REVIEW

Arch. Immunol. Ther. Exp., 2009, 57, 331–344

PL ISSN 0004-069X
DOI 10.1007/s00005-009-0039-4

Immunopathogenesis of bronchial asthma

Milan Buc1, Martin Dzurilla1, Mojmir Vrlik2 and Maria Bucova1
1
Department of Immunology, Comenius University School of Medicine, Bratislava, Slovakia
2
Martin Immunology Centre, Martin, Slovakia

Received: 2009.01.15, Accepted: 2009.04.16, Published online: 2009.08.18

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009

Abstract
Bronchial asthma is a common immune-mediated disorder characterized by reversible airway inflammation, mucus produc-
tion, and variable airflow obstruction with airway hyperresponsiveness. Allergen exposure results in the activation of numer-
ous cells of the immune system, of which dendritic cells (DCs) and Th2 lymphocytes are of paramount importance. Although
the epithelium was initially considered to function solely as a physical barrier, it is now evident that it plays a central role in
the Th2-cell sensitization process due to its ability to activate DCs. Cytokines are inevitable factors in driving immune
responses. To the list of numerous cytokines already known to be involved in the regulation of allergic reactions, new
cytokines were added, such as TSLP, IL-25, and IL-33. IgE is also a central player in the allergic response. The activity of
IgE is associated with a network of proteins, especially with its high- and low-affinity Fc receptors. Understanding the cellu-
lar and molecular mechanisms of allergic reactions helps us not only to understand the mechanisms of current treatments,
but is also important for the identification of new targets for biological intervention. An IgE-specific monoclonal antibody,
omalizumab, has already reached the clinic and similar biological agents will surely follow.
Key words: bronchial asthma, cytokines, dendritic cells, IgE, Th2 lymphocytes, corticosteroids, anti-IgE monoclonal anti-
bodies.

Corresponding author: Prof. Milan Buc, MD, Ph.D., Department of Immunology, Comenius University School of Medicine,
Bratislava, Slovakia, tel.: +421 2-59357398, fax: +421 2-59357578, e-mail: milan.buc@fmed.uniba.sk

