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Chronic Obstructive Pulmonary Disease 1

New insights into the immunology of chronic obstructive
pulmonary disease
Guy G Brusselle, Guy F Joos, Ken R Bracke

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inammatory
immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as
epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release
of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive
immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses,
which lead to the development of lymphoid follicles on chronic inammation. Viral and bacterial infections not only
cause acute exacerbations of COPD, but also amplify and perpetuate chronic inammation in stable COPD via
pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling,
extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of
microRNAs in the persistence of the pulmonary inammation despite smoking cessation.

Chronic obstructive pulmonary disease (COPD) aects
more than 200 million people worldwide and is the
fourth leading cause of death.1 Although the major
environmental risk factor for COPD is tobacco smoking,
only 20% of smokers develop COPD.2 Indoor air pollution
from burning biomass fuels is associated with an
increased risk of COPD in developing countries.3
Immune dysregulation arises in the peripheral blood of
patients with COPD, and might contribute to the
pathogenesis of the extrapulmonary eects of the disorder.4,5
Although overspill of inammation in the lung into the
circulation is suggested to cause systemic inammation in
a subset of patients with COPD,4 other pathogenic
mechanisms such as smoking, ageing, abdominal obesity,
and physical inactivity are probably involved.6 We focus on
the role of local immune responses in the airways and
lungs in the pathogenesis and progression of COPD due
to cigarette smoking (gure 1). Table 1 shows characteristics
of the innate and adaptive immune system.
Several mechanistic concepts have been implicated in
the pathogenesis of COPD. First, the hallmark of COPD is
development of exaggerated chronic inammation in the
lung in response to inhalation of cigarette smoke
compared with smokers without lung disease.7 Host
factors including genetic susceptibility, epigenetic
changes, and oxidative stress (webappendix p 2) contribute
by amplifying inammation induced by cigarette smoke.
Second, patients with deciency of 1-antitrypsin, the
main inhibitor of neutrophil elastase, develop emphysema
early in life,8 due to an imbalance between proteinases and
antiproteinases leading to a net increase in proteolytic
activity. Third, an imbalance between oxidants and
antioxidants in the lungs of patients with COPD, resulting
in excessive oxidative stress, not only amplies airway
inammation in smokers, but also induces cell death of
structural cells in the lung (mainly alveolar epithelial and
www.thelancet.com Vol 378 September 10, 2011

endothelial cells).9 Disruption of the balance between cell

death and replenishment of structural cells in the lung
contribute to the destruction of alveolar septa, leading to
emphysema. Additionally, age-related changes and cellular
senescence further impair tissue repair in response to
repetitive cigarette smoke-induced injury of the lungs.10
Autoimmunity has been proposed as a late pathogenic
event in the progressive course of the disease.11 The diverse
mechanisms do not operate separately in the pathogenesis
of COPD, but are strongly interrelated. Oxidative stress,
for example, contributes to the imbalance between
proteinase and antiproteinase by inactivating antiproteinases, whereas an excess of apoptotic cells leads to
secondary necrosis and can exaggerate continuing
pulmonary inammation.12,13

Lancet 2011; 378: 101526

This is the rst in a Series of
three papers about chronic
obstructive pulmonary disease
Laboratory for Translational
Research of Obstructive
Pulmonary Disease,
Department of Respiratory
Medicine, Ghent University
Hospital and Ghent University,
Ghent, Belgium
(Prof G G Brusselle MD,
Prof G F Joos MD,
K R Bracke PhD)
Correspondence to:
Guy G Brusselle, Department
of Respiratory Medicine 7K12,
Ghent University Hospital,
Ghent B-9000, Belgium

Innate immune responses in COPD

To prevent invasion of pathogenic microbes into the
lower respiratory tract, the airways and lungs have innate
defence mechanisms encompassing the epithelial barrier,
mucociliary clearance, humoral factors (eg, antimicrobial
peptides, complement proteins, and surfactant proteins)
and cells that participate in innate immunity: macrophages, dendritic cells, monocytes, neutrophils, natural
killer cells, and mast cells.

See Online for webappendix

Search strategy and selection criteria

We searched Medline for the past 10 years with the search terms COPD or emphysema
in combination with one of the following terms: immunity, macrophages,
neutrophils, mast cells, natural killer cells, T-cells (Th1, Th2, Th17, or Treg), B-cells
or (auto)antibodies. We largely selected publications in the past 5 years, but did not
exclude commonly referenced and highly regarded older publications. The date of the last
search was April 26, 2011. We also searched the reference lists of articles identied by this
search strategy and selected those we judged relevant. Review articles are cited to provide
readers with more details and more references than this Review has room for.




Goblet cell


Lymphoid follicle


Dendritic cell

Natural killer cell

B cell
Mast cell
CD4+ T cell

CD8+ T cell
Innate immune cells

Adaptive immune cells

Smooth muscle cells

Lymph node

Blood circulation

Figure 1: Innate and adaptive immune cells in the pathogenesis and course of chronic obstructive pulmonary disease
Cigarette smoke activates epithelial cells and innate immune cells such as macrophages, neutrophils, and natural killer cells. Activated dendritic cells orchestrate adaptive immune responses including
cytotoxic CD8+ T cells, T helper CD4+T cells, and B-cell responses, leading to the development of lymphoid follicles on chronic inammation. CD=cluster of dierentiation.

For more on the global initiative

of obstructive lung disease see


The rst step towards the induction of innate immune

responses is recognition of dierent microbes by
identication of molecules that are exclusive to microbes
pathogen-associated molecular patterns (PAMPs). This
recognition is achieved by several families of pattern
recognition receptors (PRRs) expressed in alveolar
macrophages, dendritic cells, and epithelial cells, which
rst contact microbial pathogens (webappendix p 2). The
PRRs include transmembrane Toll-like receptors (TLRs),
cytosolic NOD-like receptors (NLRs), and RIG-I-like
receptors (RLRs).14 In addition to PAMPs, PRRs are
activated by specic endogenous molecules, which are
normally intracellular, but are released after cell damage.
After release from injured or dying cells, these endogenous
molecules are called damage-associated molecular patterns
(DAMPs). The recognition of PAMPs and DAMPs by
PRRs is crucial in mediation of inammatory responses to
infection and sterile tissue damage, respectively (gure 2).
Acute exposure to cigarette smoke leads to activation of
several PRRs, either directly by individual components of
cigarette smoke, or indirectly by causing injury to
epithelial cells, which release DAMPs (table 2). Several
mechanisms, including inhalation of toxic agents and
irritants, oxidative stress, infections, and tissue hypoxia,

lead to the release of DAMPs by injured airways after

cigarette smoke exposure. Concentrations of high-mobility
group box 1 (HMGB1),15 uric acid, and extracellular ATP16
are increased in bronchoalveolar lavage uid of patients
with COPD compared with smokers without COPD.
Moreover, expression of receptor for advanced glycation
end products (RAGE), which binds HMGB1, is raised in
airway epithelium of patients with COPD.15 Activation of
PRRs such as TLRs and RAGE leads to increased
expression of pro-interleukin 1, which is subsequently
cleaved into mature interleukin 1 by NLR family, pyrin
domain-containing (NLRP) inammasomes (gure 2).
IL-1R knock-out mice showed attenuated pulmonary
inammation after acute exposure to cigarette smoke and
were signicantly protected against emphysema after
chronic exposure to cigarette smoke.17 Moreover, inhibition
of P2 purinergic receptorswhich bind extracellullar
ATPprevented the development of smoke-induced lung
injury and emphysema in a COPD model.18
In lung cells, another general inducible response to
injury resulting from exposure to cigarette smoke and
oxidative stress is autophagy (webappendix p 3). In lung
tissue from patients with COPD, as early as stage 0 on the
global initiative of obstructive lung disease scale, autophagy
www.thelancet.com Vol 378 September 10, 2011


