REVIEW

CURRENT
OPINION Immunopathogenesis of chronic obstructive
pulmonary disease
Rebecca A. Holloway and Louise E. Donnelly

Purpose of review
Chronic obstructive pulmonary disease (COPD) is defined by airflow obstruction and is associated with
an exaggerated inflammatory response to noxious stimuli, such as cigarette smoke. Inflammation and
recruitment of immune cells drives the underlying pathophysiology; however, the roles of immune cells in
the pathogenesis of COPD are evolving and this review will discuss the latest advancements in this field.
Recent findings
Leukocytes including macrophages, neutrophils and lymphocytes are increased in the airways of COPD
patients. Despite the presence of increased innate immune cells, COPD airways are often colonized with
bacteria suggesting an underlying defect. Macrophages from COPD patients have reduced phagocytic
ability which may drive the persistence of inflammation. Differing macrophage phenotypes have been
associated with disease suggesting that the surrounding pulmonary environment in COPD may generate
a specific phenotype that is permanently pro-inflammatory. COPD neutrophils are also aberrant with
increased survival and motility, but lack direction which could lead to more widespread destruction during
migration. Finally, an element of autoimmunity, driven by Th17 cells, and alterations in the ratios of
lymphocyte subsets may also be involved in disease progression.
Summary
COPD pathogenesis is complex with contributions from both the innate and adaptive immune systems, and
the interaction of these cells with their environment mediates inflammation.
Keywords
CD4þ lymphocyte, CD8þ lymphocyte, macrophage, neutrophil

INTRODUCTION review will highlight our current understanding of

Chronic obstructive pulmonary disease (COPD)
afflicts 10% of the global population over the age
of 40 [1] and will be the third leading cause
of mortality by 2020 [2]. COPD is defined as ‘.... a
common preventable and treatable disease, [that] is
characterized by persistent airflow limitation that is
usually progressive and is associated with an enhanced
chronic inflammatory response in the airways and
the lung to noxious particles or gasses. Exacerbations
or comorbidities contribute to the overall severity in
individual patients.’ [3]. In Western nations, the
noxious particles or gases are related to cigarette
smoking [4], but environmental factors also contrib-
ute to disease development. The observed persistent
inflammatory response is a key characteristic of
COPD and it is the influx of leukocytes and alter-
ations in airway structures that are thought to
drive the underlying pathogenesis of this disease.
The leukocytic influx in COPD comprises macro-
phages, neutrophils and lymphocytes, and this
their respective contribution to COPD pathology
(Fig. 1).
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE PATHOPHYSIOLOGY
COPD is associated with a heightened inflammatory
response to external stimuli, such as cigarette
smoke. This inflammation affects all areas of the
respiratory system including the central conducting
airways, the small airways and the parenchyma.
Airway Diseases, National Heart and Lung Institute, Imperial College
London, London, UK
Correspondence to Professor Louise E. Donnelly, Airway Diseases,
National Heart and Lung Institute, Imperial College London, Dovehouse
Street, London, SW3 6LY, UK. Tel: +44 207 352 8121; e-mail: l.don
nelly@imperial.ac.uk
Curr Opin Pulm Med 2013, 19:95–102
DOI:10.1097/MCP.0b013e32835cfff5

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 Obstructive, occupational and environmental diseases

damage to the parenchyma, and in particular the

KEY POINTS

Macrophages, although increased in number in
airways of COPD patients, are defective in their ability
to phagocytose bacteria and apoptotic cells, leading to
an increasingly necrotic and inflammatory environment.

Macrophages display different phenotypes depending
on their environment and it is possible that there may
be a pro-inflammatory phenotype unique to COPD.

Neutrophil motility appears to be increased in COPD
but directional accuracy is diminished which, along
with increased survival of neutrophils instigated via
IgLC, may contribute to increased inflammation.

Proteolytic destruction of lung tissue in COPD is
mediated by increased expression of proteinases, such
as neutrophil elastase, MMPs and proteinase 3, and
correlates with disease severity.

