Download Immunology of asthma and chronic obstructive pulmonary disease

f o c u s o n a l l er g Y a n d RAs
E VtIh
Em
Wa
S
Immunology of asthma and chronic
obstructive pulmonary disease
Peter J. Barnes
Abstract | Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive
airway diseases that involve chronic inflammation of the respiratory tract, but the type of
inflammation is markedly different between these diseases, with different patterns
of inflammatory cells and mediators being involved. As described in this Review, these
inflammatory profiles are largely determined by the involvement of different immune cells,
which orchestrate the recruitment and activation of inflammatory cells that drive the
distinct patterns of structural changes in these diseases. However, it is now becoming clear
that the distinction between these diseases becomes blurred in patients with severe
asthma, in asthmatic subjects who smoke and during acute exacerbations. This has
important implications for the development of new therapies.
Chronic obstructive
pulmonary disease
(COPD). A group of diseases
characterized by the
pathological limitation of
airflow in the airway, including
chronic obstructive bronchitis
and emphysema. It is most
often caused by tobacco
smoking, but can also be
caused by other airborne
irritants, such as coal dust, and
occasionally by genetic
abnormalities, such as
α1-antitrypsin deficiency.
Atopic (extrinsic) asthma
The commonest form of
asthma in which the patients
are atopic (as indicated by a
positive skin-prick test and the
presence of IgE to common
inhalant allergens, such as
house-dust mites) and have
allergic inflammation of the
airways.
Airway Disease Section,
National Heart and Lung
Institute, Imperial College
London, Dovehouse Street,
London SW3 6LY, UK.
e-mail:
[email protected]
doi:10.1038/nri2254
Published online
15 February 2008
Asthma and chronic obstructive pulmonary disease
(COPD) are both very common and their incidence
is increasing globally, placing an increasing burden
on health services in industrialized and developing
countries1–3. Both diseases are characterized by airway
obstruction, which is variable and reversible in asthma
but is progressive and largely irreversible in COPD.
In both diseases, there is chronic inflammation of the
respiratory tract, which is mediated by the increased
expression of multiple inflammatory proteins, including
cytokines, chemo­kines, adhesion molecules, inflammatory enzymes and receptors. In both diseases there are
acute episodes or exacerbations, when the intensity of
this inflammation increases. The similarity between
these airway diseases prompted the suggestion in the
1960s that asthma and COPD are different forms of
a common disease (chronic obstructive lung disease),
and this came to be known as the ‘Dutch hypothesis’.
This was countered by the ‘British hypothesis’, which
maintained that these diseases were separate entities;
the debate continues today, with evidence both for and
against these two views4,5.
Despite the similarity of some clinical features of
asthma and COPD, there are marked differences in the
pattern of inflammation that occurs in the respiratory
tract, with different inflammatory cells recruited, different mediators produced, distinct consequences of
inflammation and differing responses to therapy. In
addition, the inflammation seen in asthma is mainly
located in the larger conducting airways, and although
small airways can also be affected in more severe forms
nature reviews | immunology
of the disease, the lung parenchyma is not affected. By
contrast, COPD predominantly affects the small airways
and the lung parenchyma, although similar inflammatory changes can also be found in larger airways6,7. These
differences in disease distribution may partly reflect the
distribution of inhaled inciting agents, such as allergens
in asthma and tobacco smoke in COPD. In both diseases, there are different clinical phenotypes recognized.
Most patients with asthma are atopic (extrinsic asthma),
but a few patients are non-atopic (intrinsic asthma), and
these patients often have a more severe form of the disease8. There is a range of asthma severity, which tends
to be maintained throughout life9. Approximately 5%
of patients have severe asthma that is difficult to control with maximal inhaler therapy and for whom new
therapeutic approaches are needed. The main types of
COPD are the development of small-airway obstruction
and emphysema, which can occur alone or together, but
which both involve progressive airflow limitation and
are usually caused by tobacco smoke.
The differences in inflammation between asthma
and COPD are linked to differences in the immunological mechanisms that underlie these two diseases
(FIGS 1,2). There have been several recent important
advances in our understanding of the immunopathology of asthma and COPD, and these are discussed in
this Review. T cells have a crucial role in both asthma
and COPD and it is now recognized that different subsets are involved in orchestrating inflammation in these
two diseases, resulting in different inflammatory and
structural consequences. B cells also have an important
volume 8 | march 2008 | 183
© 2008 Nature Publishing Group
REVIEWS
Inhaled allergens
Epithelial cells
CCL11
SCF
Mast cell
TSLP
Histamine, cysteinyl
leukotrienes and
prostaglandin D2
IL-9
CCR4
Smooth-muscle
cell
Bronchoconstriction
Dendritic
cell
CCL17 and
CCL22
IgE
TH2 cell
Antibody
production
IL-13
IL-4
↓ TReg
cells?
IL-5
CCR3
Eosinophil
B cell
Eosinophilic inflammation
Figure 1 | Inflammatory and immune cells involved in asthma. Inhaled allergens
activate sensitized mast cells by crosslinking surface-bound IgE
molecules
release
Nature
Reviewsto| Immunology
several bronchoconstrictor mediators, including cysteinyl leukotrienes and
prostaglandin D2. Epithelial cells release stem-cell factor (SCF), which is important for
maintaining mucosal mast cells at the airway surface. Allergens are processed by myeloid
dendritic cells, which are conditioned by thymic stromal lymphopoietin (TSLP) secreted
by epithelial cells and mast cells to release the chemokines CC‑chemokine ligand 17
(CCL17) and CCL22, which act on CC‑chemokine receptor 4 (CCR4) to attract T helper 2
(TH2) cells. TH2 cells have a central role in orchestrating the inflammatory response in
allergy through the release of interleukin‑4 (IL‑4) and IL‑13 (which stimulate B cells to
synthesize IgE), IL‑5 (which is necessary for eosinophilic inflammation) and IL‑9 (which
stimulates mast-cell proliferation). Epithelial cells release CCL11, which recruits
eosinophils via CCR3. Patients with asthma may have a defect in regulatory T (TReg) cells,
which may favour further TH2-cell proliferation.
role, although this remains poorly understood in COPD.
The appreciation that similar immune mechanisms are
involved in both asthma and COPD has important
implications for the development of new therapies for
these troublesome diseases.
Non-atopic (intrinsic)
asthma
An uncommon form of asthma
that is more likely to be severe
and characterized by negative
skin-prick tests. The airway
inflammation is similar to that
of atopic asthma and may be
mediated by local rather than
systemic IgE production.
Emphysema
Destruction of the alveolar
walls, resulting in decreased
gas exchange and contributing
to airflow limitation by loss of
alveolar attachments to the
small airways that serve to
keep the airways open during
expiration.
Inflammatory cells and mediators
There are many differences between mild asthma and
COPD in the type of inflammation that occurs in the lungs,
with a different range of inflammatory cells and mediators
being implicated10,11. However, many of the cytokines and
chemokines that are secreted in both asthma and COPD
are regulated by the transcription factor nuclear factor-κB
(NF-κB), which is activated in airway epithelial cells and
macrophages in both diseases, and may have an important
role in amplifying airway inflammation12,13.
Histopathology. The histological appearance of airways
from asthmatic individuals is very different from the
changes that are observed in patients with COPD (FIG. 3).
Bronchial biopsies from asthmatic subjects reveal an
infiltration of eosinophils, activated mucosal mast cells
184 | march 2008 | volume 8
at the airway surface and activated T cells. There are
characteristic structural changes, with collagen deposition under the epithelium that is sometimes described
as basement-membrane thickening and is found in
all patients with asthma, and thickening of the airway
smooth-muscle cell layer as a result of hyperplasia and
hypertrophy, which is more commonly seen in patients
with severe asthma14. Epithelial cells are often shed from
asthmatic patient biopsies compared to normal control
biopsies, as they are friable and more easily detach from
the basement membrane during the biopsy procedure.
In addition, there is an increase in the number of blood
vessels (angiogenesis) in response to increased secretion of vascular-endothelial growth factor (VEGF)15.
Mucus hyperplasia is commonly seen in biopsies from
asthmatic patients, with an increase in the number of
mucus-secreting goblet cells in the epithelium and an
increase in the size of submucosal glands16.
In biopsies of the bronchial airways, small airways and
lung parenchyma from patients with COPD, there is no
evidence for mast-cell activation, but there is an infiltration of T cells and increased numbers of neutrophils,
particularly in the airway lumen17. Subepithelial fibrosis
is not apparent, but fibrosis does occur around small airways and is thought to be a main factor that contributes
to the irreversible airway narrowing that is characteristic
of this disease18. The airway smooth-muscle cell layer is
not usually increased in COPD patients compared with
normal airways, and airway epithelial cells may show
pseudostratification as a result of chronic irritation from
inhaled cigarette smoke or other irritants and the release
of epithelial-cell growth factors. As in biopsies from
asthma patients, there is mucus hyperplasia and increased
expression of mucin genes in biopsies from patients
with COPD19. A marked difference between COPD and
asthma is the destruction of alveolar walls (emphysema)
that occurs in COPD as a result of protease-mediated
degradation of connective tissue elements, particularly
elastin, and apoptosis of type I pneumocytes and possibly endothelial cells20,21. In addition, the production
of elastolytic enzymes, such as neutrophil elastase and
particularly several matrix metalloproteinases (MMPs),
is increased in the lungs of COPD patients22, and there
may be a reduction in the levels of antiproteinases, such
as α1-antitrypsin, as seen in a rare form of emphysema
caused by a congenital deficiency of α1-antitrypsin23.
