-29; Wang, Devalia, et al. 27,35). This effective elimination of eosinophils from the site of allergen exposure prevents these cells from inflicting much of their damage on bronchial epithelium and reduces eosinophil-mediated swelling. In addition to eosinophils, BDP may also decrease mast cell populations and damaged bronchial epithelial cell numbers in the lung (determined from bronchial aspirate)(Duddridge et al. 495). Finally, though BDP has not been shown to decrease lung T cell numbers, this corticosteroid does inhibit T cell activation, as evidenced by decreased expression of the activation markers CD25 and HLA-DR following BDP treatment (Wilson et al. 86,89).
Despite the remarkable anti-inflammatory effectiveness of inhaled beclomethasone
dipropionate, recent studies have revealed several harmful systemic side
effects, particularly associated with high dose usage. These side effects
range from the relatively minor oral candidiasis and hoarseness to the more
problematic adrenal suppression, decreased bone density, osteoporosis, cataract
formation, hyperglycemia and other metabolic changes, skin thinning, and
behavioral changes (Hanania et al. 196-204; Nicolaizik et al. 625,627-8).
It must be noted, however, that many of these side effects are somewhat
unsubstantiated or even contradicted by reliable studies. For example, two
recent studies find no evidence for the reputed decreases in bone density
or overall growth (Allen et al. 967; Hopp et al. 189).
Since increased BDP dosage has been directly correlated with improved lung
function and asthma control, many treatment regimens employ frequent high
doses of BDP (800-1000 µg/day), especially in patients with serious
asthmatic symptoms (Hanania et al. 197). Practically speaking, the proven
anti-inflammatory effects of beclomethasone dipropionate and other inhaled
corticosteroids far outweigh the low incidence of side effects observed,
especially considering that my usual dosage is 84 µ/day. As a matter
of precaution, numerous studies recommend that patients use as low a dose
of steroid as possible to contain asthmatic symptoms (Hanania et al. 204;
Nicolaizik et al. 628). As an interesting side note, in my research for
this paper, I came across many references to a new inhaled corticosteroid
called fluticasone propionate (FP). Several of these studies compared the
anti-asthmatic effects of FP with BDP to assess relative efficacy, and found
that one dose of FP is at least as effective as two doses of BDP in controlling
bronchial hyperresponsiveness (Bootsma et al. 1044; Fabbri et al. 817; Booth
et al. 45). In addition, another study found that FP use had markedly less
side effects than BDP use, specifically with regards to growth rate (Wolthers
and Pedersen 673-675). With further evidence, I may consult my allergy doctor
concerning a change in therapy strategies from inhaled BDP to FP to minimize
my risk (however small) of harmful side effects.
Atopic asthma is a serious inflammatory lung disease which has both genetic
and environmental components to its development. After initial sensitization,
the typical immune response to inhaled allergen is composed of two distinct
pathways. The IgE-mediated pathway activates mast cells and the bronchial
epithelium, and is responsible for the acute symptoms of an early asthma
attack. The Th2 cell-mediated pathway of eosinophil recruitment results
in the more long-term, sustained effects of chronic asthma. Together, these
pathways form an intricate web of cellular interaction. Through the use
of cytokines, granule-derived mediators, and antibodies, the many cell types
implicated in the pathogenesis of asthma communicate and regulate one another
to produce a beautiful, yet deadly amplification system for the symptomatic
effects of asthma. The management of these effects, through the use of inhaled
corticosteroids (such as BDP), has been a significant achievement of modern
medicine. However, the persistence of incomplete asthma control and drug
side effects necessitate further advances before I can breathe easily.
Figure 1: Two Major Immune Pathways Mediating Atopic
Asthma (adapted from J.M. Drazen et al. 2; and C.J.
Corrigan and A.B. Kay 505)
UNDER CONSTRUCTION
Table 1: Cytokines Mediating Immune Pathways in Atopic
Asthma (from mainly from A.E. Redington et al. 32;
J.M. Drazen et al.; and others)
| Cytokine: | Secreted from: | Effect: |
| IL-3 | Th2 cells, mast cells, eosinophils | eosinophil recruitment, survival, and activation |
| IL-4 | Th2 cells, mast cells | B cell isotype switching to IgE, upregulates expression of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin), eosinophil recruitment |
| IL-5 | Th2 cells, mast cells, eosinophils | eosinophil recruitment, survival, and activation |
| IL-8 | bronchial epithelium, mast cells | T cell and eosinophil recruitment |
| GM-CSF | Th2 cells, bronchial epithelium, mast cells, eosinophils | eosinophil recruitment, survival, and activation (autocrine effect when produced by eosinophils) |
| TNF-a | Th2 cells, mast cells | upregulates expression of endothelial adhesion molecules |
| RANTES | bronchial epithelium | eosinophil recruitment, activation, and factor release |
© Copyright 2000 Department of Biology,
Davidson College, Davidson, NC 28036
Send comments, questions, and suggestions to: macampbell@davidson.edu