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