Mast cells. Mast cells have a key role in asthma through
the release of several bronchoconstrictors, including
histamine, which is preformed and stored in granules,
and the lipid mediators leukotriene C4, leukotriene D4,
leukotriene E4 and prostaglandin D2, which are synthesized following mast-cell activation. The release of these
mediators may account for the variable bronchoconstriction seen in asthma, as these mediators are released
by various environmental triggers, such as allergens, and
an increase in plasma osmolality as a result of increased
ventilation during exercise. Mucosal mast cells are
recruited to the surface of the airways by stem-cell factor
(SCF; also known as KIT ligand) released from epithelial
cells, which acts on KIT receptors expressed by the
www.nature.com/reviews/immunol
© 2008 Nature Publishing Group
f o c u s o n a l l er g Y a n d RAs
E VtIh
Em
Wa
S
Pseudostratification
Increased proliferation of
airway epithelial cells in chronic
obstructive pulmonary disease,
as a result of the release of
epithelial-cell growth factors,
which lead to increased
thickness of the epithelial-cell
layer.
Type I pneumocytes
Flat alveolar cells that make up
most of the epithelial-cell layer
of the alveolar wall and that are
responsible for gas exchange in
the alveoli.
Bronchoconstrictor
An agent that induces
contraction of airway smooth
muscle and thereby narrows
the airways, thus reducing the
flow of air.
mast cells24. Mast cells also release cytokines that are
linked to allergic inflammation, including interleukin‑4
(IL‑4), IL‑5 and IL‑13 (Ref. 25). The presence of mast
cells in the airway smooth muscle has been linked to
airway hyper-responsiveness in asthma26, as patients with
eosinophilic bronchitis have a similar degree of eosino­
philic inflammation to that found in asthmatics and
also have subepithelial fibrosis, but they do not show
airway hyper-responsiveness, which is the physiological
hallmark of asthma. By contrast, mast cells do not seem
to have a role in COPD, which may explain the lack of
variable bronchoconstriction in this disease.
Granulocytes. The inflammation that occurs in asthma is
often described as eosinophilic, whereas that occurring
in COPD is described as neutrophilic. These differences
reflect the secretion of different chemotactic factors in
these diseases. In asthma, eosinophil chemotactic factors,
such as CC‑chemokine ligand 11 (CCL11; also known
as eotaxin‑1) and related CC‑chemokines, are mainly
secreted by airway epithelial cells. The functional role of
Cigarette smoke
(and other irritants)
Epithelial cells
Macrophage
CXCL9, CXCL10
and CXCL11
CCL2
CXCL1
and CXCL8
TGFβ
CXCR2
CXCR3
Fibroblast
TH1 cell
TC1 cell
Neutrophil
CCR2
Monocyte
Proteases (such as neutrophil
elastase and MMP9)
Airway
epithelial
cell
Mucus
Smoothmuscle
cell
Fibrosis
(small airways)
Alveoli
Alveolar wall destruction
(emphysema)
Goblet
cell
Mucus gland
Mucus
hypersecretion
Figure 2 | Inflammatory and immune cells involved in chronic obstructive
pulmonary disease (COPD). Inhaled cigarette smoke and other
Natureirritants
Reviewsactivate
| Immunology
epithelial cells and macrophages to release several chemotactic factors that attract
inflammatory cells to the lungs, including CC‑chemokine ligand 2 (CCL2), which acts on
CC‑chemokine receptor 2 (CCR2) to attract monocytes, CXC-chemokine ligand 1
(CXCL1) and CXCL8, which act on CCR2 to attract neutrophils and monocytes (which
differentiate into macrophages in the lungs) and CXCL9, CXCL10 and CXCL11, which act
on CXCR3 to attract T helper 1 (TH1) cells and type 1 cytotoxic T (TC1) cells. These
inflammatory cells together with macrophages and epithelial cells release proteases,
such as matrix metalloproteinase 9 (MMP9), which cause elastin degradation and
emphysema. Neutrophil elastase also causes mucus hypersecretion. Epithelial cells and
macrophages also release transforming growth factor‑β (TGFβ), which stimulates
fibroblast proliferation, resulting in fibrosis in the small airways.
nature reviews | immunology
eosinophils in asthma is not clear and the evidence that
links their presence to airway hyper-responsiveness has
been questioned by the finding that the administration of
IL‑5-specific blocking antibodies that markedly reduce
the number of eosinophils in the blood and sputum
does not reduce airway hyper-responsiveness or asthma
symptoms27,28. As discussed above, eosinophilic bronchitis is not associated with airway hyper-responsiveness,
but subepithelial fibrosis does occur, which suggests a
role for eosinophils in airway fibrosis. Interestingly, the
presence of eosinophils seems to be a good marker of
steroid responsiveness29.
Neutrophils are increased in the sputum of patients
with COPD and this correlates with disease severity30.
The increase in neutrophils is related to an increase
in the production of CXC-chemokines, such as CXCchemokine ligand 1 (CXCL1; also known as GROα) and
CXCL8 (also known as IL‑8), which act on CXCR2 that
is expressed predominantly by neutrophils.
Macrophages. Macrophage numbers are increased in the
lungs of patients with asthma and COPD, but their numbers are far greater in COPD than in asthma. These macrophages are derived from circulating monocytes, which
migrate to the lungs in response to chemoattractants such
as CCL2 (also known as MCP1) acting on CCR2, and
CXCL1 acting on CXCR2 (Ref. 31). There is increasing
evidence that lung macrophages orchestrate the inflammation of COPD through the release of chemokines that
attract neutrophils, monocytes and T cells and the release
of proteases, particularly MMP9 (Ref. 32).
The pattern of inflammatory cells found in the respiratory tract therefore differs in patients with asthma
and those with COPD and some of these contrasts
may be explained by differences in the immunological
mechanisms that drive these two diseases.
Immune responses
The immune mechanisms that drive the different inflammatory processes of asthma and COPD are mediated by
different types of immune cell, in particular by different
T‑cell subsets. An understanding of which immune cells
are involved is now emerging and may lead to the development of new and more-specific therapies for airway
diseases in the future (FIGS 1,2).
T cells. In asthmatic patients, there is an increase in the
number of CD4+ T cells in the airways and these are predominantly T helper 2 (TH2) cells, whereas in normal airways TH1 cells predominate33. By secreting the cytokines
IL‑4 and IL‑13, which drive IgE production by B cells,
IL‑5, which is solely responsible for eosinophil differentiation in the bone marrow, and IL‑9, which attracts and
drives the differentiation of mast cells34, TH2 cells have a
central role in allergic inflammation and therefore their
regulation is an area of intense research.
The transcription factor GATA3 (GATA-binding protein 3) is crucial for the differentiation of uncommitted
naive T cells into TH2 cells and it also regulates the secretion of TH2-type cytokines35,36. Accordingly, there is an
increase in the number of GATA3+ T cells in the airways
volume 8 | march 2008 | 185
© 2008 Nature Publishing Group
REVIEWS
Asthma
COPD
Inflammation
Airway smooth muscle
Basement membrane
Fibrosis
Alveolar disruption
Airway hyperresponsiveness
Increased narrowing of the
airways, initiated by exposure
to a defined stimulus that
usually has little or no effect
on airway function in normal
individuals. This is a defining
physiological characteristic of
asthma.
TH2 cells
(T helper 2 cells). The definition
of a CD4+ T cell that has
differentiated into a cell that
produces the cytokines
interleukin‑4 (IL‑4), IL‑5 and
IL‑13, thereby supporting
humoral immunity and
counteracting TH1-cell
responses. An imbalance of
TH1–TH2-cell responses is
thought to contribute to the
pathogenesis of various
infections, allergic responses
and autoimmune diseases.
TH1 cells
(T helper 1 cells). The definition
of a CD4+ T cell that has
differentiated into a cell that
produces the cytokines
interferon‑γ and tumournecrosis factor, thereby
promoting cell-mediated
immunity.
Inflammation
+++
+++
Airway smooth muscle
+++
+
Basement membrane
++
–
Fibrosis
+ (subepithelial)
+++ (peribronchiolar)
Alveolar disruption
–
+++
Airway vessels
++
No change
Mast cells
++ (and activated)
Normal
Dendritic cells
++
ND
Eosinophils
++
Normal
Neutrophils
Normal
++
Lymphocytes
TH2 type
TH1 and TC1 type
Epithelium
Often shed
Pseudostratified
Goblet cells
++
++
Figure 3 | Contrasting histopathology of asthma and chronic obstructive pulmonary disease (COPD). A small airway
from a patient who died from asthma and a similar sized airway from a patient with severe COPD are shown. There is an
Nature Reviews | Immunology
infiltration of inflammatory cells in both diseases. The airway smooth-muscle cell layer is thickened in asthma but only to
a minimal degree in COPD. The basement membrane is thickened in asthma due to collagen deposition (subepithelial
fibrosis) but not in COPD, whereas in COPD collagen is deposited mainly around the airway (peribronchiolar fibrosis). The
alveolar attachments are intact in asthma, but disrupted in COPD as a result of emphysema. Images courtesy of Dr J. Hogg
(Vancouver, Canada). Other differences in the cellular infiltrate in the two diseases are also shown. ND, not determined;
TC1, type 1 cytotoxic T; TH1, T helper 1.
of asthmatic subjects compared with normal subjects37,38.