is increased as indicated by increased autophagic vacuoles

(autophagosomes and autolysosomes) on electronic
microscopic analysis and by increased activation of
autophagic proteins such as Atg4B, Atg5-Atg12, and Atg7.19
In human pulmonary epithelial cells, exposure to cigarette
smoke extract in vitro rapidly induces autophagy. The
autophagic protein microtubule-associated protein 1 light
chain 3B (LC3B) has a pivotal role not only in autophagy,
but also in apoptosis since it associates with the extrinsic
apoptotic factor Fas; LC3B knock-out mice have signicantly
decreased rates of apoptosis in the lungs after exposure to
cigarette smoke and display resistance to cigarette-smokeinduced emphysema in vivo.20 The transcription factor
early growth response-1 (Egr-1) is believed to regulate LC3B
and promote autophagy and apoptosis in response to
cigarette smoke, because activation of autophagic proteins
and apoptotic factors is attenuated in Egr-1 knock-out mice
that are exposed to cigarette smoke.19
In the eector phase of innate immune responses,
cigarette-smoke-induced release of proinammatory
cytokines and chemokinessuch as tumour necrosis
factor (TNF) and chemokine (c-x-c motif) ligand
(CXCL)8by airway epithelial cells and alveolar
macrophages elicits the expression of adhesion molecules
on endothelial cells and the recruitment of neutrophils
and inammatory monocytes to the lungs. Numbers of
neutrophils and macrophages are increased in the lungs
of smokers and patients with COPD. At sites of sterile
inammation neutrophils contribute to wound healing,
but can cause tissue damage. Activated neutrophils and
macrophages cause lung destruction through the release
of oxygen radicals and proteolytic enzymes such as
neutrophil elastase and matrix metalloproteinases
(MMPs), including MMP-8, MMP-9, and MMP-12
(formerly called macrophage elastase).21,22 CD8+ T cells
and natural killer cells contribute to cytotoxicity of lung
tissue cells through the release of the proteolytic enzymes
perforin and granzyme B.23,24 In addition to its ability to
breakdown extracellular matrix, neutrophil elastase is a
potent stimulator of mucin production and secretion.
Neutrophil elastase-induced production of mucin occurs
via proteolytic cleavage of transforming growth factor
(TGF), a ligand of epidermal growth factor receptor.
Excessive mucus production and impaired mucociliary
clearance contribute to airway obstruction in patients
with COPD.25
In models of COPD, chronic exposure of mice to cigarette
smoke for 6 months induces several pathological hallmarks
of the disorder, including pulmonary inammation, airway
remodelling and airspace enlargement due to destruction
of alveolar walls (ie, emphysema).26 In much the same way
as dierences in genetic susceptibility in human smokers
aect development of COPD, the induction of emphysema
in mice is strain dependent.27 Importantly, in immunodecient mice lacking B cells and T cells, the innate
immune system suces to develop cigarette smokeinduced inammation28,29 and emphysema.28
www.thelancet.com Vol 378 September 10, 2011

Innate immunity

Adaptive immunity


Pattern recognition receptors

T-cell and B-cell receptors


Pathogen-associated molecular
patterns; damage-associated
molecular patterns

Processed antigens; antigen-antibody




Delayed (45 days)


Fixed repertoire



Immunological memory






Neutrophils, macrophages,
dendritic cells, eosinophils,
natural killer cells

T lymphocytes, B lymphocytes

Cellular component

Eector molecules

Epithelial cells

Follicular dendritic cells

Acute phase proteins,

complement, cytokines,
chemokines, growth factors,
antimicrobial peptides

B cells: immunoglobulins (antibodies)

CD4+ T cells: Th1,Th2, Th17, Treg cytokines
CD8+ T cells: perforins, granzymes

CD=cluster of dierentiation. Th=T helper. Treg=regulatory T cell.

Table 1: Characteristics of innate and adaptive immune systems

Although mast cells have been traditionally associated

with the pathophysiological mechanisms of allergic
asthma, evidence suggests that mast cells could be
implicated in the pathogenesis of COPD. Histological
studies of human lungs have shown that as COPD progresses to its severe stages mast cell populations undergo
changes in density, morphology, and distribution, including
an increase in the number of luminal mast cells.30 Although
natural killer cells are classied as lymphocytes on the
basis of their morphology, the expression of lymphoid
markers, and their origin from a common lymphoid
progenitor cell, they are deemed components of innate
immune defence because they lack antigen-specic cell
surface receptors.31 Natural killer cells act as cytolytic
eector lymphocytes, which can directly induce the death
not only of virus-infected cells and tumour cells, but also of
structural cells in the lungs, which die by apoptosis or
necrosis from damage caused by perforin and
granzyme B.11,24 Increased proportions of natural killer cells
that are CD3 and CD56+ and increased cytotoxic activity
of natural killer cells expressing both perforin and
granzyme B, have been shown in induced sputum of
patients with COPD compared with healthy smokers.24
Additionally, natural killer cells cross-talk with dendritic
cells, promoting the maturation of dendritic cells by
producing interferon and TNF.32

Dendritic cells and innate and adaptive immunity

Dendritic cells are specialised antigen-presenting cells
that link innate and adaptive immune responses (gure 1
and webappendix p 3).33 By the integration of many
signals of the microenvironment dendritic cells promote
CD4+ T helper (Th) cell dierentiation and CD8+


Sensing cigarette smoke and danger signals




Cell death






Uric a



ukin 1




, HA


Interleukin 1R




Eector phase

cytokines and chemokines
(TNF, interleukin 1, CXCL8,...)


interleukin 1
interleukin 1

Proteolytic enzymes
(NE, MMP-9, MMP-12,...)
Interleukin 1 secretion

Figure 2: Aerent and eerent part of innate immune responses in chronic obstructive pulmonary disease
Cigarette smoke activates epithelial cells, macrophages, and neutrophils via oxidative stress and by triggering pattern recognition receptors (PRR) such as
Toll-like receptors (TLRs) and purinergic receptors (eg, P2X7 and P2Y2), either directly by cigarette components or indirectly via the release of damage-associated
molecular patterns (DAMPs) by dyingautophagic death, apoptotic or necroticcells. Viral and bacterial respiratory tract infections amplify the chronic
inammation in COPD by triggering PRRs via pathogen-associated molecular patterns (PAMPs). On activation, the innate immune cells release
pro-inammatory cytokines and chemokines, reactive oxygen species (ROS) and proteolytic enzymes (neutrophil elastase [NE] and matrix metalloproteinases
[MMPs]). More research is needed to show the importance of NOD-like receptor family, pyrin domain containing (NLRP) inammasomes in chronic obstructive
pulmonary disease. HSP=heat shock protein. HMGB1=high-mobility group box 1. HA=hyaluronic acid. NF-B=nuclear factor B. CXCL=chemokine (c-x-c motif)
ligand. RAGE=Receptor for Advanced Glycation End products.

cytotoxicity (gure 3). Smoking of cigarettes has been

associated with an expansion in the population of
Langerhans-like dendritic cells in the epithelial surface
of the lower respiratory tract. After acute smoke exposure,
myeloid dendritic cells are immediately and selectively
recruited into the bronchoalveolar lavage uid of
smokers.34 Moreover, expression of Langerin and CD1a
(markers of Langerhans-like dentritic cells) is increased,
as is that of costimulatory markers CD80 and CD86 on
myeloid dendritic cells from the bronchoalveolar lavage
uid of smokers compared with never-smokers.
In COPD, several dendritic cell subsets in the
lung parenchyma showed signicant increases in
costimulatory molecule expression, which correlated with
COPD severity.35 By immunohistochemistry we showed
selective accumulation of Langerin+ myeloid dendritic
cells in the small airways of patients with COPD, which
increased with disease severity and was associated with

increased expression of chemokine (c-c motif) ligand

(CCL) 2036 (gure 4). The Langerin+ subset of myeloid
dendritic cells is mainly present in the airway epithelium
and is segregated from the interstitial myeloid dendritic
cell subset that is positive for dendritic cell-specic
intracellular adhesion molecule 3grabbing non-integrin,
which is located in the lamina propria and adventitia and
does not increase in patients with COPD (gure 4).
Langerin+ dendritic cells have been linked to the induction
of CD8+ T-cell responses by cross-presentation.37