The presence of Th17 cells suggests that COPD may
have an element of autoimmunity. However, the Treg
cells also increase suggesting that an imbalance in
lymphocyte subsets may contribute to
disease progression.
COPD encompasses three main pathophysiological
features: emphysema, chronic bronchitis and small
airways disease. Emphysema describes irreversible
destruction of elastin fibres and components of the
extracellular matrix, via uncontrolled proteolysis.
This process is mediated by an imbalance between
proteinases, such as neutrophil elastase and matrix
metalloproteinases (MMPs), and their endogenous
inhibitors such as alpha-1 antitrypsin or tissue
inhibitors of metalloproteinases (TIMPs) [5]. Neu-
trophil elastase also contributes to mucus hyper-
secretion [6] via stimulation of goblet cells in the
large airways which, along with persistent inflam-
mation, is a key feature of chronic bronchitis.
Small airways disease is defined by uncontrolled
inflammation together with fibrosis of the airway
walls leading to loss of function, and is also
associated with increases in inflammatory cells
and mediators [7,8]. Taken together, these three
key features contribute to the symptoms associated
with COPD.
CURRENT TREATMENTS
Although COPD is a leading cause of morbidity
and mortality globally, current therapeutic strat-
egies have shown little success at addressing inflam-
mation and disease progression. Unlike asthma,
which features reversible airflow limitation [9],
b2-adrenergic agonists have little effect on the

Monocyte
CCL2
Neutrophil CXCL1
CXCL8 Macrophage
LTB4
CXCL1
TGF-β

CXCL9
CXCL10
Neutrophil CXCL11
elastase MMP-9 Small airway
cathepsins disease
CD8+
Chronic bronchitis

Granzyme B
perforin
Emphysema

FIGURE 1. Overview of the contribution of immune cells to the pathophysiology of chronic obstructive pulmonary disease.
Cigarette smoke activates macrophages to produce cytokines and chemokines. CCL2 and CXCL1 will recruit monocytes to the
lung and increase macrophage number. CXCL1, CXCL8 and LTB4 will recruit neutrophils and CXCL9, CXCL10, and CXCL11 will
recruit T cells including CD8þ lymphocytes. Once present, macrophages will release matrix metalloproteinases (MMPs) that
contribute to emphysema along with neutrophil elastase and other proteinases from neutrophils. Granzymes and perforins from
CD8þ cells will damage the alveolar epithelium and contribute to emphysema. Neutrophil elastase will also stimulate goblet cells
within the airway epithelium to drive mucus hypersecretion and chronic bronchitis. Macrophages will also release factors
including transforming growth factor (TGF)-b that contributes to the fibrotic lesions and remodelling of the small airways.