Following simultaneous ligation of the T‑cell receptor
(TCR) and co-receptor CD28 by antigen-presenting
cells, T‑cell GATA3 is phosphorylated and activated
by the mitogen-activated protein kinase (MAPK) p38.
Activated GATA3 then translocates from the cytoplasm
to the nucleus, where it activates gene transcription39.
GATA3 expression in T cells is regulated by the transcription factor STAT6 (signal transducer and activator
of transcription 6), which is in turn regulated by IL‑4
receptor activation.
For TH1-cell differentiation and secretion of the TH1type cytokine interferon‑γ (IFNγ), the crucial transcription factor is T‑bet. Consistent with the prominent role
of TH2 cells in asthma, T‑bet expression is reduced in
T cells from the airways of asthmatic patients compared
with non-asthmatic subjects40. When phosphorylated,
T‑bet can associate with and inhibit the function of
GATA3, by preventing it from binding to its DNA target
sequences41. T‑bet-deficient mice show increased expression of GATA3 and production of TH2-type cytokines,
confirming that T‑bet is an important regulator of
GATA3 (Ref. 40). GATA3 expression is also regulated by
IL‑27, a recently identified member of the IL‑12 family,
which downregulates GATA3 expression and upregulates T‑bet expression, thereby favouring the production
186 | march 2008 | volume 8
TH1-type cytokines, which then act to further inhibit
GATA3 expression42. In turn, GATA3 inhibits the production of TH1-type cytokines by inhibiting STAT4, the
key transcription factor activated by the T‑bet-inducing
cytokine IL‑12 (Ref. 43) (FIG. 4). Nuclear factor of activated
T cells (NFAT) is a T‑cell-specific transcription factor
and appears to enhance the transcriptional activation of
GATA3 by targeting the IL4 promoter44. Finally, IL‑33, a
newly discovered member of the IL‑1 family of cytokines,
seems to promote TH2-cell differentiation by translocating to the nucleus and regulating transcription through
an effect on chromatin structure45, but it also acts as a
selective chemo­attractant of TH2 cells by binding the surface receptor IL‑1-receptor-like 1 (also known as ST2),
which is specifically expressed by these cells46.
In contrast to asthma, the CD4+ T cells that accumulate in the airways and lungs of patients with COPD are
mainly TH1 cells. TH1 cells express the chemokine receptor CXCR3 (Ref. 47) and may be attracted to the lungs by
the IFNγ-induced release of the CXCR3 ligands CXCL9
(also known as MIG), CXCL10 (also known as IP‑10)
and CXCL12 (also known as I‑TAC), which are present
at high levels in COPD airways48,49. However, there is
some evidence that TH2 cells are also increased in lavage
fluid of patients with COPD50; likewise, in patients with
more severe asthma, TH1 cells are activated, as well as
www.nature.com/reviews/immunol
© 2008 Nature Publishing Group
f o c u s o n a l l er g Y a n d RAs
E VtIh
Em
Wa
S
Regulatory T cells
A specialized type of CD4+
T cells that can suppress the
responses of other T cells.
These cells provide a crucial
mechanism for the
maintenance of peripheral selftolerance and a subset of these
cells is characterized by
expression of CD25 and the
transcription factor forkhead
box P3 (FOXP3).
Allergic rhinitis
Allergic inflammation that is
caused by the pollen of specific
seasonal plants, such as
grasses (causing hay fever), and
house dust (causing perennial
rhinitis) in people who are
allergic to these substances. It
is characterized by sneezing,
and a runny and blocked nose.
TH17 cells
(T helper 17 cells). A subset of
CD4+ T helper cells that
produce interleukin‑17 (IL‑17)
and that are thought to be
important in inflammatory and
autoimmune diseases. Their
generation involves IL‑23 and
IL‑21, as well as the
transcription factors RORγt
(retinoic-acid-receptor-related
orphan receptor-γt) and STAT3
(signal transducer and activator
of transcription 3).
Invariant natural killer T
(iNKT) cells
Lymphocytes that express
a particular variable gene
segment, Vα14 (in mice) and
Vα24 (in humans), precisely
rearranged to a particular Jα
(joining) gene segment to yield
T‑cell receptor α-chains with an
invariant sequence. Typically,
these cells co-express cellsurface markers that are
encoded by the natural killer
(NK) locus, and they are
activated by recognition of
CD1d, particularly when
α‑galactosylceramide is bound
in the groove of CD1d.
Type 1 cytotoxic T (TC1) and
TC2 cells
A designation that is used to
describe subsets of CD8+
cytotoxic T cells. TC1 cells
typically secrete interferon‑γ
and granulocyte/macrophage
colony-stimulating factor, and
have strong cytotoxic capacity,
whereas TC2 cells secrete
interleukin‑4 (IL‑4) and IL‑10
and are less effective killers.
TH2 cells51, making the distinction between the TH‑cell
patterns in these two diseases less clear.
Other subtypes of CD4+ T cells that may have an
important role in airway diseases are regulatory T cells,
which have a suppressive effect on other CD4+ T cells
and may have a role in regulating TH2-cell function
in asthma33,52. There is evidence that the numbers of
CD4+CD25+ regulatory T cells that express the transcription factor forkhead box P3 (FOXP3) are reduced
in individuals with allergic rhinitis (hay fever) compared
with non-atopic individuals, and this may be important
in enabling high numbers of TH2 cells to develop in allergic disease53. However, by contrast, asthmatic patients
seem to have an increase in FOXP3-expressing regulatory T cells compared with patients with mild asthma,
at least among circulating cells54. Analysis of sputum
from COPD patients suggests that the numbers of
CD4+CD25+FOXP3+ regulatory T cells are reduced, but
similar changes are also seen in people who smoke but do
not have airflow obstruction55. So, the role of regulatory
T cells in asthma and COPD remains unclear and further research is therefore needed, particularly in defining
the role of different types of regulatory T cells56.
Another subset of CD4+ T cells, known as TH17 cells,
has recently been described and shown to have an
important role in inflammatory and autoimmune diseases57,58. Little is known about the role of TH17 cells in
asthma or COPD, but increased concentrations of IL‑17
(the predominant product of T H17 cells) have been
reported in the sputum of asthma patients59. IL‑17 and
the closely related cytokine IL‑17F have been linked to
neutrophilic inflammation by inducing the release of
CXCL1 and CXCL8 from airway epithelial cells60 (FIG. 5).
As well as IL‑17, TH17 cells also produce IL‑21, which
is important for the differentiation of these cells and
thus acts as a positive autoregulatory mechanism, but
it also inhibits FOXP3 expression and regulatory T‑cell
development61,62. Another cytokine IL‑22 is also released
by these cells and stimulates the production of IL‑10 and
acute-phase proteins63. However, more work is needed
to understand the role and regulation of TH17 cells in
asthma and COPD, as they may represent important
new targets for future therapies.
A subset of CD4+ T cells termed invariant natural killer T
(iNKT) cells, which secrete IL‑4 and IL‑13, has been shown
to account for 60% of all CD4+ T cells in bronchial biopsies from asthmatic patients64, but this has been disputed
in another study that failed to show any increase in iNKTcell numbers in bronchial biopsies, bronchoalveolar lavage
or sputum of either asthma or COPD patients65. The role
of iNKT cells in asthma is currently uncertain as there
appears to be a discrepancy between the data from murine
models of asthma and humans with the disease33.
CD8+ T cells predominate over CD4+ T cells in the
airways and lung parenchyma of patients with COPD66,
but their role in disease pathogenesis is not yet certain.
Type 1 cytotoxic T (TC1) cells, which secrete IFNγ, predominate and express CXCR3, suggesting that they are attracted
to the lungs by CXCR3-binding chemokines47,49. These
CXCR3 ligands suppress signalling through CCR3, the
receptor for CCL11, suggesting that they might suppress
nature reviews | immunology
eosinophilic inflammation67. The production of CCL5
(also known as RANTES), which attracts CD4+ and CD8+
T cells via CCR5, is also increased in the sputum of COPD
patients compared with controls and may also be involved
in T‑cell recruitment49. TC1 cells release granzyme B and
perforins, which are also present at higher levels in the
sputum of COPD patients than normal control subjects
who also smoke68, and may induce apoptosis of type 1
pneumocytes, thereby contributing to the development of
emphysema20. TC1- and TH1-cell-driven inflammation is
likely to be self-perpetuating as IFNγ stimulates the release
of CXCR3 ligands, which then attract more TH1 and TC1
cells into the lungs (FIG. 6). TC2 cells, which secrete IL‑4,
have also been described in COPD50. In asthma, CD8+
T cells are present in patients with more severe disease
and irreversible airflow obstruction69 and these cells may
be of either the TC1 or TC2 type70.