Adaptive immune responses in COPD

In both the airway and alveolar compartment, the CD8+
cytotoxic T cell is the predominant T cell in patients
with COPD.11,23 The number of pulmonary CD8+ T cells
in COPD increases substantially with higher stages of
airow limitation and emphysema.23 The expression of
the chemokine receptor CXCR3, preferentially
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expressed on type 1 T lymphocytes, and its ligand

interferon-induced protein 10 (also known as CXCL10)
(table 3) is increased in peripheral airways of smokers
with COPD, suggesting that the axis between CXCL10
and chemokine (c-x-c motif ) receptor (CXCR) 3 might
be implicated in CD8+ T-cell recruitment in COPD.38
On activation, CD8+ T cells release proteolytic enzymes
such as perforin and granzymes, which cause cell death
of structural cells by apoptosis or necrosis11,24 (gure 5).
Numbers of CD4+ T cells are raised in the airways and
lungs of smokers with COPD. At least two dierent types
of eector CD4+ Th cells accumulate in the lungs of
patients with stable COPD: Th1 cells and Th17 cells.39,40 Th1
cells expressing chemokine receptors CCR5 and CXCR3
produce interferon and promote accumulation of
inammatory cells to the lungs. Lung lymphocytes in
patients with COPD and emphysema have higher
percentages of CD4+ Th1 cells and secrete more interferon
than in control smokers.39 Interleukin 18, which promotes
Th1 cell development, is strongly expressed in alveolar
macrophages, CD8+ T cells, and both bronchiolar and
alveolar epithelia in lungs of patients with severe COPD.41
Th17 cells are a distinct lineage of activated CD4+
T cells, regulating tissue inammation by producing
interleukin 17A and interleukin 17F.42 They mediate
immunity against extracellular pathogens, but have also
been implicated in autoimmunity.42 Th17 cytokines
induce epithelial cells to produce antimicrobial peptides
(such as defensins), chemokines, and the granulocyte
growth factors G-CSF and GM-CSF to promote neutrophil
accumulation at the site of tissue injury. Patients with
COPD have increased numbers of interleukin 23+
immunoreactive cells in the bronchial epithelium and
interleukin 17A+ cells in the bronchial submucosa.40
However, because interleukin 17A production is linked to
structural cells such as endothelial cells, sources other
than T cells might be important.40
Regulatory T cells (Treg) are subsets of CD4+ T cells with
immunoregulatory functions, which inhibit autoimmunity
and suppress inammation. The two most abundant
subsets of Treg are the natural Treg and the adaptive or
inducible Treg. Natural Treg leave the thymus as eector
cells and are essential in maintaining self-tolerance,
whereas induced Treg mature in the periphery and are
activated by exogenous antigens. Treg exert their
suppressive eect on other T cells or on antigen-presenting
dendritic cells via contact-dependent mechanisms or the
production of anti-inammatory cytokines such as interleukin 10 and transforming growth factor (TGF).43 They
are characterised by expression of the transcription factor
FOXP3 (forkhead box P3) and bright expression of the
surface marker CD25, the interleukin 2 receptor chain.
Smokers with COPD and emphysema had signicantly
fewer Treg cells in the lungs, less messenger RNA (mRNA)
for FOXP3, and less interleukin 10 secretion from the
whole lung than controls.44 CD4+ CD25-bright cells were
signicantly increased in bronchoalveolar lavage uid in
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Receptor (cellular [soluble])

Cigarette smoke components
Endotoxin (lipopolysaccharide)

TLR4 and CD14, [lipopolysaccharide-binding protein]



Reactive oxygen species, free radicals




Polycyclic aromatic hydrocarbon


DAMP released from stressed, apoptotic, and necrotic cells



Uric acid


High-mobility group box 1


S100 molecules


Heat shock proteins

TLR2, TLR4, CD91, CD24, CD14, CD40



Interleukin 1

Interleukin 1R

DNA (mitochondrial)


Formyl peptides (mitochondrial)


DAMP released from breakdown of ECM

Hyaluronic acid

TLR2 , TLR4, CD44


TLR4, 51 integrin, V3 integrin

Heparan sulphate








TLR=Toll-like receptor. CD=cluster of dierentiation. nAChR=nicotinic acetylcholine receptor. TRPA1=transient

receptor potential A1. AhR=aryl hydrocarbon receptor. P2XR=purinergic receptor P2XR. P2YR=purinergic receptor
P2YR. NLRP3=NOD-like receptor family, pyrin domain containing 3. RAGE=receptor for advanced glycation end
products; FPR1=formyl peptide receptor 1. ECM=extracellular matrix. CXCR=chemokine (c-x-c motif) receptor.

Table 2: Sensing of cigarette smoke components and Damage Associated Molecular patterns (DAMP) by
Pattern Recognition Receptors (PRR) and other receptors of the innate immune system

smokers with normal lung function compared with people

who had never smoked and patients with moderate COPD
in one study,45 whereas bronchoalveolar lavage CD4+
CD25-bright cells were increased in smokers and patients
with COPD compared with healthy people who had never
smoked in another study.46 Because these cells encompass
both FOXP3+ Treg and non-regulatory activated Th cells,
additional multicolour owcytometric and functional
studies of bronchoalveolar lavage uid and lung digests
are warranted to resolve this discrepancy. T cells that are
FOXP3+ and CD4+ are raised in lymphoid follicles of
patients with moderate COPD compared with control
smokers,47 suggesting that Treg might regulate inammatory responses to prevent autoimmunity.11 Treg that are
CD4+, CD25+, and FOXP3+ resolve experimental lung
injury in mice after intratracheal lipopolysaccharide
administration and are present in the bronchoalveolar
lavage uid of patients with acute lung injury, suggesting
that Treg modify innate immune responses during
resolution of lung injury.48

B cells
B cells are increased in large airways of patients with
COPD, as shown in central bronchial biopsy specimens.


CD8+ cytotoxic T cell


Perforins, granzymes

CD80 CD28
CD4+ T helper cell

CD80 CD28

, IL
12 in
IL lept
IL 4 2A
; IL

IL 12R
IL 18R


IL 23R


IL 4, IL 5, IL 13

IL 10, TGF

IL 17A, IL 17F, IL 21, IL 22

Figure 3: Dendritic cells driving CD4+ T helper cell dierentiation and CD8+ T-cell cytotoxicity
MHC I-restricted dendritic cells present antigenic peptides to CD8+ T cells, whereas MHC II-restricted dendritic
cells drive the dierentiation of naive CD4+ T cells towards T helper (Th) 1, Th2, Th17 cells or regulatory T cells
(Treg) depending on the cytokine balance in the local microenvironment. The dierent Th cell subsets and
Treg cells are characterised by dierent transcription factors and membrane-bound receptors (eg, chemokine
receptors) and produce dierent cytokines. IL=interleukin. CXCR=chemokine (c-x-c motif) receptor.
CCR=chemokine (c-c motif) receptor. INF=interferon. TNF=tumour necrosis factor . GATA-3=GATA binding
protein 3. GITR=glucocorticoid-induced tumour necrosis factor-related protein. CD=cluster of dierentiation.
CTLA=cytotoxic T-lymphocyte antigen. TGF=transforming growth factor . FOXP3=forkhead box P3.
RORT=retinoid related orphan receptor gamma T.

Moreover, B cells organised into lymphoid follicles have

been shown around small airways49 and in lung
parenchyma50 of patients with COPD, especially in severe
and very severe disease. As seen in other tissues that are
aected by chronic inammation, lymphoid follicles in
patients with COPD result from lymphoid neogenesis51
and belong to the inducible Bronchus-Associated
Lymphoid Tissue (iBALT), an ectopic lymphoid tissue
that is formed on infection or inammation in both mice
and man.52 iBALT acquires antigens from the airways,
initiates local immune responses, and maintains memory
cells in the lungs.
Lymphoid follicles are anatomically and functionally
well organised, consisting of a specic arrangement of
memory and naive B cells, T cells, dendritic cells, and
follicular dendritic cells, which allow for T-cell and B-cell
priming and clonal expansion.51 Plasmacytoid dendritic
cells have been recorded in peribronchiolar lymphoid
follicles of patients with COPD.53 B-cell activating factor
of tumour necrosis factor family (BAFF) is overexpressed
in lymphoid follicles in lungs of patients with COPD,
compared with controls, suggesting that the BAFF to
BAFF-receptor pathway contributes to the development
and maintenance of lymphoid follicles in COPD.54
Moreover, pulmonary BAFF expression correlates to the
degree of airow limitation and hypoxia, two important
markers of disease severity.

