Pathogenesis of Allergic Airway Inflammation
Devendra K. Agrawal & Zhifei Shao
Published online: 31 December 2009
#
Springer Science+Business Media, LLC 2010
Abstract Advances have been made in defining the
mechanisms for the control of allergic airway inflamma-
tion in response to inhaled antigens. Several genes,
including ADAM33, DPP10, PHF11, GPRA, TIM-1,
PDE4D, OPN3,andORMDL3, have been implicated in
the pathogenesis and susceptibility to atopy and asthma.
Growing evidence associates asthma with a systemic
propensity for allergic T-helper type 2 cytokines. Disor-
dered coagulation and fibrinolysis also exacerbate asthma
symptoms. Balance among functionally distinct dendritic
cell subsets contributes to the outcome of T-cell-mediated
immunity. Allergen-specific T-regulatory cells play a
pivotal role in the development of tolerance to allergens
and immune suppression. The major emphasis on immu-
notherapy for asthma during the past decade has been to
direct the immune response to a type 1 response, or
immune tolerance. In this review, we discuss the current
information on the pathogenesis of allergic airway
inflammation and potential immunotherapy, which could
be beneficial in the treatment of airway inflammation,
allergy, and asthma.
Keywords Allergic airway inflammation
.
Asthma
.
Asthma gene
.
Coagulation system
.
Cytotoxic Tcell
.
Dendritic cell
.
Flt3 ligand
.
KCa3.1
.
Matrix metalloproteinase
.
T helper cell
.
T regulatory cell
Introduction
Asthma is a disease of chronic airway inflammation
characterized by reversible airway obstruction, airway
hyperresponsiveness (AHR), infiltration of eosinophils and
T-helper type 2 (Th2) cells into the airway submucosa,
mucus hypersecretion, and airway remodeling [1]. Allergic
asthma is classified as a type 1 hypersensitivity reaction.
This involves allergen-specific immunoglobulins of the IgE
class bound to high-affinity Fcε receptors on the surfaces of
basophils and mast cells present in the subepithelial layer of
the airways. Cross-linking of these bound IgE molecules
results in an immediate release of mediators, including
leukotrienes, prostaglandins, and histamine, that are capable
of contracting airway smooth muscle cells and that induce
edema and mucus secretion, leading to narrowed, con-
stricted airways. Locally produced chemokines stimulate
the recruitment of eosinophils, macrophages, neutrophils,
and T lymphocytes [1]. Once present, effector cells such as
eosinophils release a collection of toxic granules that in turn
cause prolonged bronchoconstriction and damage epithelial
layers. This damage, coupled with profibrotic cytokines
also released by eosinophils and epithelial cells may lay the
groundwork for airway remodeling to begin [2]. Cytokines
released at the time of mast cell degranulation can have
more global effects. These include recruiting eosinophils
from bone marrow and peripheral sources in addition to
encouraging their survival (primarily via interleukin [IL]-5
and granulocyte-macrophage colony-stimulating factor) and
the stimulation and continued production of IgE by B cells,
as well as the induction of vascular cell adhesion molecule-
1 by endothelial cells (IL-4) [1]. Cytokines such as IL-4,
IL-5, IL-6, and IL-13 ensure that this cycle of allergic
inflammation persists (Table 1). The prevalence of asthma
has been increasing steadily for several decades. Although
D. K. Agrawal (*)
:
Z. Shao
Center for Clinical and Translational Science,
Creighton University School of Medicine,
CRISS II, Room 510, 2500 California Plaza,
Omaha, NE 68178, USA
e-mail: dkagr@creighton.edu
Curr Allergy Asthma Rep (2010) 10:39–48
DOI 10.1007/s11882-009-0081-7

there is an appreciable genetic component [1], external
influences may regulate/influence the immune system by
affecting the differentiation and activation of T lympho-
cytes. Therapeutic approaches targeting intrinsic and
extrinsic factors have been under extensive investigation.