B cells. B cells have an important role in allergic diseases,
including asthma, through the release of allergen-specific
IgE which binds to high-affinity Fc receptors for IgE
(FcεRI) expressed by mast cells and basophils, and to
low-affinity Fc receptors for IgE (FcεRII) expressed by
other inflammatory cells, including B cells, macrophages
and possibly eosinophils71. The TH2-type cytokines IL‑4
and IL‑13 induce B cells to undergo immunoglobulin class
switching to produce IgE. Blocking IgE with the monoclonal antibody omalizumab reduces the response to
allergens, airway inflammation and asthma exacerbations, indicating that IgE drives allergic inflammation in
asthma72. In both atopic asthma and non-atopic asthma,
IgE may be produced locally by B cells in the airways73.
Interestingly, IgE secretion is not observed in patients
with COPD, but in the peripheral airways of patients
with more severe disease there is a marked increase in
the number of B cells, which are organized into lymphoid follicles that are surrounded by T cells18. The
class of immunoglobulin they secrete and how they
IL-27
IL-12
IL-4
STAT1
STAT4
STAT6
TH1 cells
T-bet
TH1-type cytokines
(IL-2 and IFNγ)
IL-33
GATA3 TH2 cells
TH2-type cytokines
(IL-4, IL-5, IL-9 and IL-13)
Allergic inflammation
Figure 4 | Interactions between TH1 and TH2 cells in
asthma. The transcription factor GATA3 (GATA-binding
Nature Reviews
| Immunology
protein 3) is regulated by interleukin‑4
(IL‑4) via
STAT6
(signal transducer and activator of transcription 6) and
regulates the expression of IL‑4, IL‑5, IL‑9 and IL‑13 from
T helper 2 (TH2) cells and also inhibits the expression of
T‑bet via inhibition of STAT4. IL‑33 enhances the actions of
GATA3. T‑bet regulates T helper 1 (TH1)-cell secretion of IL‑2
and interferon‑γ (IFNγ) and also has an inhibitory action on
GATA3. T‑bet is regulated by IL‑12 via STAT4 and by IL‑27
via STAT1. This demonstrates the complex interplay of
cytokines and transcription factors in asthma.
volume 8 | march 2008 | 187
© 2008 Nature Publishing Group
REVIEWS
IL-6
IL-23
TGFβ
?
TH17 cell
RORγ t
STAT3
IL-21
TNF
IL-6
IL-22
IL-17 and
IL-17F
CD8+ T cell
CXCL1 and
CXCL8
Neutrophils
Epithelial cells
↑
↑
IL-10
Acute-phase
proteins
Figure 5 | TH17 cells and airway inflammation. T helper 17
(TH17) cells are a newly described subset of CD4+ T cells
that may have a role in chronic obstructive
pulmonary
Nature Reviews
| Immunology
disease (COPD) and severe asthma. These cells release
interleukin‑17 (IL‑17) and IL‑17F, which act on airway
epithelial cells to release CXC-chemokine ligand 1 (CXCL1)
and CXCL8, which attract neutrophils, and IL‑6, which
enhances the activation of TH17 cells. TH17 cells also release
IL‑21, which promotes TH17-cell differentiation via a
positive autoregulatory loop involving the transcription
factor STAT3 (signal transducer and activator of
transcription 3) and IL‑22, which induces the release of
IL‑10 and acute-phase proteins. The regulation of TH17 cells
is predominantly via IL‑23 through the activation of the
transcription factor retinoic-acid-receptor-related orphan
receptor-γt (RORγt), whereas transforming growth factor‑β
(TGFβ) may have an inhibitory effect in human cells.
TNF, tumour-necrosis factor.
Immunoglobulin class
switching
The somatic-recombination
process by which the class of
immunoglobulin expressed by
activated B cells is switched
from IgM to IgG, IgA or IgE.
Corticosteroids
Anti-inflammatory drugs that
are derived from cortisol
secreted by the adrenal cortex
and that are effective in
suppressing inflammation
in asthma but not in chronic
obstructive pulmonary disease.
FEV1
(Forced expiratory volume in
1 second). The amount of air
that can be forcibly exhaled in
1 second, measured in litres.
It is used as a measurement of
airway obstruction in asthma
and chronic obstructive
pulmonary disease.
of myeloid DCs and the recruitment of TH2 cells to the
airways by inducing the release of CCL17 (also known as
TARC) and CCL22 (also known as MDC), which bind to
CCR4 that is selectively expressed by TH2 cells80.
Cigarette smoking is associated with an expansion
of the DC population and with a marked increase in
the number of mature DCs in the airways and alveolar
walls of people who smoke81. However, the role of DCs
in COPD is currently unclear as there are no obvious
antigenic stimulants, apart from α‑glycoprotein, which
is isolated from tobacco and known to have a powerful
immunostimulatory effect82. However, a recent electron
microscopy study has demonstrated a decrease in DCs
in the airways of patients with COPD who smoke compared to smokers without airway obstruction, suggesting
that they do not have a key role in COPD83.
Similarities between asthma and COPD
Although the inflammatory and immune mechanisms of
asthma and COPD described above are markedly different, there are several situations where they become more
similar and the distinction between asthma and COPD
becomes blurred (TABLE 1).
are regulated is currently unknown, but they might be
activated by bacterial or viral antigens as a consequence
of the chronic bacterial colonization or latent viral infection in the airways of these patients. Alternatively, it has
been suggested that COPD might have an autoimmune
component characterized by the development of new
antigenic epitopes as a result of the tissue damage induced
by cigarette smoking, oxidative stress or chronic bacterial infection21,74. CD4+ T cells isolated from the lungs of
patients with severe emphysema are oligoclonal, which is
consistent with antigenic stimulation by infective organisms or autoimmunity75. Indeed, in a mouse model of
emphysema induced by tobacco smoke, an autoimmune
mechanism has been proposed with a role for antibodies
specific for neutrophil elastase76.
Severe asthma. Although only about 5% of the asthmatic
population develop severe disease, such cases account for
more than half of the healthcare spending in asthma and
they are poorly controlled by currently available therapies84. The inflammatory pattern that occurs in cases of
severe asthma, contrary to mild asthma, is more similar
to that which occurs in COPD, with increased numbers
of neutrophils in the sputum and increased amounts of
CXCL8 and tumour-necrosis factor85, increased oxidative
stress and a poor response to corticosteroids as is observed
in patients with COPD (TABLE 1). Moreover, whereas in
mild asthma TH2 cells predominate, in more severe
asthmatic disease there is a mixture of TH1 and TH2
cells present in bronchial biopsies, as well as more CD8+
T cells and this more closely resembles the immune-cell
infiltration seen in COPD51,69,70. The neutrophilic inflammation seen in cases of severe asthma may be induced by
IL‑17 production by TH17 cells, which induces the release
of the neutrophilic chemokine CXCL8 from airway epithelial cells59,60. A neutrophilic pattern of inflammation,
with high levels of CXCL8, is also found in the sputum
of asthmatic individuals who smoke86. Similar to patients
with severe disease or COPD, these individuals also have
a poor response to corticosteroids, even if given orally at
high doses.
Dendritic cells. Dendritic cells (DCs) have an important role in asthma as regulators of T H2 cells and in
the presentation of processed peptides from inhaled
allergens to TH2 cells77. They are not only involved in
the initial sensitization to allergens, but also in driving
the chronic inflammatory response in the lungs, and
therefore provide a link between allergen exposure and
allergic inflammation in asthma. The cytokine thymic
stromal lymphopoietin (TSLP), which is secreted in large
amounts by epithelial cells and mast cells of asthmatic
patients78,79, might have a critical role in the maturation
Reversible COPD. Approximately 10% of patients with
COPD have a reversibility of bronchoconstriction, showing greater than 12% improvement in lung function as
assessed by forced expiratory volume in 1 second (FEV1),
and therefore behave more like asthmatics. Furthermore,
compared with most patients with COPD, these patients
more frequently have eosinophils in their sputum, an
increase in exhaled nitric oxide and respond better to
corticosteroid treatment, all of which are characteristic
features of asthma87,88. It therefore seems likely that these
patients have concomitant asthma and COPD.
188 | march 2008 | volume 8
www.nature.com/reviews/immunol
© 2008 Nature Publishing Group
f o c u s o n a l l er g Y a n d RAs
E VtIh
Em
Wa
S
Acute exacerbations. Acute exacerbations (worsening of
symptoms) occur in patients with asthma and COPD,
and are a major cause of patient suffering and medical
expenditure89,90. Exacerbations in asthmatic individuals
are usually triggered by upper respiratory tract infections,
such as with rhinoviruses, and less commonly by inhaled
allergens and air pollutants, whereas exacerbations in
patients with COPD are usually triggered by either bacterial or viral infections. In both diseases, exacerbations are
associated with a further increase in airway inflammation, increased numbers of cells infiltrating the lungs and
higher concentrations of inflammatory mediators than are
present in the steady state. However, there may also be
changes in the pattern of inflammation. In exacerbations
of asthma triggered by viruses, there can be increases in
the numbers of neutrophils, as well as of eosinophils89,
whereas in COPD exacerbations, particularly those due to
viruses, there may be an increase in eosinophil numbers91.
So, during episodes of disease exacerbation, the pattern of
inflammation becomes similar in COPD and asthma.
Theophylline
A drug that is used at high
doses as a bronchodilator in
the treatment of asthma and
chronic obstructive pulmonary
disease. However, it is now less
widely used as the high doses
can have side effects, including
nausea, headaches, cardiac
arrhythmias and seizures.