The compartmentalisation of lymphoid follicles in

B-cell and T-cell areas isas in lymph nodesregulated
by homoeostatic chemokines, which dictate homing and
motility of lymphocytes and dendritic cells in lymphoid
tissues.55 CCL19 and CCL21 attract naive T lymphocytes
expressing CCR7 and mature dendritic cells into the
T-cell areas, whereas the CXC chemokine CXCL13
attracts B cells expressing CXCR5 (table 3). Whereas in
lymph nodes lymphotoxin induces the expression of
the chemokines CCL19 and CXCL13, interleukin 17 is
needed for the induction of these chemokines in iBALT.56
Once formed, iBALT is longlasting and participates in
local immune responses.52
In these lymphoid folliclesespecially in germinal
centres of secondary lymphoid folliclesantigen
retention, immunoglobulin class switching, and anity
maturation occur.52 The B cells are oligoclonal in nature,
suggesting antigen-specic induction of the B-cell
follicles.50 Which antigens might be involved is not
known, but microbial antigens, cigarette smoke-derived
antigens, breakdown products from extracellular matrix,
and autoantigens have been suggested.51 Therefore, the
pathogenic role of the follicular B-cell response is
controversial; it might be benecial, if protective against
microbial colonisation and infection of the lower
respiratory tract; or by contrast, it could be detrimental, if
directed against lung tissue antigens, suggesting an
autoimmune component in the pathogenesis of COPD
and especially emphysema.11

Infection in COPD
Infections of the respiratory tract contribute to the
pathogenesis and course of COPD in at least two dierent
ways.57 First, viral and bacterial infections are the most
important cause of acute exacerbations of COPD. As
airow obstruction progresses in COPD, the frequency
of exacerbations greatly increases.58 Second, colonisation
and chronic infection of the lower airways by respiratory
pathogens can amplify and perpetuate chronic inammation in stable COPD. The frequency of chronic
bacterial colonisation and infection increases progressively with disease severity.59,60
Importantly, in COPD, phagocytosis of bacteria such
as Haemophilus inuenzae and Streptococcus pneumoniae
by alveolar macrophages is impaired.61,62 Monocytederived macrophages and alveolar macrophages from
patients with COPD showed signicantly decreased
phagocytic responses to bacteria compared with nonsmokers and smokers.63 The impairment of phagocytosis
of bacteria by alveolar macrophages in COPD
contributes to chronic bacterial colonisation and to
acute infectious exacerbations.
Bacteria such as H inuenzae, S pneumonia, and
Moraxella catarrhalis are detected in about 25% of patients
with stable COPD and in more than 50% of patients
during COPD exacerbations.64 Bacterial exacerbations
lead to increased airway and systemic inammation, as a
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result of direct eects of bacteria and of the host response.57

Several PAMPs of bacteria, including lipopolysaccharides,
peptidoglycans, and outer-membrane proteins, are sensed
by specic PRRs on epithelial cells and innate immune
cells (table 4), triggering the nuclear factor-B pathway
and other signal transduction pathways such as p38
mitogen-activated protein kinase and interferon regulatory
factors, resulting in the production of pro-inammatory
cytokines and chemokines (gure 2). TLR signalling in
macrophages seems to link phagocytosis, a biological
process to remove extracellular organisms, to autophagy,
(webappendix p 3).65,66 Not only an increase in the
concentration of bacteria that colonise the lower airways
in patients with COPD, but also the acquisition of a new
bacterial strain is crucial in the pathogenesis of
exacerbations.67 In patients with severe COPD, exacerbations can be caused by Pseudomonas aeruginosa.
Viruses can be detected in 1015% of sputum samples
in patients with stable COPD, and in 3060% of those
with COPD exacerbations, dependent on the sensitivity of
the detection method.68 Rhinoviruses and inuenza virus
are the respiratory viruses that are most frequently
associated with exacerbations of COPD. Rhinoviruses are
isolated from nasal and lung uid from patients with
acute exacerbations of COPD,69 indicating that rhinoviruses infect upper and lower airway epithelial cells.
In induced rhinovirus infection in volunteers with
COPD, Johnston and colleagues70 showed a causal relation
between rhinovirus infection and COPD exacerbations.
After rhinovirus infection, patients with COPD developed
lower respiratory symptoms, airow obstruction, and
systemic and airway inammation that were greater and
lengthier than in controls; virus load was higher in
patients with COPD, whereas interferon production by
bronchoalveolar lavage cells was impaired.70
Severe COPD exacerbations needing hospitalisation
were associated with increased sputum neutrophilia,
irrespective of viral or bacterial infections, whereas
sputum eosinophils were increased during viral
exacerbations.71 CD4+ T cells from bronchoalveolar lavage
uid from patients with COPD showed a mixed Th1 and
Th2 cell cytokine phenotype during acute rhinovirus
infection.69 Human rhinovirus-encoded proteinase 2A
induced strong Th1 and Th2 immune responses from
CD4+ T cells, implicating this microbial proteinase as an
adjuvant factor during respiratory tract infections in
patients with COPD69 (gure 3).
Studies of sputum and bronchoalveolar lavage showed
increased concentrations of neutrophils, CXCL8, TNF,
and proteases (neutrophil elastase and MMP-9) in
COPD patients and bacterial colonisation compared
with those without bacterial pathogens.57 The
colonisation-induced triggering of PRR by microbial
PAMPs thus amplies the chronic neutrophilic airway
inammation in COPD. Patients with COPD develop
specic adaptive immune responses to colonising
bacteria. These adaptive immune responses contribute
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100 m

100 m

100 m

100 m

Figure 4: Dendritic cells in chronic obstructive pulmonary disease (COPD)

(A and B) Accumulation of dendritic cells in small airways of patients with COPD. Langerin+ dendritic cells (brown) in
human lung tissue cryosections of (A) a smoker without COPD and (B) a patient with stage II COPD according to the
global initiative for chronic obstructive lung disease (GOLD) scale. (C) Immunohistochemical double staining for
dendritic cell-specic intercellular adhesion molecule-3-grabbing non-integrin+ (DC-SIGN+) interstitial-type
dendritic cells (red) and langerin+ Langerhans type dendritic cells (blue) in small airways of human lung. Langerin+
cells are mainly present in the epithelium, whereas DC-SIGN+ cells are localised in the lamina propria and adventitia.
There are no double positive cells, conrming the segregation of these two dendritic cell subsets in human lung.
(D) Identication of plasmacytoid dendritic cells in a lymphoid follicle of a patient with COPD GOLD stage II. Triple
staining of a cryosection of human lung tissue for CD3 (blue colour indicates the T-cell zone), CD20 (red-pink colour
indicates the B-cell zone) and BDCA-2 (brown colour indicates plasmacytoid dendritic cells). Plasmacytoid dendritic
cells (arrows) are mainly found in the T-cell zone of lymphoid follicles.

Target cells

CC-motif chemokine receptors




CCL3/MIP-1, CCL4/MIP-1, CCL5/RANTES Monocytes, immature dendritic cells, T cells

Monocytes, immature dendritic cells, T cells



Immature dendritic cells, T cells



Mature dendritic cells, T cells, B cells

CXC-motif chemokine receptors





Neutrophils, monocytes
Neutrophils, monocytes



T cells



B cells

Simplied and non-limiting table of chemokines and chemokine receptors implicated in COPD. CCL=chemokine
(c-c motif) ligand. CXCL=chemokine (c-x-c motif) ligand. MCP 1=monocyte chemoattractant protein 1.
MIP=macrophage inammatory protein. RANTES=regulated on activation normal T-cell expressed and secreted.
SLC=secondary lymphoid tissue chemokine. IL 8=interleukin 8. GRO-=growth related oncogene . Mig=monokine
induced by interferon . IP-10=interferon- inducible protein of 10 kDa. I-TAC=interferon-inducible T-cell-
chemoattractant. BCA-1=B-cell attracting chemokine.