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irreversible obstruction observed in COPD. Another
mainstay of airways disease treatment are the gluco-
corticosteroids; however, inflammation associated
with COPD has been shown to be largely steroid
insensitive [10]. Exacerbations of COPD also con-
tribute to disease progression and occur in response
to bacterial and/or viral infections [11,12] together
with noninfectious exposures, such as periods
of increased air pollution and climate changes
[13,14]. In these cases, patients tend to be treated
symptomatically with antibiotics where appropriate
and/or oxygen therapy. In severe disease, treatment
options are limited to home oxygen therapy and,
where suitable, lung volume reduction surgery
may improve gas exchange. The current therapeutic
situation highlights the fact that novel targets
require investigation and therefore the mechanisms
behind the pathogenesis of COPD need to be further
elucidated.
INFLAMMATORY CELLS IN CHRONIC
OBSTRUCTIVE PULMONARY DISEASE
COPD is described as an inflammatory lung
condition; however, the contribution of this inflam-
matory environment in the lung to the underlying
pathophysiology and progression of COPD is not
fully understood. The role of specific inflammatory
cells and how they may influence disease patho-
genesis and treatment efficacy is now emerging and
further dissection of these mechanisms may provide
targets for alternative therapeutic strategies.
Macrophages
Macrophages are professional phagocytes that act
in the lung to maintain airway sterility. However, in
COPD patients, the lower airways are often colon-
ized with both Gram-positive and Gram-negative
bacteria and these bacterial infections may contri-
bute to disease exacerbation [15]. The number of
macrophages in COPD airways is increased [16] but
persistent colonization suggests that bacterial clear-
ance by phagocytosis in COPD is defective [17]. Both
alveolar macrophages [18] and monocyte-derived
macrophages (MDM) [19] from COPD patients have
a reduced capacity to phagocytose bacteria com-
monly found in the lung (Haemophilus influenzae
and Streptococcus pneumoniae) compared with cells
from healthy donors [15]. The mechanism behind
this defect is yet to be fully elucidated but there
appears to be little change in the surface receptors
that mediate recognition of bacteria and their sub-
sequent demise [19]. Not only is the clearance of
bacteria diminished in COPD cells but these macro-
phages also fail to clear apoptotic cells [20], leading
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Immunopathogenesis of COPD Holloway and Donnelly
Healthy/Smokers COPD
Bacteria
Apoptotic cells
Bacteria
Apoptotic cells
Necrotic cells
Activation
Airway sterility Airway damage
colonization
FIGURE 2. Defective macrophage clearance in chronic
obstructive pulmonary disease (COPD). In macrophages from
healthy controls and smokers, macrophages remove inhaled
pathogens and clear apoptotic cells thus maintaining airway
patency and sterility. In COPD, the capacity of the
macrophage to fulfil these tasks is diminished leading to
bacterial colonization and the persistence of inflammation
due to activation of macrophages and other immune cells.
The failure to clear and remove apoptotic material leads to
increased necrosis, further driving the inflammatory cycle.
to accumulation of necrotic material in the lung
and hence perpetuation of inflammation. Adminis-
tration of the macrolide azithromycin improves
phagocytosis of apoptotic cells [21] but shows no
effect on the phagocytic response of COPD MDM to
common respiratory bacteria [19]. However, more
recently, with low-dose oral administration of this
drug to COPD patients over a period of 12 weeks
there is an improvement in the ability of both
MDM and alveolar macrophages to phagocytose
&
Escherichia coli [22 ] suggesting a longer term effect
in vivo. Impaired macrophage phagocytosis [17] is
now a target for directed therapies in COPD and
exposure of macrophages from COPD patients to
the antioxidant sulforophane improves bacterial
clearance by these cells and is associated with
upregulation of the scavenger receptor macrophage
&
receptor with collagenous structure (MARCO) [23 ]
(Fig. 2).
Sulforophane activates the transcription factor,
nuclear erythroid related factor 2 (Nrf2) [24]. This
transcription factor is activated and expressed
following oxidative stress and this mechanism
may be important in regulating the aberrant gluco-
corticosteroid response observed in macrophages
&
from COPD patients [25 ]. Glucocorticosteroid
insensitivity is thought to be linked to decreased
expression and activity of histone deacetylase