Th1/Th2 Polarized Immunity
It is generally accepted that allergic respiratory disease in
adults is associated with active T-cell immune responses to
inhaled allergens that are skewed toward the Th2 pheno-
type, which is in contrast to a Th1-skewed immunity in
healthy individuals. Th1 cells secrete interferon (IFN)-γ,
IL-12, and lymphotoxin (tumor necrosis factor-β), whereas
Th2 cells secrete IL-4, IL-5, IL-9, and IL-13 (Fig. 1). Th1
cells enhance cellular immune responses; Th2 cells favor
humoral antibody production (IgE), such as allergic
asthmatic response. The improved hygiene results in a
decreased stimulation of a type 1 response and thus leads to
a greater stimulation of type 2 responses and a consequent
predisposition to allergic diseases. Unequal apoptosis of Th1
and Th2 effector cells in atopic patients leads to preferential
deletion of circulating memory or effector Th1 cells [3],
especially the high IFN-γ-producing Th1 cells [4? ], which
contributes to the skewing of the immune response toward
surviving Th2 cells. New effector T-cell lineages were
identified recently. Th17 cells, which differentiate from naïve
CD4
+
T cells under the influence of IL-6/IL-21/IL-23 and
transforming growth factor (TGF)-β via signal transducer
and activator of transcription 3 (STAT3)-RORγt pathway,
are mainly responsible for neutrophilia in allergic asthma
(Fig. 1)[5? ]. In the presence of IL-4 and TGF-β, Th2 cells
can be reprogrammed to a new T-cell lineage expressing IL-
9 and IL-10, namely Th9 cells (Fig. 1)[6? ].
Transcription Factors Responsible for the Th1/Th2
Dichotomy
The determination of T-helper lineage fates of Th1 or Th2
is accompanied by a differential activation, expression, and
Table 1 Release of cytokines and other mediators and their effects from various cells involved in allergic airway inflammation
Inflammatory cells infiltrated in the lung Cytokines/mediators released Biological effects
Cells that exacerbate inflammation and asthma
Eosinophils,
neutrophils
Oxygen radicals and lipid mediators , cytokines
(IL-1, IL-2, IL-3, IL-4, IL-5,
IL -6, IL-10, IL-12, and IL-13; TNF-α; and GM-CSF),
chemokines (IL-8, RANTES, and MIP-1α), fibrogenic
cytokines (TGF-β, IL-11, IL-17, and IL-25)
Prolonged bronchoconstriction,
damaged epithelium, airway
remodeling
Basophils, mast cells Histamine, MBP Vasculature exudation, increased
mucus in the airways
Th2 cells IL-4, IL-5, IL-9, IL-13 Humoral antibody production,
chemotaxis and survival of
eosinophils
Th17 cells IL-6, IL-8, IL-17A, IL-17F, IL-22, IL-26 Neutrophilia, AHR, airway
remodeling
Dendritic cells IL-4, IL-12, GM-CSF Induction of Th2 cells, suppression
of Th1 cells
CD8
+
T cells IL-4, IL-5, IL-9, IL-13 AHR, eosinophilia
Cells that suppress allergic and asthmatic response
T-regulatory cells IL-10, TGF-β Prevention of T-cell expansion
CD8
+
T cells IFN-γ, IL-12 Suppression of allergic immune
response
Th1 cells IL-2, IFN-γ, lymphotoxin (TNF-β) Enhanced cellular response,
suppression of Th2 cells
Plasmacytoid
dendritic cells
IL-10, TGF-β T-cell suppression
Regulatory dendritic
cells
IL-12 (LPS, bacterial CpG, CpR oligonucleotides) Induction of Th1 cells
AHR—airway hyperresponsiveness; CpG—cytosine-phosphorothiolated guanine; CpR—cytosine-phosphorothiolated 2 -dioxy-7-deazaguanosine;
GM-CSF—granulocyte-macrophage colony-stimulating factor; IFN—interferon; IL—interleukin; LPS—lipopolysaccharide; MBP—major basic
protein; MIP—macrophage inflammatory protein; RANTES—regulated on activation, normal T-cell expressed and secreted; TGF—transforming
growth factor; Th —T-helper type cell, TNF—tumor necrosis factor
40 Curr Allergy Asthma Rep (2010) 10:39–48