Table 3: Chemokines and chemokine receptors in chronic obstructive pulmonary disease (COPD)

locally to the development of B-cell lymphoid follicles

and mucosal IgA production, and systemically to the
production of IgG antibodies in serum. Strain-specic
immunoglobulin responses reduce the risk of
exacerbation after acquisition of a new bacterial strain
and contribute to clearance of the pathogen.72



Lymphoid follicle
IL 1

Plasma cell

IL 18/IL 23

ECM breakdown fragments


IgM, IgG

IL 23R


CD8+ cytotoxic
T cell



Th17 cell

Th1 cell


B cell
T cell





IL 17A
IL 17F
IL 21
IL 22

Smooth muscle cell

Dendritic cell

Figure 5: Adaptive immune responses in chronic obstructive pulmonary disease (COPD)

Cigarette smoke-derived antigens, microbial antigens (from viral or bacterial colonisation and infection of the lower respiratory tract), breakdown products from extracellular matrix (such as collagen
and elastin fragments) and possibly lung tissue autoantigens (eg, epithelial antigens or smooth muscle antigens) can elicit adaptive immune responses in the lungs of patients with COPD,
encompassing cytotoxic CD8+ T cells, T helper (Th)1 and Th17 CD4+ T cells, and B-cell responses with antibody production. Peribronchiolar lymphoid follicles are organised in T-cell and B-cell
compartments through the lymphoid homoeostatic chemokines CCL19 and CCL21 (attracting CCR7+ naive T cells and dendritic cells) and CXCL12 and CXCL13 (binding to CXCR5 on B cells),
respectively. In these lymphoid follicleswhich belong to the inducible Bronchus-Associated Lymphoid Tissuelocal immunoglobulin production, including production of protective mucosal
immunoglobulin (Ig) A, occurs rapidly and eciently. sIgA=secretory immunoglobulin A. FDC= follicular dendritic cells. BAFF=B-cell activating factor of tumour necrosis factor family.
BAFF-R=B-cell activating factor of tumour necrosis factor family-receptor. CCL=chemokine (c-c motif) ligand. CCR=chemokine (c-c motif) receptor. CXCL=chemokine (c-x-c motif) ligand.
CXCR=chemokine (c-x-c motif) receptor. HEV=high endothelial venules. LT=lymphotoxin. ECM=extracellular matrix. TNF=tumour necrosis factor . CD=cluster of dierentiation.

Is COPD an autoimmune disease?

On the basis of the presence of B-cell lymphoid follicles
in patients with advanced COPD and the detection of
diverse autoantibodies in serum of a subgroup of patients
with COPD,44,73,74 COPD has been regarded as an autoimmune disease.11 Lee and colleagues44 showed the
presence of antielastin antibody and Th1 responses in
patients with COPD, which correlated with severity of
emphysema. However, several other research groups
could not detect increased antielastin antibody titres in
patients with COPD. Greene and colleagues75 reported no
signicant dierences in the levels of antielastin or
anti-N-acetylated proline-glycine-proline (Pro-Gly-Pro)
autoantibodies in three groups of patients with chronic
inammatory lung disease (cystic brosis, 1-antitrypsin
deciency, and COPD) compared with healthy controls.
Moreover, smoke exposure but not disease state seemed
to be the main determinant of antielastin antibody
concentrations.76 Antibodies against primary pulmonary

epithelial cells, including anti-Hep-2 epithelial cell IgG

autoantibodies, were recorded more frequently in patients
with COPD than in controls.73 Serum concentrations of
antitissue antibodies, especially antismooth muscleantigen antibodies, were present in a fth of patients with
COPD with a recent history of hospitalisation for
exacerbation of COPD, and correlated with the severity of
airow limitation.74 Finally, antinuclear autoantibodies
were more prevalent in patients with COPD than in
healthy controls, but these molecules were not associated
with smoking status or FEV1, hence the pathological
importance of these observations is unclear.74,75

Why does pulmonary inammation persist

despite smoking cessation?
Airway inammation in patients with COPD persists
after smoking cessation.76 Although autoimmunity might
contribute to the perpetuation of pulmonary inammation
in a subgroup of patients with advanced COPD and
www.thelancet.com Vol 378 September 10, 2011


emphysema, several other mechanisms are likely to be

involved in persistence of the inammatory response
despite smoking cessation. These mechanisms are not
mutually exclusive and encompass self-perpetuating
innate immune responses, airway wall remodelling,
impaired macrophage clearance, chronic colonisation
and infection of the lower airways, oxidative stress, tissue
hypoxia, genetic susceptibility, and epigenetic changes.21
First, destruction of extracellular matrix (collagen,
elastin, and hyaluronan), releases proinammatory
fragments that are chemotactic for neutrophils and
monocytes, sustaining inammation even when the
initial stimulus is gone.77 CXC chemokines mediate
neutrophil attraction to sites of tissue injury, and matrix
fragments of collagenincluding the tripeptide N-acetyl
Pro-Gly-Proare important neutrophil chemoattractants.78 Furthermore, fragments of elastin have major
chemotactic activity, inducing recruitment of monocytes
and macrophages in experimental models of emphysema.
Additionally, other constituents or fragments of the
extracellular matrix such as tenascin C, biglycan, and low
molecular weight hyaluronan contribute to the
perpetuation of the inammatory response, partly
through activation of TLR2, or TLR4, or both (table 2).
Second, the removal of apoptotic cells (termed
eerocytosis) is a highly conserved process, and is
essential for the resolution of inammation and the
maintenance of lung integrity.13 In COPD, apoptotic cells
are increased because of enhanced induction of apoptosis
and decient phagocytosis of apoptotic cells by alveolar
macrophages, which lead to impaired resolution of
inammation. In a murine model of COPD, acute and
subacute cigarette exposure suppresses eerocytosis by
alveolar macrophages.79 Moreover, apoptosis of neutrophils
followed by eerocytosis not only prevents damage, but
also induces an anti-inammatory macrophage phenotype
(M2 or alternatively activated macrophages). By contrast,
failed eerocytosis of apoptotic neutrophils leads to
secondary necrosis, which results in the release of
DAMPs, neutrophil elastase, and other toxic components
into the extracellular space (gure 2).
Third, impaired innate lung defences predispose
patients to microbial colonisation and infection of the
lower respiratory tract, which causes additional airway
epithelial injury. This cyclical sequence of events amplies
chronic inammation and perpetuates microbial
infections that are characteristic of severe COPD.57 Fourth,
local tissue hypoxia in patients with COPD can perpetuate
lung inammation, because of an important bidirectional
communication between hypoxia and inammation.80 In
hypoxic conditions, hypoxia-inducible factor 1 (HIF1)
translocates frFom the cytoplasm to the nucleus, inducing
transcription of multiple genes, including those of TLRs
and nuclear factor-B. HIF-1 prolongs the lifespan of
neutrophils by inhibiting apoptosis. Conversely, inamed
tissues often become hypoxic and activation of the
nuclear factor-B pathway leads to the transcription of
www.thelancet.com Vol 378 September 10, 2011


PRR (cellular [soluble])

Streptococcus pneumoniae

Lipoteichoic acid, pneumolysin

CpG dinucleotides



Haemophilus inuenzae


TLR4 and CD14, [LBP]


Moraxella catarrhalis

Usp A1
Usp A2

TLR4 and CD14, [LBP]


Pseudomonas aeruginosa


TLR4 and CD14, [LBP]










TLR=Toll-like receptor. PAFR=plateled-activating factor receptor. NOD=nucleotide-binding oligomerisation

domain-containing protein. LBP=lipopolysaccharide-binding protein. CRP=C-reactive protein. LPS=lipopolysaccharide.
OMP=outer membrane protein. Usp=ubiquitous surface protein. CAECAM1=carcinoembryonic antigen-related cell
adhesion molecule 1. dsRNA=double stranded RNA. ssRNA=single stranded RNA. MDA5=melanoma
dierentiation-associated gene 5. RIG-I=retinoic acid-inducible gene I.