(HDAC) 2. HDAC2 deacetylates histones causing
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 Obstructive, occupational and environmental diseases
chromatin refolding and the prevention of the
transcription of pro-inflammatory mediator genes
[26]. In COPD, HDAC2 expression is decreased and
is negatively correlated with disease severity [27],
but when overexpressed in COPD cells there is
restoration of glucocorticosteroid sensitivity [28].
As a result, HDAC2 is a target for improving the
response to steroids in COPD patients. Nrf2 and
HDAC2 are closely associated; Nrf2 controls
denitrosylation of HDAC2 and restores glucocorti-
costeroid insensitivity in macrophages from COPD
&
patients [25 ]. HDAC2, however, is not the only
HDAC to be implicated in COPD pathogenesis.
HDAC3 activity is reduced by approximately 30%
after exposure to cigarette smoke, although there is
&
no decrease in mRNA expression [29 ], and changes
in activity were associated with a reduction in pro-
inflammatory cytokine release but not with
&
glucocorticosteroid sensitivity [29 ]. This suggests
interplay between different HDACs may contribute
to COPD pathogenesis.
There is increasing evidence suggesting that
macrophages display an element of plasticity and
will exhibit different phenotypes, both pro-inflam-
matory and anti-inflammatory, depending on their
local environment. This concept has given rise to
the M1/M2 hypothesis of macrophage polarization
[30,31]. M1 macrophages are considered pro-inflam-
matory and are attuned to classically activated
macrophages that are stimulated by mediators such
as interferon (IFN)g and lipopolysaccharide (LPS).
In contrast, M2 macrophages are more closely
associated with alternatively activated macro-
phages, and are stimulated with mediators such as
interleukin (IL)-4 and IL-13 [30]. More recently, ‘M2’
macrophages have been further sub-divided to
encompass resolving cells and are activated by
anti-inflammatory mediators such as IL-10 [30].
However, this system may not explain all aspects
of macrophage biology and a spectrum of macro-
phage activation has also been proposed to encom-
pass these different functional phenotypes [31].
COPD macrophages are highly inflammatory
with a low phagocytic capacity suggestive of an
‘M1’-like classically activated phenotype. However,
Shaykhiev et al. [32] have shown that alveolar
macrophages from healthy smokers show character-
istics of a more ‘M2’ resolving phenotype that
was exaggerated in alveolar macrophages from
patients with COPD. Indeed, Hodge et al. [33]
showed decreased ‘M1’ characteristics in macro-
phages derived from bronchoalveolar lavage (BAL)
fluid from COPD patients compared with healthy
nonsmokers, and that the percentage of ‘M2-like’
macrophages in BAL fluid from ex-smoker COPD
patients is lower than from currently smoking
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COPD patients, suggesting that removal of an
external noxious stimuli drives lung macrophages
&&
toward a more anti-inflammatory phenotype [34 ].
However, there was no change in inflammatory
mediators from the same samples. This field
of research requires further investigation into
how polarization of macrophages contributes to
COPD pathogenesis or whether there is a distinct
macrophage phenotype unique to the COPD lung
environment.
Neutrophils
Neutrophils are also increased in the airways of
COPD patients and are rapidly recruited to areas
of inflammation where they become activated and
release inflammatory mediators such as CXCL8,
reactive oxygen species and proteases [35]. CXCL8
is a potent neutrophil chemoattractant and activa-
tor and may act in an autocrine fashion to
sustain neutrophilic inflammation. Neutrophils,
unlike macrophages, are short-lived and normally
become apoptotic and are subsequently cleared
by macrophages [36]. However, since COPD macro-
phages fail to clear apoptotic cells appropriately,
necrotic material accumulates thereby contributing
further to the inflammatory environment. Acti-
vation of neutrophils has been associated with
cross-linking of the Fc receptors by immuno-
globulins (Ig), such as IgG [37]; however, there
is recent evidence to suggest that activation
can also occur via binding and cross-linking by
Healthy/Smokers COPD
Chemotactic
Chemotactic
gradient
gradient
FIGURE 3. Aberrant neutrophil migration in chronic
obstructive pulmonary disease (COPD). Neutrophils from
healthy controls move along a chemotactic gradient in an
orderly fashion with minimal damage to tissue. In contrast,
neutrophils from COPD patients migrate in a haphazard
manner, causing damage to tissue as they travel.
Volume 19
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March 2013