Bronchial asthma is a chronic inflammatory disease
characterized by a variable degree of airflow obstruction
occurring spontaneously or in response to nonspecific
triggers such as exercise, smoke, and fumes. Most
patients have mild disease, but a significant minority
suffers from more severe forms of the disease despite
optimal medical management. There are basically two
forms of asthma, allergic and non-allergic (intrinsic).
The immunopathology of non-allergic asthma appears
to be very similar to that of allergic asthma, although
there are some differences (Humbert et al. 1999). Aller-
gic asthma is a disease derived from airway inflamma-
tion and bronchoconstriction, which is, however, a sec-
ondary phenomenon of the disease (1991). In developed
countries, 30% of the population is atopic, but only
10–12% of the population actually suffers from asthma
(Hammad and Lambrecht 2008). It is therefore crucial
to understand the genetic and environmental factors as
well as pathogenic mechanisms leading to allergic
inflammation that all eventually result in bronchial asth-
ma development. Much progress in our knowledge of
atopic reactions has been made in recent years and the
aim of this article is to offer the reader a review of these
achievements and their impacts on immunotherapy.
UPTAKE AND TRANSPORT
OF INHALED ALLERGENS
Under physiological circumstances, the epithelium
forms a highly regulated and almost impermeable bar-
rier through the formation of tight junctions. The
epithelial cell layer acts as a molecular sieve that
excludes inhaled antigens and pathogens. However,
some antigens can be recognized by cells of the
immune system and induce an immune response.
Mucosal dendritic cells (DCs) are extremely efficient
sentinels in the defense against antigen challenge.
They are strategically positioned within the epithelium
in the basolateral space, separated from the inhaled air
only by the epithelium tight junction barrier. However,
DCs extend their processes between epithelial cells
directly into the airway lumen (Fig. 1). This
“periscope” function provides a mechanism for contin-
332
Fig. 1. Periscope function of DCs (modified from Hammad and
Lambrecht 2008). DCs intercalate their dendrites between epithe-
lial cells, which enables them to sample the airway lumen. DCs
form tight junctions with epithelial cells through their expression
of adhesive molecules and by E-cadherin homotypic interactions.
uous immune surveillance of the airway luminal sur-
face (Jahnsen et al. 2006).
Although the sampling function of airway DCs
ensures that virtually any inhaled protein will be rec-
ognized and presented to T cells following inhalation,
some allergens, for example those from house dust
mites, compromise the epithelial barrier function by
degrading tight junction proteins, thus facilitating
allergen delivery across epithelial layers (Runswick et
al. 2007; Shakib et al. 2008). Other allergens that lack
protease activity, such as cockroach-derived allergens,
can increase the permeability of bronchial airway
epithelial cells indirectly through the induction of vas-
cular endothelial growth factor (VEGF) (Antony et al.
2002).
Despite the fact that most inhaled antigens are
transported to the lymph nodes by DCs, the usual out-
come following the inhalation of harmless protein anti-
gens is the induction of tolerance. This is because they
cannot fully activate DCs to induce an effective T-cell
response (Reis e Sousa 2006). It follows that DCs have
to be somehow activated to break tolerance.
Conventional DCs express numerous pattern-recogni-
tion receptors, including Toll-like receptors (TLRs),
nucleotide-binding oligomerization domain and C-type
lectin receptors (Sandor and Buc 2005a; Buc 2005b; Buc
2005c; Suarez et al. 2008). As most inhaled allergens,
such as those derived from cockroaches and house-dust
mites, are contaminated with lipopolysaccharides
(LPSs) and peptidoglycans, they can activate DCs. In
fact it was shown that the main house dust mite allergen,
Der p 2, acted as a functional homologue of myeloid dif-
ferentiation factor 2 (MyD2) that drove airway inflam-
mation in a TLR4-dependent manner (Trompette et al.
2009). MyD2 physically associates with the extracellular
domain of human TLR4 and binds the lipid A region of
LPS without the need for LPS-binding protein
(Viriyakosol et al. 2000). Given that many allergens,
including Der p 2, are members of the MyD2-like lipid-
-binding protein family and that more than 50% of
M. Buc et al.: Immunopathogenesis of bronchial asthma
major allergens are lipid-binding proteins, such mimicry
could also explain the immunogenicity of these allergens.
In the absence of contaminating TLR ligands, some
allergens can activate DCs by triggering protease-acti-
vated receptors (PARs). They are present on many cell
types, including epithelial cells, fibroblasts, smooth mus-
cle cells, endothelial cells, and on a number of inflam-
matory cells. There is increasing evidence that besides
DC activation, they are also involved in mesenchymal
cell proliferation and airway wall remodeling (Berger et
al. 2001).
The ligation of TLRs and PARs leads to a cascade of
events that culminates in the production of chemokines
that attract neutrophils, monocytes, and DCs to the air-
ways and to the production of cytokines that can induce
DC maturation and Th2 polarization (Kiss et al. 2007).
Thymic stromal lymphopoietin (TSLP), granulocyte-
monocyte colony-stimulating factor (GM-CSF), and
interleukin (IL)-25 are among the most important.
TSLP is a cytokine with a strong capacity to modu-
late an immune response. TSLP-stimulated DCs are
able to prime human CD4+ T cells into Th2 cytokine-
-producing cells (Ito et al. 2005; Wang et al. 2006).
Moreover, it was shown that TSLP was able to prime
Th2 differentiation directly, in the absence of DCs; the
treatment of naïve CD4+ T cells with TSLP in the pres-
ence of T cell receptor (TCR) stimulation led to IL-4
production and their differentiation into the Th2 subset
(Omori and Ziegler 2007). In addition to its effects on
DCs and naïve CD4+ T cells, TSLP can also activate
mast cells to produce Th2-cell associated effector
cytokines (Holgate 2008).
GM-CSF is another important cytokine that is pro-
duced by airway epithelial cells in response to proteolyt-
ic allergen exposure. Known Th2-cell sensitizers such as
diesel exhaust particles, ambient particulate matter, and
cigarette smoke also induce the release of GM-CSF
from epithelial cells (Bleck et al. 2006). GM-CSF stimu-
lates the proliferation and differentiation of precursors
of neutrophils, eosinophils, and monocytes. It also func-
tionally activates the corresponding mature forms,
enhancing, for example, the expression of certain cell-
-surface adhesion proteins (LFA-1, Mac-1). The over-
-expression of these proteins could be one explanation
for the observed local accumulation of neutrophils and
eosinophils at sites of inflammation. Moreover, GM-
-CSF stimulates in them the release of arachidonic acid
metabolites and the increased generation of reactive
oxygen intermediates (ROI) (Holgate 2008).
Antigen uptake and TSLP trigger the maturation of
DCs and their migration to mediastinal lymph nodes,
during which they up-regulate the expression of HLA
class II antigens and co-stimulatory molecules. When
they enter the lymph nodes, the already mature DCs
induce the activation and polarization of naïve T-helper
cells. This process involves interactions between the co-
-stimulatory molecules OX40 (CD134) in the membranes
of naïve T cells and OX40L (CD134L) in the membranes
of DCs. The co-stimulatory interactions result in the