More recently, it has been
shown to have antiinflammatory effects at lower
doses and may reverse
corticosteroid resistance by
increasing the activity of
histone deacetylase.
Cyclosporin A and
tacrolimus
Calcineurin inhibitors that are
used to prevent transplant
rejection and that function by
inhibiting nuclear factor of
activated T cells (NFAT).
Rapamycin
An immunosuppressive drug
that, in contrast to calcineurin
inhibitors, does not prevent
T‑cell activation but blocks
interleukin‑2-mediated clonal
expansion by blocking mTOR
(mammalian target of
rapamycin).
Mycophenolate mofetil
An immunosuppressant that
inhibits purine synthesis and
has an inhibitory effect on
T cells and B cells. It is
currently used to treat
transplant rejection and
rheumatoid arthritis.
Implications for therapy
In view of the different inflammatory and immune
patterns of asthma and COPD, it is not surprising that
they should respond differently to anti-inflammatory
therapies.
Corticosteroid responsiveness. Asthma is usually highly
responsive to corticosteroid therapy and inhaled corticosteroids have become the mainstay of disease
management. Corticosteroids suppress inflammation
by inducing the recruitment of the nuclear enzyme
histone deacetylase 2 (HDAC2) to multiple activated
inflammatory genes, which leads to deacetylation of the
hyperacetylated genes, thereby suppressing inflammation92. By contrast, patients with COPD respond poorly
to corticosteroid treatment, and even high doses of
inhaled or oral corticosteroids fail to suppress inflammation. This appears to be related to decreased activity
and expression of HDAC2 in the inflammatory cells and
peripheral lungs of COPD patients93. This is the result of
increased oxidative and nitrative stress, which together
generate peroxynitrite that nitrates tyrosine residues
in HDAC2, impairing enzyme activity and decreasing
expression93,94. The poor response to corticosteroid treatment seen in patients with severe asthma, in asthmatics
who smoke and during acute exacerbations may also
reflect a reduction in HDAC2 protein levels and function, as oxidative and nitrative stress are also increased
in these situations95. So, patients with severe asthma have
a relative corticosteroid resistance, and this is linked to
impaired HDAC2 function96,97. Reversal of corticosteroid
resistance may therefore be a useful therapeutic strategy
in the future for patients with COPD and severe asthma.
Interestingly, low concentrations of the drug theophylline,
which was previously used at high doses as a bronchodilator in the treatment of asthma and COPD, are able to
restore HDAC2 activity in vitro to normal levels and
have been shown to reverse corticosteroid resistance in
cells from COPD patients, so may provide a means of
restoring corticosteroid responsiveness clinically98.
nature reviews | immunology
Immunomodulation. Specific immunotherapy to inhibit
allergic responses has been successful in treating individuals with hay fever, in which there is a single type of allergen involved, but so far such an approach has not proved
to be very effective for treating asthma and, because it
is potentially dangerous through triggering anaphylactic
responses, it is not recommended in current treatment
guidelines. More effective and safer immunotherapy for
asthma using DNA vaccines, T‑cell peptides and sublingual immunotherapy is currently under investigation99.
Suppression of T cells may be a useful therapeutic
approach in the treatment of asthma and COPD, given
their role in driving inflammation in both diseases.
Cyclosporin A, a non-selective inhibitor of T cells, although
early studies showed it had some clinical benefit100, it has
subsequently been found to be of little benefit to asthmatics in several clinical trials and is now not recommended
as a therapy, particularly in view of its toxicity101. Lesstoxic immunomodulators, such as tacrolimus, rapamycin
and mycophenolate mofetil (CellCept; Roche), which are
currently used in the prevention of transplantation rejection, have not been tested in clinical studies of asthma
and there are no studies assessing the efficacy of immuno­
suppressants in patients with COPD. More specific
immunomodulators that selectively inhibit TH2 cells have
been sought for the treatment of asthma, as yet without
success. Suplatast tosilate (IPD; Taiho Pharmaceutical)
is a drug that apparently inhibits TH2 cells and TH2-type
cytokine release102, but its mechanisms of action are not
known. It has only weak clinical effects and is currently
only available in Japan. In COPD patients, treatments
that target CD8+ T cells might be more appropriate.
IFNγ
Epithelial cells
Macrophage
CXCL9, CXCL10 and CXCL11
CXCR3
TH1 cell
TC1 cell
Perforin and
granzyme B
Emphysema
(apoptosis of type I
pneumocytes)
Figure 6 | CD8+ T cells in chronic obstructive
pulmonary disease (COPD). Epithelial cells and
macrophages are stimulated by interferon‑γ (IFNγ) to
Nature Reviews
| Immunology
release the chemokines CXC-chemokine
ligand
9 (CXCL9),
CXCL10 and CXCL11, which together act on CXCchemokine receptor 3 (CXCR3) expressed on T helper 1
(TH1) cells and type 1 cytotoxic T (TC1) cells to attract them
into the lungs. TC1 cells, through the release of perforin and
granzyme B, induce apoptosis of type I pneumocytes,
thereby contributing to emphysema. IFNγ released by TH1
and TC1 cells then stimulates further release of CXCR3
ligands, resulting in a persistent inflammatory activation.
volume 8 | march 2008 | 189
© 2008 Nature Publishing Group
REVIEWS
Table 1 | Comparison between patterns of inflammation in asthma and COPD Asthma
COPD
Refs
Mild
Severe
Exacerbation
Mild
Severe
Exacerbation
Neutrophils
0
++
++++
++
+++
++++
Eosinophils
+
++
+++
0
0
+
110,111
Mast cells
++
+++
+++?
0
0
?
7,26,112
Macrophages
+
+
?
+++
++++
++++
T cells
TH2 cells: ++
iNKT cells: ?
TH1 cells: +
TH2 cells: +
TC1 cells: +
TC2 cells: +? TH17 cells: ?
?
TC1 cells: +
TC1 cells: +++
TH1 cells: +++
TH17 cells: ?
?
18,66,114
B cells
IgE producing
IgE producing
?
+
+++
?
18,73
Dendritic cells
+
?
?
+?
+?
?
115
Chemokines
CCL11: +
CXCL8: +
CXCL8: ++
CXCL8: +
CXCL1: +
CCL2: +
CXCL8: ++
CXCL8: +++
116
Cytokines
IL-4: ++
IL-5: ++
IL-13: ++
TNF: ++
?
TNF: +
TNF: ++
TNF: +++
117,118
Lipid mediators
LTD4: ++
PGD2: +
LTB4: ++
PGD2: +
?
LTB4: +
LTB4: ++
LTB4: +++
10,11
Oxidative stress
0
++
+++
++
+++
++++
Steroid response
++++
++
+
0
0
0
7
113
119–122
92
0, no response; + to ++++, magnitude scale; ?, uncertain. CCL, CC-chemokine ligand; COPD, chronic obstructive pulmonary disease; CXCL, CXC-chemokine ligand;
iNKT, invariant natural killer T; LTB4, leukotriene B4; LTD4, leukotriene D4; PGD2, prostaglandin D2; TC1, type 1 cytotoxic T; TH, T helper; TNF, tumour-necrosis factor.
Given the role of B cells in both asthma and COPD,
non-selective B‑cell inhibitors, such as the CD20specific monoclonal antibody rituximab (Rituxan;
Genentech, Inc. and Biogen Idec) might be beneficial,
as it is in rheumatoid arthritis and other autoimmune
diseases103. However, there are concerns about the safety
of using rituximab, particularly in COPD patients who
are susceptible to recurrent bacterial infections, as the
airways of patients with more severe disease are often
colonized by bacteria.
Other novel therapeutic approaches. Several novel
therapeutic approaches are currently in development
for treating inflammation in asthma and COPD104,105,
for example, one type of therapy involves targeting specific transcription factors that are known to be active in
these diseases106. In both airway diseases, NF‑κB activation appears to be important for activating multiple
but different inflammatory genes, so inhibition of this
transcription factor using small molecule inhibitors of
IKK2 (inhibitor of NF‑κB kinase 2) would be a logical
approach. For the treatment of asthma, inhibition of
GATA3 function and therefore TH2-type cytokine production may be a more specific approach and this might
be possible using inhibitors of the GATA3-activating
kinase p38 MAPK39. Indeed, downregulation of p38
MAPK expression using an antisense oligonucleo­tide
has proved to be effective in inhibiting TH2-type cytokine
production in a mouse model of asthma107. For the treatment of COPD, inhibition of the TH1-cell-inducing transcription factor T‑bet would be more appropriate and
190 | march 2008 | volume 8
this could be achieved by blocking STAT4 activity, but
no such drugs have so far been developed.
Given that chemokines are crucial mediators in
the recruitment of inflammatory cells to the lungs of
patients with asthma and COPD, antagonism of specific chemo­kine receptors would be a logical approach
for treating these diseases108,109. In asthma, chemokine
receptors on eosinophils (CCR3) and TH2 cells (CCR4,
CCR8 and CXCR4) are the main targets, whereas in
COPD, receptors on neutrophils (CXCR2), monocytes
(CXCR2 and CCR2), TH1 cells (CXCR3) and TC1 cells
(CXCR3) are the major foci of drug development. Small
molecule inhibitors for all of these receptors are now
in development.