immunoglobulin free light chains (IgLC) leading to
&
CXCL8 release from neutrophils [38 ]. IgLC are
increased in serum from COPD patients compared
to healthy controls and this increase correlated with
&
disease progression [38 ]. IgLC are produced by B
cells [39] and so their increase in COPD is suggestive
of an increase in these cells also. As well as driving
neutrophils to release CXCL8, IgLC also promote
&
neutrophil survival [38 ,40] and this extended
presence of the neutrophil in the lung may also
prolong the inflammatory response (Fig. 3).
Activated neutrophils also release proteolytic
enzymes, such as neutrophil elastase, cathepsin G,
proteinase 3 and MMPs, and this may promote
a discrepancy in the proteinase/antiproteinase
balance in favour of proteolysis [41]. The neutrophil
proteinase that has been studied the most exten-
sively in relation to COPD is neutrophil elastase.
This enzyme degrades many components of the
extracellular matrix, in particular elastin [42], and
increased urinary excretion of elastin fragments
has been correlated with COPD severity [43].
Degradation of elastin in the lung parenchyma leads
to alveolar destruction and loss of elastic recoil,
thereby enhancing loss of lung function. Not only
does neutrophil elastase cause direct proteolysis of
lung tissue, it can also activate MMPs by cleaving the
pro-peptide [44]. MMP-9 is important in the proteo-
lytic destruction of human lungs and, along with
neutrophil elastase, is increased in the lungs of
COPD patients and released by COPD macrophages
[41,45]. Normally the actions of MMPs are counter-
balanced by TIMPs but as neutrophils do not express
these inhibitors [46], increased neutrophil release of
MMP-9 can become uncontrolled leading to further
destruction of the lung parenchyma. Several other
MMPs are also implicated in COPD and can be
detected in sputum from these patients [47], includ-
ing MMP-8, which is considered a neutrophil-
associated MMP. Moreover, levels of these mediators
negatively correlate with FEV1 but positively with
the percentage of neutrophils in the sputum [47].
Other neutrophil-derived proteinases implicated
in COPD include proteinase-3 that is elevated in
the sputum of stable COPD patients but increases
further during exacerbations associated with neutro-
&
philic influx [48 ].
Migration of neutrophils from the circulation to
the tissue is mediated by chemoattractants includ-
ing CXCL8 and CXCL1 [49]. However, there is evi-
dence to suggest that although neutrophils from
COPD patients can move at a greater speed, their
accuracy in reaching their final destination is greatly
reduced compared with cells from healthy donors
&&
[50 ]. This wayward chemotaxis was not associated
with a difference in receptor expression but COPD
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Immunopathogenesis of COPD Holloway and Donnelly
neutrophils extended fewer pseudopods in compari-
son to their healthy counterparts and this defect
could be restored by use of a phosphoinositide (PI)
&&
3-kinase inhibitor [50 ]. In essence, this suggests
that the defect in cellular movement is due to
an aberrant signalling fault rather than receptor
expression and as such may present a possible target
for therapeutics.
Lymphocytes
Macrophages and neutrophils are components
of the innate immune system and their increased
numbers in COPD is suggestive of an exaggerated
innate response. However, cells of the adaptive
immune system are also increased in the lungs
of patients with COPD. In particular, there is an
increase in activated lymphocytes, both CD4þ and
CD8þ T cells [51–53]. CD8þ T cells release numerous
cytokines and may contribute to the Th1-type
inflammation observed in COPD [54,55]. However,
Th2 responses may also be aberrant in COPD.
Circulating CD4þ cells and IL-2 expression were
inversely associated with COPD severity [56],
with a similar association with IL-17F expressing
CD4þ cells [57]. Increased cytokine production by
lymphocytes from COPD patients has now been
identified in a number of studies. In BAL fluid from
COPD patients, expression of IL-4 was associated
with TC2 cells [58] and more recently CD8þ cells
isolated from lung resection tissue express high
levels of tumour necrosis factor a, IFNg, granulocyte
macrophage-colony stimulating facto (GM-CSF)
and perforins following stimulation [59], suggesting
they can also play a role in the pathophysiology of
COPD. Smoking cessation does not appear to impact
upon this activation of CD8þ cells [53], indicating
that once inflammation is established, smoking
habits do not influence this aspect of disease.
Furthermore, stimulated IFNg release from activated
BAL fluid lymphocytes is glucocorticosteroid insen-
&&
sitive [60 ] and may contribute to the steroid insen-
sitivity observed in these patients.
Recently, several groups have suggested that
COPD may have an autoimmune component
[61–63]. A subset of CD4þ T cells, Th17 cells, has
been associated with other autoimmune conditions
such as psoriasis and rheumatoid arthritis [64], and
their presence in COPD could support an auto-
&&
immune hypothesis. Vargas-Rojas et al. [65 ] have
shown an increase in Th17 cells in the peripheral
blood of COPD patients, which predicted both the
presence and severity of airflow limitation in these
patients. Th17 cells release IL-17, which can act on
epithelial cells, smooth muscle cells and airway
fibroblasts to release neutrophil chemoattractants
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 Obstructive, occupational and environmental diseases