Table 4: Microbial pathogens, pathogen associated molecular patterns (PAMP), and pattern recognition
receptors (PRR) in chronic obstructive pulmonary disease

inammatory genes and HIF-1.80 Fifth, expression of

several microRNAswhich negatively regulate protein
expression (webappendix p 4)is signicantly decreased
in induced sputum of patients with COPD.81 Of particular
interest is the decreased expression of microRNA let-7c in
sputum of smoking patients with COPD, because let-7c
not only regulates several inammatory genes such as
TNFR-II, but has also been implicated in oncogenesis
(eg, lung cancer).82,83
Importantly, in patients with COPD oxidative stress
persists after smoking cessation, and has a crucial role in
perpetuation of pulmonary inammation (webappendix
p 2). The reduced histone deacetylase 2 activity in COPD
has been linked to increased acetylation of the central
antioxidant transcription factor Nrf 2, impairing Nrf 2
activity and the upregulation of antioxidant enzymes in
response to oxidative stress.84 Impairment of Nrf2mediated antioxidant defences and epigenetic changes
induced by reactive oxygen species (eg, histone
modications) contribute to the persistence of oxidative
stress in COPD.9,85,86

Therapeutic implications
Smoking cessation attenuates the accelerated decrease
in lung function in patients with COPD.87,88 A pooled
analysis of three bronchial biopsy studies showed that,
in established COPD, the numbers of inammatory
cells in the bronchial mucosa are much the same as in
former smokers and in persistent smokers.76 However, analysis of bronchoalveolar lavage uid of
COPD patients suggests that smoking cessation
partly changes the macrophage polarisation from a


For more on clinical trials for

COPD see http://clinicaltrials.


proinammatory M1 towards an anti-inammatory

M2 macrophage phenotype.89
Regular treatment with long-acting bronchodilators is
the mainstay of therapy in symptomatic patients with
moderate to severe COPD, but only a few randomised
controlled trials have investigated the eects of pharmacological treatment on the underlying bronchial and
pulmonary inammation.9092 3-month treatment with the
inhaled corticosteroid uticasone-propionate did not
reduce numbers of CD8+ T cells, macrophages, or
neutrophils in bronchial biopsy samples,91 whereas
combination therapy of salmeterol xinafoate and
uticasone was associated with a reduction in CD8+ cells
on biopsy samples.92 Whereasespecially mild to
moderateasthma is usually highly responsive to inhaled
corticosteroid therapy, COPD patients respond poorly to
such treatment. The dierences in corticosteroid
responsiveness between asthma and COPD are due to
several molecular mechanisms, including oxidative stress.83
Cigarette smoke and stress from reactive oxygen species
can prevent nuclear translocation of the glucocorticoid
receptor or decrease the activity of the co-repressor protein
histone deacetylase 2, reducing the ability of corticosteroids
to switch o inammatory gene expression.85,93 Additionally,
dierences in the type of the underlying immune responses
between asthma and COPD, might contribute to
dierential corticosteroid responsiveness.93,94 The Th2driven eosinophilic airway inammation in mild allergic
asthma is highly responsive to inhaled corticosteroids,
implicating this drug class as the mainstay treatment in
persistent asthma. By contrast, the chronic neutrophilic
airway inammation in COPD is resistant to steroids.95
Short-term courses of oral corticosteroids are eective for
acute exacerbations of COPD. However, chronic treatment
with systemic corticosteroids should be avoided in patients
with stable COPD.96
In patients with COPD, the specic phosphodiesterase-4
inhibitor roumilast signicantly reduced the absolute
number of neutrophils in sputum and the concentrations
of CXCL8 and neutrophil elastase in sputum supernatants.97 This anti-inammatory eect of roumilast
might correlate with its reduction of exacerbations in
severe COPD patients with chronic bronchitic symptoms
and a history of COPD exacerbations.98 In this COPD
subphenotype, long-term macrolide therapy was
associated with signicant reductions in the rate of
exacerbations compared with placebo.99 Low dose
macrolide treatment shows much the same benets in
other chronic neutrophilic airway diseases, including
diuse panbronchiolitis, bronchiolitis obliterans
syndrome after lung transplantation, cystic brosis, and
non-cystic brosis bronchiectasis. The anti-inammatory
mechanisms of macrolides need to be fully elucidated,
but probably encompass pleiotropic inhibitory eects on
neutrophil elastase, interleukin 17 production by
T lymphocytes and CXCL8 and GM-CSF release from
epithelial cells, and upregulation of the expression of the

mannose receptor on alveolar macrophages, which

improves the phagocytosis of apoptotic cells.100
Several molecular and cellular mediators of the innate
and adaptive immune responses, are regarded as new
therapeutic targets. Possible new drugs for COPD
encompass modulators of TLRs, chemokine receptor
antagonists, protease inhibitors (eg, small-molecule
neutrophil elastase inhibitors and inhibitors of MMP-9
and MMP-12) and anti-interleukin-17 targeted therapies
(including anti-interleukin-17 monoclonal antibodies and
tocilizumab, which targets the interleukin-6 receptor and
thereby favours the dierentiation towards Treg instead of
Th17 cells). However, specic targeted anti-inammatory
therapy with the anti-TNF monoclonal antibody
iniximab has failed in COPD.101 An alternative approach
is to try to restore glucocorticoid sensitivity in patients
with COPD.85 Dependent on the underlying molecular
mechanism of glucocorticoid resistance, patient-specic
therapies need to be investigated, encompassing antioxidants, theophylline, or kinase inhibitors such as
mitogen-activated protein kinase inhibitors or phosphatidylinositol-3 kinase inhibitors.86,102,103
GGB contributed to the literature search, writing and revision of the report.
GFJ co-supervised the preclinical and clinical work that is the basis of this
report and reviewed and edited the report. KRB contributed to the literature
search, created the tables and gures, and reviewed and edited the report.
Conicts of interest
GGB is a member of advisory boards for AstraZeneca,
Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; has been a
consultant for Amakem; and has received speakers fees from
AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck,
Novartis, Pzer, and UCB. GFJ is a member of advisory boards for
AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Novartis,
and Nycomed; has received grants or has grants pending from
AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and
UCB; and has received speakers fees from Almirall, AstraZeneca,
Boehringer-Ingelheim, GlaxoSmithKline, Merk Novartis, Pzer, and
UCB. KRB declares that he has no conicts of interest.
We thank all collaborators at the Laboratory for Translational Research of
Obstructive Pulmonary Disease, Department of Respiratory Medicine,
Ghent University Hospital and Ghent University, Ghent, Belgium;
Professor Patrick Venables for helpful insights into autoantibodies; and
the Interuniversity Attraction Poles Program (Belgian State, Belgian
Science Policy, Project P6/35), the Fund for Scientic Research Flanders
and the Concerted Research Action of Ghent University for funding.
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global
and regional burden of disease and risk factors, 2001: systematic
analysis of population health data. Lancet 2006; 367: 174757.
Pauwels R, Rabe K. Burden and clinical features of chronic
obstructive pulmonary disease (COPD). Lancet 2004; 364: 61320.
Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in
non-smokers. Lancet 2009; 374: 73343.
Sinden NJ, Stockley RA. Systemic inammation and comorbidity
in COPD: a result of overspill of inammatory mediators from the
lungs? Review of the evidence. Thorax 2010; 65: 93036.
Wouters EF, Reynaert NL, Dentener MA, Vernooy JH. Systemic and
local inammation in asthma and chronic obstructive pulmonary
disease: is there a connection? Proc Am Thorac Soc 2009; 6: 63847.
Wouters EF, Groenewegen KH, Dentener MA, Vernooy JH.
Systemic inammation in chronic obstructive pulmonary disease:
the role of exacerbations. Proc Am Thorac Soc 2007; 4: 62634.