Conclusions and future perspectives
Although both COPD and asthma involve chronic
inflammation of the respiratory tract, the pattern of
inflammation is markedly different between these two
diseases. Mild asthma is characterized by eosinophilic
inflammation driven by TH2 cells and DCs, and is associated with mast-cell sensitization by IgE, and by the
release of multiple bronchoconstrictors. By contrast,
COPD is characterized by neutrophilic inflammation
that can be driven by a marked increase in the number
of lung-resident macrophages, which also attract CD4+
and CD8+ T cells to the lungs. This lymphocytic infiltration can also be driven by chronic stimulation by
viral and bacterial antigens or by autoantigens released
following lung injury. Mast cells and DCs, which have
such a key role in asthma, have little or no known
www.nature.com/reviews/immunol
© 2008 Nature Publishing Group
f o c u s o n a l l er g Y a n d RAs
E VtIh
Em
Wa
S
involvement in COPD. However, these distinctions
between asthma and COPD may not be as clear as
previously believed, as in patients with severe asthma
and in asthmatic individuals who smoke there is a
neutrophilic pattern of inflammation, and acute exacerbations of asthma and of COPD have similar inflammatory features. The role of TH17 cells in severe asthma
and COPD as a driving mechanism of neutrophilic
inflammation is not yet fully understood and deserves
more research; understanding these mechanisms may
lead to new therapeutic approaches.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Barnes, P. J. Chronic obstructive pulmonary disease:
a growing but neglected epidemic. PLoS Med. 4, e112
(2007).
Mannino, D. M. & Buist, A. S. Global burden of
COPD: risk factors, prevalence, and future trends.
Lancet 370, 765–773 (2007).
A comprehensive recent review of the various risk
factors involved in COPD and the current global
prevalence of the disease.
Pearce, N. et al. Worldwide trends in the prevalence of
asthma symptoms: phase III of the International Study
of Asthma and Allergies in Childhood (ISAAC). Thorax
62, 758–766 (2007).
This paper provides the most recent data showing
the worldwide prevalence of asthma.
Kraft, M. Asthma and chronic obstructive pulmonary
disease exhibit common origins in any country!
Am. J. Respir. Crit. Care Med. 174, 238–240
(2006).
Barnes, P. J. Against the Dutch hypothesis: asthma
and chronic obstructive pulmonary disease are
distinct diseases. Am. J. Respir. Crit. Care. Med. 174,
240–243 (2006).
Barnes, P. J. Mechanisms in COPD: differences from
asthma. Chest 117, 10S–14S (2000).
Jeffery, P. K. Comparison of the structural and
inflammatory features of COPD and asthma. Chest
117, 251S–260S (2000).
Wenzel, S. E. Asthma: defining of the persistent adult
phenotypes. Lancet 368, 804–813 (2006).
This paper provides a discussion of the different
phenotypes of asthma that are discussed in this
Review.
Phelan, P. D., Robertson, C. F. & Olinsky, A. The
Melbourne Asthma Study: 1964–1999. J. Allergy
Clin. Immunol. 109, 189–194 (2002).
Barnes, P. J., Chung, K. F. & Page, C. P. Inflammatory
mediators of asthma: an update. Pharmacol. Rev. 50,
515–596 (1998).
Barnes, P. J. Mediators of chronic obstructive
pulmonary disease. Pharm. Rev. 56, 515–548 (2004).
Hart, L. A., Krishnan, V. L., Adcock, I. M., Barnes, P. J.
& Chung, K. F. Activation and localization of
transcription factor, nuclear factor-κB, in asthma.
Am. J. Respir. Crit. Care Med. 158, 1585–1592
(1998).
Caramori, G. et al. Nuclear localisation of p65 in
sputum macrophages but not in sputum neutrophils
during COPD exacerbations. Thorax 58, 348–351
(2003).
Benayoun, L., Druilhe, A., Dombret, M. C., Aubier, M.
& Pretolani, M. Airway structural alterations
selectively associated with severe asthma. Am. J.
Respir. Crit. Care Med. 167, 1360–1368 (2003).
This study quantifies the changes in airway smooth
muscle that occur in asthmatic patients.
Siddiqui, S. et al. Vascular remodeling is a feature of
asthma and nonasthmatic eosinophilic bronchitis.
J. Allergy Clin. Immunol. 120, 813–819 (2007).
Ordonez, C. L. et al. Mild and moderate asthma is
associated with airway goblet cell hyperplasia and
abnormalities in mucin gene expression. Am. J.
Respir. Crit. Care Med. 163, 517–523 (2001).
Hogg, J. C. Pathophysiology of airflow limitation in
chronic obstructive pulmonary disease. Lancet 364,
709–721 (2004).
Hogg, J. C. et al. The nature of small-airway
obstruction in chronic obstructive pulmonary disease.
N. Engl. J. Med. 350, 2645–2653 (2004).
An important study quantifying the inflammation in
small airways in patients with differing severity of
COPD.
New therapeutic approaches may also stem from a
greater understanding and appreciation of the similarities
between asthma and COPD. Although there are highly
effective treatments for mild asthma, severe asthma and
asthma in people who smoke are poorly treated with current therapies and because of the similarities with COPD,
it is likely that new anti-inflammatory treatments that
are effective in COPD may also be effective in refractory
asthma. Whether therapies based on the immune mechanisms will be safe and effective in treating airway diseases
also deserves further research.
19. Caramori, G. et al. Mucin expression in peripheral
airways of patients with chronic obstructive pulmonary
disease. Histopathology 45, 477–484 (2004).
20. Majo, J., Ghezzo, H. & Cosio, M. G. Lymphocyte
population and apoptosis in the lungs of smokers and
their relation to emphysema. Eur. Respir. J. 17,
946–953 (2001).
A demonstration of increased numbers of CD8+
T cells in the lung parenchyma of patients with
COPD and their relationship to apoptosis of type I
pneumocytes.
21. Taraseviciene-Stewart, L. et al. Is alveolar destruction
and emphysema in chronic obstructive pulmonary
disease an immune disease? Proc. Am. Thorac. Soc.
3, 687–690 (2006).
22. Ohnishi, K., Takagi, M., Kurokawa, Y., Satomi, S. &
Konttinen, Y. T. Matrix metalloproteinase-mediated
extracellular matrix protein degradation in human
pulmonary emphysema. Lab. Invest. 78, 1077–1087
(1998).
23. Tuder, R. M., Yoshida, T., Arap, W., Pasqualini, R. &
Petrache, I. State of the art. Cellular and molecular
mechanisms of alveolar destruction in emphysema:
an evolutionary perspective. Proc. Am. Thorac. Soc. 3,
503–510 (2006).
24. Reber, L., Da Silva, C. A. & Frossard, N. Stem cell
factor and its receptor c‑Kit as targets for
inflammatory diseases. Eur. J. Pharmacol. 533,
327–340 (2006).
25. Galli, S. J. et al. Mast cells as “tunable” effector and
immunoregulatory cells: recent advances. Annu. Rev.
Immunol. 23, 749–786 (2005).
26. Brightling, C. E. et al. Mast-cell infiltration of airway
smooth muscle in asthma. N. Engl. J. Med. 346,
1699–1705 (2002).
This paper shows that mast-cell numbers are
present in the airway smooth muscle of asthmatic
patients, whereas this is not seen in non-asthmatic
subjects or patients with eosinophilic bronchitis
who do not have asthma.
27. Leckie, M. J. et al. Effects of an interleukin‑5 blocking
monoclonal antibody on eosinophils, airway
hyperresponsiveness and the late asthmatic response.
Lancet 356, 2144–2148 (2000).
This study reports a surprising finding that
blocking IL‑5 in asthmatic patients does not reduce
the response to allergen or airway hyperresponsiveness despite a profound reduction in
circulating and sputum eosinophils.
28. Flood-Page, P. et al. A study to evaluate safety and
efficacy of mepolizumab in patients with moderate
persistent asthma. Am. J. Respir. Crit. Care Med.
176, 1062–1071 (2007).
29. Green, R. H. et al. Analysis of induced sputum in
adults with asthma: identification of subgroup with
isolated sputum neutrophilia and poor response to
inhaled corticosteroids. Thorax 57, 875–879
(2002).
30. Keatings, V. M., Collins, P. D., Scott, D. M. &
Barnes, P. J. Differences in interleukin‑8 and tumor
necrosis factor‑α in induced sputum from patients with
chronic obstructive pulmonary disease or asthma.
Am. J. Respir. Crit. Care Med. 153, 530–534 (1996).
31. Traves, S. L., Smith, S. J., Barnes, P. J. & Donnelly, L. E.
Specific CXC but not CC chemokines cause elevated
monocyte migration in COPD: a role for CXCR2.
J. Leukoc. Biol. 76, 441–450 (2004).
32. Barnes, P. J. Macrophages as orchestrators of COPD.
COPD 1, 59–70 (2004).
33. Meyer, E. H., DeKruyff, R. H. & Umetsu, D. T.
T cells and NKT cells in the pathogenesis of asthma.
Annu. Rev. Med. 59, 281–292 (2008).
nature reviews | immunology
34. Kay, A. B. The role of T lymphocytes in asthma.
Chem. Immunol. Allergy. 91, 59–75 (2006).
35. Ho, I. C. & Pai, S. Y. GATA‑3 — not just for Th2 cells
anymore. Cell Mol. Immunol. 4, 15–29 (2007).