Smokers COPD

Treg Treg

Treg Treg Treg Treg

Treg
Treg Treg
Treg Treg Treg Treg

Th2

Th1 Th2 Th1 Th2

Th1 Th1

Th17 Th17 Th17

Th17 Th17

Th17 Th17 Th17 Th17

Th17 Th17
Th17 Th17

Th17 Th17

FIGURE 4. Abnormal T-cell responses in chronic obstructive pulmonary disease (COPD). In the healthy lung, T-cell homeostasis
is maintained but in smokers there is an increase in lymphocytes in response to cigarette smoke. These cells are constrained by
the presence of Treg cells, which control the proliferation of the other subtypes including the Th17 cells. In COPD, the
suppressive effect of the Treg cells is lost despite an increase in their numbers. This leads to increased Th17 cells and
potentially increased autoimmune responses.

including CXCL8 [66], leading to increased neutro-
philia. However, other T-cell subsets may also pro-
duce IL-17 and there is an increase in CD8þ T cells
that can also produce this cytokine in the lungs of
COPD patients [67]. Other T-cell populations are
also skewed in the lungs of COPD patients with
reported increases in the presence of Th1 and Treg
&&
cells also [65 ]. Normally, Treg cells control the
proliferation of Th17 cells [68] but since both cell
types are increased in COPD, it is likely that this
mechanism has failed and an imbalance in the T-cell
subsets persists, which may be responsible for the
&&
inappropriate inflammation seen in COPD [65 ].
Exactly why there appears to be an increase in
lymphocytes in COPD is not clear; however, there
is an evidence of reduced apoptosis of CD8þ cells
that might account for this accumulation and
&
persistence [69 ] (Fig. 4).
Although there is some evidence to suggest an
autoimmune component of COPD this hypothesis
of pathogenesis is contentious. A key feature of
autoimmunity is the presence of antinuclear anti-
bodies as well as the production of ‘self-antigens’. To
date, there is contradictory evidence from several
groups pertaining to these antibodies. It has been
suggested that components of the extracellular
matrix such as elastin fragments [70] may be poten-
&&
tial targets as auto antigens. Rinaldi et al. [71 ] have
investigated T-cell immune responses to elastin,
collagen I and collagen V and have shown that
there is no response to elastin or collagen I in
COPD patients. In contrast, there was a response
to collagen V in both smokers and COPD patients.
Other cell types
Although macrophages, neutrophils and lympho-
cytes have been considered the main contributors to
inflammatory COPD phenotypes, the identification
of increased numbers of mast cells in the airway
smooth muscle of lung resection tissue taken from
patients with emphysema highlights novel findings
&
that may explain heterogeneity of the disease [72 ].
This study showed that in sections from patients with
centrilobular emphysema, there were increased
numbers of mast cells compared with sections from
patients with panlobular emphysema and that
&
this correlated with airways hyper-reactivity [72 ],
suggesting a role for these cells in the pathophysio-
logy of a distinct COPD phenotype.
The role of eosinophils in the pathogenesis of
COPD is not well understood; however, sputum
eosinophilia is associated with some exacerbations
&
of COPD [73 ], and both blood and sputum eosino-
phil counts may be useful predictors for the efficacy
of glucocorticosteroid use in these patients [74,75].

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CONCLUSION
This review aimed to discuss recent findings in the
immunopathogenesis of COPD and we have shown
further evidence for the roles of the macrophage,
neutrophil and T cell in this disease, with emerging
data suggesting potential roles for mast cells and
eosinophils. The pathogenesis of COPD is complex
concerning both effects of single cell types as well as
their interactions and their surrounding environ-
ment. As such, it is likely that successful therapeutic
strategies will be multifaceted. Research into the
immunopathogenesis of COPD is a continuing field
and therefore it is important to frequently assess the
roles that different cells and their mediators play in
this disease.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 19
Number 2
March 2013