www.thelancet.com Vol 378 September 10, 2011




















Hogg JC, Timens W. The pathology of chronic obstructive

pulmonary disease. Annu Rev Pathol 2009; 4: 43559.
Laurell CB ES. The electrophoretic alpha-1 globulin pattern of serum in
alpha-1 antitrypsin deciency. Scand J Clin Lab Invest 1963; 15: 13240.
Rahman I, Adcock IM. Oxidative stress and redox regulation of lung
inammation in COPD. Eur Respir J 2006; 28: 21942.
Tsuji T, Aoshiba K, Nagai A. Cigarette smoke induces senescence
in alveolar epithelial cells. Am J Respir Cell Mol Biol 2004; 31: 64349.
Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic
obstructive pulmonary disease. N Engl J Med 2009; 360: 244554.
Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG. Role
of apoptosis in the pathogenesis of COPD and pulmonary
emphysema. Respir Res 2006; 7: 53.
Vandivier RW, Henson PM, Douglas IS. Burying the dead: the
impact of failed apoptotic cell removal (eerocytosis) on chronic
inammatory lung disease. Chest 2006; 129: 167382.
Opitz B, van Laak V, Eitel J, Suttorp N. Innate immune recognition
in infectious and noninfectious diseases of the lung.
Am J Respir Crit Care Med 2010; 181: 1294309.
Ferhani N, Letuve S, Kozhich A, et al. Expression of high-mobility
group box 1 and of receptor for advanced glycation end products in
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2010; 181: 91727.
Lommatzsch M, Cicko S, Muller T, et al. Extracellular adenosine
triphosphate and chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2010; 181: 92834.
Churg A, Zhou S, Wang X, Wang R, Wright JL. The role of
interleukin-1beta in murine cigarette smoke-induced emphysema and
small airway remodeling. Am J Respir Cell Mol Biol 2009; 40: 48290.
Cicko S, Lucattelli M, Muller T, et al. Purinergic receptor inhibition
prevents the development of smoke-induced lung injury and
emphysema. J Immunol 2010; 185: 68897.
Chen ZH, Kim HP, Sciurba FC, et al. Egr-1 regulates autophagy
in cigarette smoke-induced chronic obstructive pulmonary disease.
PLoS One 2008; 3: e3316.
Chen ZH, Lam HC, Jin Y, et al. Autophagy protein
microtubule-associated protein 1 light chain-3B (LC3B) activates
extrinsic apoptosis during cigarette smoke-induced emphysema.
Proc Natl Acad Sci USA 2010; 107: 1888085.
Chung KF, Adcock IM. Multifaceted mechanisms in COPD:
inammation, immunity, and tissue repair and destruction.
Eur Respir J 2008; 31: 133456.
Demedts IK, Morel-Montero A, Lebecque S, et al. Elevated MMP-12
protein levels in induced sputum from patients with COPD. Thorax
2006; 61: 196201.
Saetta M, Di Stefano A, Turato G, et al. CD8+ T-lymphocytes in
peripheral airways of smokers with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1998; 157: 82286.
Urbanowicz RA, Lamb JR, Todd I, Corne JM, Fairclough LC.
Enhanced eector function of cytotoxic cells in the induced sputum
of COPD patients. Respir Res 2010; 11: 76.
Fahy JV, Dickey BF. Airway mucus function and dysfunction.
N Engl J Med 2010; 363: 223347.
Shapiro SD. Transgenic and gene-targeted mice as models for chronic
obstructive pulmonary disease. Eur Respir J 2007; 29: 37578.
Guerassimov A, Hoshino Y, Takubo Y, et al. The development of
emphysema in cigarette smoke-exposed mice is strain dependent.
Am J Respir Crit Care Med 2004; 170: 97480.
DHulst A I, Maes T, Bracke KR, et al. Cigarette smoke-induced
pulmonary emphysema in scid-mice. Is the acquired immune
system required? Respir Res 2005; 6: 147.
Botelho FM, Gaschler GJ, Kianpour S, et al. Innate immune
processes are sucient for driving cigarette smoke-induced
inammation in mice. Am J Respir Cell Mol Biol 2010; 42: 394403.
Andersson CK, Mori M, Bjermer L, Lofdahl CG, Erjefalt JS.
Alterations in lung mast cell populations in patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2010;
181: 20617.
Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity?
The example of natural killer cells. Science 2011; 331: 4449.
Degli-Esposti MA, Smyth MJ. Close encounters of dierent kinds:
dendritic cells and NK cells take centre stage. Nat Rev Immunol
2005; 5: 11224.

www.thelancet.com Vol 378 September 10, 2011



















Lambrecht BN, Hammad H. The role of dendritic and epithelial

cells as master regulators of allergic airway inammation. Lancet
2010; 376: 83543.
Lommatzsch M, Bratke K, Knappe T, et al. Acute eects of tobacco
smoke on human airway dendritic cells in vivo. Eur Respir J 2010;
35: 113036.
Freeman CM, Martinez FJ, Han MK, et al. Lung dendritic cell
expression of maturation molecules increases with worsening
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2009; 180: 117988.
Demedts IK, Bracke KR, Van Pottelberge G, et al. Accumulation
of dendritic cells and increased CCL20 levels in the airways of
patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2007; 175: 9981005.
Heath WR, Carbone FR. Dendritic cell subsets in primary and
secondary T cell responses at body surfaces. Nat Immunol 2009;
10: 123744.
Saetta M, Mariani M, Panina-Bordignon P, 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 2002; 165: 140409.
Grumelli S, Corry DB, Song LZ, et al. An immune basis for lung
parenchymal destruction in chronic obstructive pulmonary disease
and emphysema. PLoS Med 2004; 1: e8.
Di Stefano A, Caramori G, Gnemmi I, et al. T helper type 17-related
cytokine expression is increased in the bronchial mucosa of stable
chronic obstructive pulmonary disease patients. Clin Exp Immunol
2009; 157: 31624.
Imaoka H, Hoshino T, Takei S, et al. Interleukin-18 production
and pulmonary function in COPD. Eur Respir J 2008; 31: 28797.
Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper
T cells. N Engl J Med 2009; 361: 88898.
Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all
trades, master of regulation. Nat Immunol 2008; 9: 23944.
Lee SH, Goswami S, Grudo A, et al. Antielastin autoimmunity in
tobacco smoking-induced emphysema. Nat Med 2007; 13: 56769.
Barcelo B, Pons J, Ferrer JM, Sauleda J, Fuster A, Agusti AG.
Phenotypic characterisation of T-lymphocytes in COPD: abnormal
CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking.
Eur Respir J 2008; 31: 55562.
Smyth LJ, Starkey C, Vestbo J, Singh D. CD4-regulatory cells
in COPD patients. Chest 2007; 132: 15663.
Plumb J, Smyth LJ, Adams HR, Vestbo J, Bentley A, Singh SD.
Increased T-regulatory cells within lymphocyte follicles in moderate
COPD. Eur Respir J 2009; 34: 8994.
DAlessio FR, Tsushima K, Aggarwal NR, et al.
CD4+CD25+Foxp3+ Tregs resolve experimental lung injury
in mice and are present in humans with acute lung injury.
J Clin Invest 2009; 119: 2898913.
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway
obstruction in chronic obstructive pulmonary disease. N Engl J Med
2004; 350: 264553.
van der Strate BW, Postma DS, Brandsma CA, et al. Cigarette
smoke-induced emphysema: A role for the B cell?
Am J Respir Crit Care Med 2006; 173: 75158.
Brusselle GG, Demoor T, Bracke KR, Brandsma CA, Timens W.
Lymphoid follicles in (very) severe COPD: benecial or harmful?
Eur Respir J 2009; 34: 21930.
Randall TD. Bronchus-associated lymphoid tissue (BALT) structure
and function. Adv Immunol 2010; 107: 187241.
Van Pottelberge GR, Bracke KR, Van den Broeck S, et al.
Plasmacytoid dendritic cells in pulmonary lymphoid follicles
of patients with COPD. Eur Respir J 2010; 36: 78191.
Polverino F, Baraldo S, Bazzan E, et al. A novel insight into adaptive
immunity in chronic obstructive pulmonary disease: B cell
activating factor belonging to the tumor necrosis factor family.
Am J Respir Crit Care Med 2010; 182: 101119.
Mueller SN, Hosiawa-Meagher KA, Konieczny BT, et al. Regulation
of homeostatic chemokine expression and cell tracking during
immune responses. Science 2007; 317: 67074.
Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M,
et al. The development of inducible bronchus-associated lymphoid
tissue depends on IL-17. Nat Immunol 2011; 12: 63946.
