36. Barnes, P. J. Role of GATA‑3 in allergic diseases.
Curr. Mol. Med. (in the press) (2008).
37. Caramori, G. et al. Expression of GATA family of
transcription factors in T‑cells, monocytes and bronchial
biopsies. Eur. Respir. J. 18, 466–473 (2001).
38. Nakamura, Y. et al. Gene expression of the GATA‑3
transcription factor is increased in atopic asthma.
J. Allergy Clin. Immunol. 103, 215–222 (1999).
39. Maneechotesuwan, K. et al. Regulation of Th2 cytokine
genes by p38 MAPK-mediated phosphorylation of
GATA‑3..J. Immunol. 178, 2491–2498 (2007).
This study shows that in human T cells GATA3
translocates to the nucleus after phosphorylation
by p38 MAPK, which is activated by TCR and coreceptor activation.
40. Finotto, S. et al. Development of spontaneous airway
changes consistent with human asthma in mice
lacking T‑bet. Science 295, 336–338 (2002).
This paper shows that the lack of T‑bet results in
eosinophilic inflammation in mouse lungs and a
reduction in T cells expressing T‑bet in the airways
of asthmatic patients.
41. Hwang, E. S., Szabo, S. J., Schwartzberg, P. L. &
Glimcher, L. H. T helper cell fate specified by kinasemediated interaction of T‑bet with GATA‑3. Science
307, 430–433 (2005).
42. Yoshimoto, T., Yoshimoto, T., Yasuda, K., Mizuguchi, J.
& Nakanishi, K. IL‑27 suppresses Th2 cell
development and Th2 cytokines production from
polarized Th2 cells: a novel therapeutic way for
Th2-mediated allergic inflammation. J. Immunol. 179,
4415–4423 (2007).
43. Usui, T. et al. T‑bet regulates Th1 responses through
essential effects on GATA‑3 function rather than on
IFNG gene acetylation and transcription. J. Exp. Med.
203, 755–766 (2006).
44. Avni, O. et al. TH cell differentiation is accompanied by
dynamic changes in histone acetylation of cytokine
genes. Nature Immunol. 3, 643–651 (2002).
45. Carriere, V. et al. IL‑33, the IL‑1‑like cytokine ligand
for ST2 receptor, is a chromatin-associated nuclear
factor in vivo. Proc. Natl Acad. Sci. USA 104,
282–287 (2007).
46. Komai-Koma, M. et al. IL‑33 is a chemoattractant for
human Th2 cells. Eur. J. Immunol. 37, 2779–2786
(2007).
47. Grumelli, S. et al. An immune basis for lung
parenchymal destruction in chronic obstructive
pulmonary disease and emphysema. PLoS Med. 1,
75–83 (2004).
This study shows that the numbers of TH1 and TC1
cells, both of which express CXCR3, are increased
in the lung parenchyma of patients with COPD.
48. Saetta, M. et al. Increased expression of the
chemokine receptor CXCR3 and its ligand CXCL10 in
peripheral airways of smokers with chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med.
165, 1404–1409 (2002).
49. Costa, C. et al. CXCR3 and CCR5 chemokines in the
induced sputum from patients with COPD. Chest 133,
26–33 (2008).
50. Barczyk, A. et al. Cytokine production by
bronchoalveolar lavage T lymphocytes in chronic
obstructive pulmonary disease. J. Allergy Clin.
Immunol. 117, 1484–1492 (2006).
51. Kurashima, K. et al. Asthma severity is associated
with an increase in both blood CXCR3+ and CCR4+
T cells. Respirology 11, 152–157 (2006).
volume 8 | march 2008 | 191
© 2008 Nature Publishing Group
REVIEWS
52. Larche, M. Regulatory T cells in allergy and asthma.
Chest 132, 1007–1014 (2007).
53. Ling, E. M. et al. Relation of CD4+CD25+ regulatory
T‑cell suppression of allergen-driven T‑cell activation
to atopic status and expression of allergic disease.
Lancet 363, 608–615 (2004).
54. Lee, J. H. et al. The levels of CD4+CD25+ regulatory
T cells in paediatric patients with allergic rhinitis and
bronchial asthma. Clin. Exp. Immunol. 148, 53–63
(2007).
55. Smyth, L. J., Starkey, C., Vestbo, J. & Singh, D.
CD4-regulatory cells in COPD patients. Chest 132,
156–163 (2007).
56. Wan, Y. Y. & Flavell, R. A. Regulatory T cells,
transforming growth factor-β, and immune
suppression. Proc. Am. Thorac. Soc. 4, 271–276
(2007).
57. Stockinger, B. & Veldhoen, M. Differentiation and
function of Th17 T cells. Curr. Opin. Immunol. 19,
281–286 (2007).
58. Weaver, C. T., Harrington, L. E., Mangan, P. R.,
Gavrieli, M. & Murphy, K. M. Th17: an effector CD4
T cell lineage with regulatory T cell ties. Immunity 24,
677–688 (2006).
59. Bullens, D. M. et al. IL‑17 mRNA in sputum of
asthmatic patients: linking T cell driven inflammation
and granulocytic influx? Respir. Res. 7, 135 (2006).
60. Laan, M., Lotvall, J., Chung, K. F. & Linden, A.
IL‑17‑induced cytokine release in human bronchial
epithelial cells in vitro: role of mitogen-activated
protein (MAP) kinases. Br. J. Pharmacol. 133,
200–206 (2001).
61. Nurieva, R. et al. Essential autocrine regulation by
IL‑21 in the generation of inflammatory T cells. Nature
448, 480–483 (2007).
62. Spolski, R. & Leonard, W. J. Interleukin‑21: basic
biology and implications for cancer and autoimmunity.
Annu. Rev. Immunol. 8 November 2007 (doi:10.1146/
annurev.immunol.26.021607.090316).
63. Wolk, K. & Sabat, R. Interleukin‑22: a novel T‑ and
NK‑cell derived cytokine that regulates the biology
of tissue cells. Cytokine Growth Factor Rev. 17,
367–380 (2006).
64. Akbari, O. et al. CD4+ invariant T‑cell‑receptor+
natural killer T cells in bronchial asthma. N. Engl.
J. Med. 354, 1117–1129 (2006).
65. Vijayanand, P. et al. Invariant natural killer T cells in
asthma and chronic obstructive pulmonary disease.
N. Engl. J. Med. 356, 1410–1422 (2007).
A careful study showing that there is no increase
in iNKT cells in asthma or COPD in contrast to
reference 64.
66. Saetta, M. et al. CD8+ T‑lymphocytes in peripheral
airways of smokers with chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med.
157, 822–826 (1998).
67. Xanthou, G., Duchesnes, C. E., Williams, T. J. &
Pease, J. E. CCR3 functional responses are regulated
by both CXCR3 and its ligands CXCL9, CXCL10 and
CXCL11. Eur. J. Immunol. 33, 2241–2250 (2003).
68. Chrysofakis, G. et al. Perforin expression and cytotoxic
activity of sputum CD8+ lymphocytes in patients with
COPD. Chest 125, 71–76 (2004).
69. van Rensen, E. L. et al. Bronchial CD8 cell infiltrate
and lung function decline in asthma. Am. J. Respir.
Crit. Care Med. 172, 837–841 (2005).
70. Cho, S. H., Stanciu, L. A., Holgate, S. T. & Johnston, S. L.
Increased interleukin‑4, interleukin‑5, and interferon-γ in
airway CD4+ and CD8+ T cells in atopic asthma.
Am. J. Respir. Crit. Care Med. 171, 224–230 (2005).
71. Gould, H. J., Beavil, R. L. & Vercelli, D. IgE isotype
determination: epsilon-germline gene transcription,
DNA recombination and B‑cell differentiation.
Br. Med. Bull. 56, 908–924 (2000).
72. Avila, P. C. Does anti-IgE therapy help in asthma?
Efficacy and controversies. Annu. Rev. Med. 58,
185–203 (2007).
73. Takhar, P. et al. Class switch recombination to IgE in
the bronchial mucosa of atopic and nonatopic patients
with asthma. J. Allergy Clin. Immunol. 119, 213–218
(2007).
An important study demonstrating that IgE is
produced locally in the airways of patients with
non-atopic (intrinsic) asthma.
74. Agusti, A., Macnee, W., Donaldson, K. & Cosio, M.
Hypothesis: does COPD have an autoimmune
component? Thorax 58, 832–834 (2003).
75. Sullivan, A. K. et al. Oligoclonal CD4+ T cells in the
lungs of patients with severe emphysema. Am. J.
Respir. Crit. Care Med. 172, 590–596 (2005).
76. Lee, S. H. et al. Antielastin autoimmunity in tobacco
smoking-induced emphysema. Nature Med. 13,
567–569 (2007).
77. Hammad, H. & Lambrecht, B. N. Recent progress
in the biology of airway dendritic cells and implications
for understanding the regulation of asthmatic
inflammation. J. Allergy Clin. Immunol. 118, 331–336
(2006).
78. Ying, S. et al. Thymic stromal lymphopoietin
expression is increased in asthmatic airways and
correlates with expression of Th2-attracting
chemokines and disease severity. J. Immunol. 174,
8183–8190 (2005).