Sethi S, Murphy TF. Infection in the pathogenesis and course

of chronic obstructive pulmonary disease. N Engl J Med 2008;
359: 235565.
Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway
inammation and bronchial bacterial colonization in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2006;
173: 99198.
Hurst JR, Vestbo Jr, Anzueto A, et al. Susceptibilty to exacerbation
in chronic obstructive pulmonary disease. N Engl J Med 2010;
363: 112838.
Hilty M, Burke C, Pedro H, et al. Disordered microbial
communities in asthmatic airways. PLoS One 2010; 5: e8578.
Berenson CS, Garlipp MA, Grove LJ, Maloney J, Sethi S. Impaired
phagocytosis of nontypeable Haemophilus inuenzae by human
alveolar macrophages in chronic obstructive pulmonary disease.
J Infect Dis 2006; 194: 137584.
Taylor AE, Finney-Hayward TK, Quint JK, et al. Defective macrophage
phagocytosis of bacteria in COPD. Eur Respir J 2010; 35: 103947.
Rosell A, Monso E, Soler N, et al. Microbiologic determinants
of exacerbation in chronic obstructive pulmonary disease.
Arch Intern Med 2005; 165: 89197.
Sanjuan MA, Dillon CP, Tait SW, et al. Toll-like receptor signalling
in macrophages links the autophagy pathway to phagocytosis.
Nature 2007; 450: 125357.
Levine B, Mizushima N, Virgin HW. Autophagy in immunity
and inammation. Nature 2011; 469: 32335.
Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria
and exacerbations of chronic obstructive pulmonary disease.
N Engl J Med 2002; 347: 46571.
Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory
viruses, symptoms, and inammatory markers in acute
exacerbations and stable chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2001; 164: 161823.
Singh M, Lee SH, Porter P, et al. Human rhinovirus proteinase 2A
induces TH1 and TH2 immunity in patients with chronic obstructive
pulmonary disease. J Allergy Clin Immunol 2010; 125: 136978e2.
Mallia P, Message SD, Gielen V, et al. Experimental rhinovirus
infection as a human model of chronic obstructive pulmonary
disease exacerbation. Am J Respir Crit Care Med 2011; 183: 73442.
Papi A, Bellettato CM, Braccioni F, et al. Infections and airway
inammation in chronic obstructive pulmonary disease severe
exacerbations. Am J Respir Crit Care Med 2006; 173: 111421.
Murphy TF, Brauer AL, Grant BJB, Sethi S. Moraxella catarrhalis
in chronic obstructive pulmonary disease: burden of disease and
immune response. Am J Respir Crit Care Med 2005; 172: 19599.
Feghali-Bostwick CA, Gadgil AS, Otterbein LE, et al. Autoantibodies
in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2008; 177: 15663.
Nunez B, Sauleda J, Anto JM, et al. Anti-tissue antibodies are
related to lung function in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2011; 183: 102531.
Greene CM, Low TB, ONeill SJ, McElvaney NG.
Anti-proline-glycine-proline or antielastin autoantibodies are not
evident in chronic inammatory lung disease.
Am J Respir Crit Care Med 2010; 181: 3135.
Wood AM, de Pablo P, Buckley CD, Ahmad A, Stockley RA. Smoke
exposure as a determinant of autoantibody titre in {alpha}1-antitrypsin
deciency and COPD. Eur Respir J 2011; 37: 3238.
Bonarius HP, Brandsma CA, Kerstjens HA, et al. Antinuclear
autoantibodies are more prevalent in COPD in association with low
body mass index but not with smoking history. Thorax 2010; 66: 10107.
Gamble E, Grootendorst DC, Hattotuwa K, et al. Airway mucosal
inammation in COPD is similar in smokers and ex-smokers:
a pooled analysis. Eur Respir J 2007; 30: 46771.
Sorokin L. The impact of the extracellular matrix on inammation.
Nat Rev Immunol 2010; 10: 71223.
Weathington NM, van Houwelingen AH, Noerager BD, et al.
A novel peptide CXCR ligand derived from extracellular matrix
degradation during airway inammation. Nat Med 2006; 12: 31723.
Richens TR, Linderman DJ, Horstmann SA, et al. Cigarette smoke
impairs clearance of apoptotic cells through oxidant-dependent
activation of RhoA. Am J Respir Crit Care Med 2009; 179: 101121.



















Eltzschig HK, Carmeliet P. Hypoxia and inammation.

N Engl J Med 2011; 364: 65665.
Van Pottelberge GR, Mestdagh P, Bracke KR, et al. MicroRNA
expression in induced sputum of smokers and patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2011;
183: 898906.
Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression
of the let-7 microRNAs in human lung cancers in association with
shortened postoperative survival. Cancer Res 2004; 64: 375356.
Mercado N, Thimmulappa R, Thomas CM, et al. Decreased histone
deacetylase 2 impairs Nrf2 activation by oxidative stress.
Biochem Biophys Res Commun 2011; 406: 29298.
Ito K, Ito M, Elliott WM, et al. Decreased Histone Deacetylase
Activity in Chronic Obstructive Pulmonary Disease. N Engl J Med
2005; 352: 196776.
Adcock IM, Tsaprouni L, Bhavsar P, Ito K. Epigenetic regulation
of airway inammation. Curr Opin Immunol 2007; 19: 694700.
Fletcher C, Peto R. The natural history of chronic airow
obstruction. BMJ 1977; 1: 164548.
Kohansal R, Martinez-Camblor P, Agusti A, Buist AS,
Mannino DM, Soriano JB. The natural history of chronic airow
obstruction revisited: an analysis of the Framingham ospring
cohort. Am J Respir Crit Care Med 2009; 180: 310.
Kunz LI, Lapperre TS, Snoeck-Stroband JB, et al. Smoking status
and anti-inammatory macrophages in bronchoalveolar lavage and
induced sputum in COPD. Respir Res 2011; 12: 34.
Lapperre TS, Snoeck-Stroband JB, Gosman MM, et al. Eect of
uticasone with and without salmeterol on pulmonary outcomes
in chronic obstructive pulmonary disease: a randomized trial.
Ann Intern Med 2009; 151: 51727.
Hattotuwa KL, Gizycki MJ, Ansari TW, Jeery PK, Barnes NC.
The eects of inhaled uticasone on airway inammation in chronic
obstructive pulmonary disease: a double-blind, placebo-controlled
biopsy study. Am J Respir Crit Care Med 2002; 165: 159296.
Barnes NC, Qiu YS, Pavord ID, et al. Antiinammatory eects
of salmeterol/uticasone propionate in chronic obstructive lung
disease. Am J Respir Crit Care Med 2006; 173: 73643.
Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid
resistance. Chest 2008; 134: 394401.
Barnes PJ. Immunology of asthma and chronic obstructive
pulmonary disease. Nat Rev Immunol 2008; 8: 18392.
Vanaudenaerde BM, Verleden SE, Vos R, et al. Innate and Adaptive
Interleukin-17-producing Lymphocytes in Chronic Inammatory
Lung Disorders. Am J Respir Crit Care Med 2011; 183: 97786.
Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in
sputum neutrophil and eosinophil numbers by the PDE4 inhibitor
roumilast in patients with COPD. Thorax 2007; 62: 108187.
Rabe KF, Hurd S, Anzeuto A, et al. Global strategy for the
diagnosis, management, and prevention of chronic obstructive
pulmonary disease: GOLD executive summary.
Am J Respir Crit Care Med 2007; 176: 53255.
Calverley PM, Rabe KF, Goehring UM, et al, for the M2-124
and M2-125 study groups. Roumilast in symptomatic chronic
obstructive pulmonary disease: two randomised clinical trials.
Lancet 2009; 374: 68594.
Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ,
Wedzicha JA. Long-term erythromycin therapy is associated with
decreased chronic obstructive pulmonary disease exacerbations.
Am J Respir Crit Care Med 2008; 178: 113947.
Hodge S, Hodge G, Jersmann H, et al. Azithromycin improves
macrophage phagocytic function and expression of mannose
receptor in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2008; 178: 13948.
Rennard SI, Fogarty C, Kelsen S, et al. The safety and ecacy
of iniximab in moderate to severe chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 2007; 175: 92634.
Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ.
Theophylline restores histone deacetylase activity and steroid
responses in COPD macrophages. J Exp Med 2004; 200: 68995.
Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ.
Treatment eects of low-dose theophylline combined with an
inhaled corticosteroid in COPD. Chest 2010; 137: 133844.

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