79. Allakhverdi, Z. et al. Thymic stromal lymphopoietin
is released by human epithelial cells in response to
microbes, trauma, or inflammation and potently
activates mast cells. J. Exp. Med. 204, 253–258
(2007).
This study highlights an important role for TSLP
released from airway epithelial cells in the
activation of mast cells, providing a link between
environmental factors and mast-cell activation in
asthma.
80. Liu, Y. J. Thymic stromal lymphopoietin: master switch
for allergic inflammation. J. Exp. Med. 203, 269–273
(2006).
81. Soler, P., Moreau, A., Basset, F. & Hance, A. J.
Cigarette smoking-induced changes in the number
and differentiated state of pulmonary dendritic cells/
Langerhans cells. Am. Rev. Respir. Dis. 139,
1112–1117 (1989).
82. Francus, T., Klein, R. F., Staiano-Coico, L., Becker, C. G.
& Siskind, G. W. Effects of tobacco glycoprotein (TGP)
on the immune system. II. TGP stimulates the
proliferation of human T cells and the differentiation
of human B cells into Ig secreting cells. J. Immunol.
140, 1823–1829 (1988).
83. Rogers, A. V., Adelroth, E., Hattotuwa, K., Dewar, A. &
Jeffery, P. K. Bronchial mucosal dendritic cells in
smokers and ex-smokers with COPD: an electron
microscopic study. Thorax 63,108–114 (2008).
84. Wenzel, S. E. & Busse, W. W. Severe asthma: lessons
from the Severe Asthma Research Program. J. Allergy.
Clin. Immunol. 119, 14–21 (2007).
85. Jatakanon, A. et al. Neutrophilic inflammation in
severe persistent asthma. Am. J. Respir. Crit. Care
Med. 160, 1532–1539 (1999).
86. Thomson, N. C., Chaudhuri, R. & Livingston, E.
Asthma and cigarette smoking. Eur. Respir. J. 24,
822–833 (2004).
87. Papi, A. et al. Partial reversibility of airflow limitation
and increased exhaled NO and sputum eosinophilia in
chronic obstructive pulmonary disease. Am. J. Respir.
Crit. Care Med. 162, 1773–1777 (2000).
88. Brightling, C. E. et al. Sputum eosinophilia and the
short term response to inhaled mometasone in
chronic obstructive pulmonary disease. Thorax 60,
193–198 (2005).
89. Wark, P. A. & Gibson, P. G. Asthma exacerbations. 3:
pathogenesis. Thorax 61, 909–915 (2006).
90. Celli, B. R. & Barnes, P. J. Exacerbations of chronic
obstructive pulmonary disease. Eur. Respir. J. 29,
1224–1238 (2007).
91. Papi, A., Luppi, F., Franco, F. & Fabbri, L. M.
Pathophysiology of exacerbations of chronic
obstructive pulmonary disease. Proc. Am. Thorac. Soc.
3, 245–251 (2006).
92. Barnes, P. J. How corticosteroids control inflammation.
Br. J. Pharmacol. 148, 245–254 (2006).
A review of the molecular mechanisms involved in
the anti-inflammatory actions of corticosteroids
and a discussion of the mechanisms of
corticosteroid resistance in airway diseases.
93. Ito, K. et al. Decreased histone deacetylase activity
in chronic obstructive pulmonary disease. N. Engl.
J. Med. 352, 1967–1976 (2005).
This paper shows that HDAC2 activity and
expression are reduced in peripheral lungs, airways
and alveolar macrophages of COPD patients, and
that this is associated with an increase in
inflammatory gene expression.
94. Barnes, P. J. Reduced histone deacetylase in COPD:
clinical implications. Chest 129, 151–155 (2006).
95. Barnes, P. J., Ito, K. & Adcock, I. M. A mechanism of
corticosteroid resistance in COPD: inactivation of
histone deacetylase. Lancet 363, 731–733 (2004).
96. Cosio, B. G. et al. Histone acetylase and deacetylase
activity in alveolar macrophages and blood monocytes
in asthma. Am. J. Respir. Crit. Care Med. 170,
141–147 (2004).
97. Hew, M. et al. Relative corticosteroid insensitivity of
peripheral blood mononuclear cells in severe asthma.
Am. J. Respir. Crit. Care Med. 174, 134–141 (2006).
98. Barnes, P. J. Theophylline: new perspectives on an old
drug. Am. J. Respir. Crit. Care Med. 167, 813–818
(2003).
192 | march 2008 | volume 8
99. Finegold, I. Allergen immunotherapy: present and
future. Allergy Asthma Proc. 28, 44–49 (2007).
100. Alexander, A., Barnes, N. C. & Kay, A. B. Cyclosporin A
in chronic severe asthma: a double-blind placebocontrolled trial. Am. Rev. Respir. Dis. 143, A633
(1991).
101. Evans, D. J., Cullinan, P. & Geddes, D. M. Cyclosporin
as an oral corticosteroid sparing agent in stable
asthma. Cochrane Database Syst. Rev. 2, CD002993
(2001).
102.Tamaoki, J. et al. Effect of suplatast tosilate, a Th2
cytokine inhibitor, on steroid-dependent asthma: a
double-blind randomised study. Lancet 356,
273–278 (2000).
103.Edwards, J. C. & Cambridge, G. B‑cell targeting in
rheumatoid arthritis and other autoimmune diseases.
Nature Rev. Immunol. 6, 394–403 (2006).
104.Barnes, P. J. New therapies for asthma. Trends Mol.
Med. 12, 515–520 (2006).
105.Barnes, P. J. & Hansel, T. T. Prospects for new drugs
for chronic obstructive pulmonary disease. Lancet
364, 985–996 (2004).
106.Barnes, P. J. Transcription factors in airway diseases.
Lab. Invest. 86, 867–872 (2006).
107. Duan, W. et al. Inhaled p38α mitogen-activated
protein kinase antisense oligonucleotide attenuates
asthma in mice. Am. J. Respir. Crit. Care Med. 171,
571–578 (2005).
108.Smit, J. J. & Lukacs, N. W. A closer look at
chemokines and their role in asthmatic responses.
Eur. J. Pharmacol. 533, 277–288 (2006).
109.Donnelly, L. E. & Barnes, P. J. Chemokine receptors as
therapeutic targets in chronic obstructive pulmonary
disease. Trends Pharmacol. Sci. 27, 546–553
(2006).
110. Saetta, M. et al. Airway eosinophilia and expression of
interleukin‑5 protein in asthma and in exacerbations
of chronic bronchitis. Clin. Exp. Allergy 26, 766–774
(1996).
111. Zhu, J. et al. Exacerbations of bronchitis: bronchial
eosinophilia and gene expression for interleukin‑4,
interleukin‑5, and eosinophil chemoattractants.
Am. J. Respir. Crit. Care Med. 164, 109–116 (2001).
112. Gamble, E. et al. Airway mucosal inflammation in
COPD is similar in smokers and ex-smokers: a pooled
analysis. Eur. Respir. J. 30, 467–471 (2007).
113. Retamales, I. et al. Amplification of inflammation in
emphysema and its association with latent adenoviral
infection. Am. J. Respir. Crit. Care Med. 164,
469–473 (2001).
114. Humbert, M. et al. The immunopathology of extrinsic
(atopic) and intrinsic (non-atopic) asthma: more
similarities than differences. Immunol. Today 20,
528–533 (1999).
115. Jahnsen, F. L. et al. Rapid dendritic cell recruitment to
the bronchial mucosa of patients with atopic asthma
in response to local allergen challenge. Thorax 56,
823–826 (2001).
116. Lukacs, N. W., Hogaboam, C. M. & Kunkel, S. L.
Chemokines and their receptors in chronic pulmonary
disease. Curr. Drug Targets Inflamm. Allergy 4,
313–317 (2005).
117. Chung, K. F. & Barnes, P. J. Cytokines in asthma.
Thorax 54, 825–857 (1999).
118. Chung, K. F. Cytokines in chronic obstructive pulmonary
disease. Eur. Respir. J. 34, 50S–59S (2001).
119. Montuschi, P. et al. Increased 8‑Isoprostane, a marker
of oxidative stress, in exhaled condensates of
asthmatic patients. Am. J. Respir. Crit. Care Med.
160, 216–220 (1999).
120.Paredi, P., Kharitonov, S. A. & Barnes, P. J. Elevation
of exhaled ethane concentration in asthma. Am. J.
Respir. Crit. Care Med. 162, 1450–1454 (2000).
121.Montuschi, P. et al. Exhaled 8‑isoprostane as an
in vivo biomarker of lung oxidative stress in patients
with COPD and healthy smokers. Am. J. Respir. Crit.
Care Med. 162, 1175–1177 (2000).
122.Rahman, I., Biswas, S. K. & Kode, A. Oxidant and
antioxidant balance in the airways and airway
diseases. Eur. J. Pharmacol. 533, 222–239 (2006).
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
CCR2 | CCR3 | CCR4 | CXCR2 | CXCR3 | CXCR4 | GATA3 |
IFNγ | IL‑4 | IL‑5 | IL-6 | IL-9 | IL‑13 | IL‑17 | IL‑33 | p38 | TSLP
FURTHER INFORMATION
Peter Barnes’s homepage: http://www1.imperial.ac.uk/
medicine/people/p.j.barnes.html
All links are active in the online pdf
www.nature.com/reviews/immunol
© 2008 Nature Publishing Group