Series

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 inflammatory Lancet 2011; 378: 1015–26
immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as This is the first in a Series of
epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release three papers about chronic
obstructive pulmonary disease
of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive
Laboratory for Translational
immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses,
Research of Obstructive
which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only Pulmonary Disease,
cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via Department of Respiratory
pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, Medicine, Ghent University
Hospital and Ghent University,
extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of
Ghent, Belgium
microRNAs in the persistence of the pulmonary inflammation despite smoking cessation. (Prof G G Brusselle MD,
Prof G F Joos MD,
Introduction endothelial cells).9 Disruption of the balance between cell K R Bracke PhD)

Chronic obstructive pulmonary disease (COPD) affects
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 effects of the disorder.4,5
Although overspill of inflammation in the lung into the
circulation is suggested to cause systemic inflammation 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 (figure 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 inflammation 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 inflammation induced by cigarette smoke.
Second, patients with deficiency of α1-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 amplifies airway
inflammation in smokers, but also induces cell death of
structural cells in the lung (mainly alveolar epithelial and
death and replenishment of structural cells in the lung Correspondence to:
Guy G Brusselle, Department
contribute to the destruction of alveolar septa, leading to
of Respiratory Medicine 7K12,
emphysema. Additionally, age-related changes and cellular Ghent University Hospital,
senescence further impair tissue repair in response to Ghent B-9000, Belgium
repetitive cigarette smoke-induced injury of the lungs.10 guy.brusselle@ugent.be
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 anti-
proteinases, whereas an excess of apoptotic cells leads to
secondary necrosis and can exaggerate continuing
pulmonary inflammation.12,13
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: macro-
phages, 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 identified 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.

www.thelancet.com Vol 378 September 10, 2011 1015

 Series
Macrophage
Neutrophil
Lumen
Epithelium
Mucosa
Dendritic cell
Natural killer cell
Mast cell
Innate immune cells
Smooth muscle cells
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 inflammation. CD=cluster of differentiation.
The first step towards the induction of innate immune
responses is recognition of different microbes by
identification 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
first 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 specific 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 inflammatory responses to
infection and sterile tissue damage, respectively (figure 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
For more on the global initiative
epithelial cells, which release DAMPs (table 2). Several
of obstructive lung disease see mechanisms, including inhalation of toxic agents and
http://www.goldcopd.org irritants, oxidative stress, infections, and tissue hypoxia,
1016
Goblet cell
Lymphoid follicle
B cell
CD4+ T cell
CD8+ T cell
Adaptive immune cells
Lymph node
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 fluid 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 1β, which is subsequently
cleaved into mature interleukin 1β by NLR family, pyrin
domain-containing (NLRP) inflammasomes (figure 2).
IL-1R knock-out mice showed attenuated pulmonary
inflammation after acute exposure to cigarette smoke and
were significantly protected against emphysema after
chronic exposure to cigarette smoke.17 Moreover, inhibition
of P2 purinergic receptors—which bind extracellullar
ATP—prevented 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
 Series

is increased as indicated by increased autophagic vacuoles

Innate immunity Adaptive immunity
(autophagosomes and autolysosomes) on electronic
microscopic analysis and by increased activation of Recognition

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 significantly
decreased rates of apoptosis in the lungs after exposure to
cigarette smoke and display resistance to cigarette-smoke-
induced 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 effector phase of innate immune responses,
cigarette-smoke-induced release of proinflammatory
cytokines and chemokines—such as tumour necrosis
factor α (TNFα) and chemokine (c-x-c motif) ligand
(CXCL)8—by airway epithelial cells and alveolar
macrophages elicits the expression of adhesion molecules
on endothelial cells and the recruitment of neutrophils
and inflammatory monocytes to the lungs. Numbers of
neutrophils and macrophages are increased in the lungs
of smokers and patients with COPD. At sites of sterile
inflammation 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 α
(TGFα), 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 inflammation, airway
remodelling and airspace enlargement due to destruction
of alveolar walls (ie, emphysema).26 In much the same way
as differences in genetic susceptibility in human smokers
affect development of COPD, the induction of emphysema
in mice is strain dependent.27 Importantly, in immuno-
deficient mice lacking B cells and T cells, the innate
immune system suffices to develop cigarette smoke-
induced inflammation28,29 and emphysema.28
Receptors Pattern recognition receptors T-cell and B-cell receptors
Molecules Pathogen-associated molecular Processed antigens; antigen-antibody
patterns; damage-associated complexes
molecular patterns
Response
Onset Immediate Delayed (4–5 days)
Specificity Fixed repertoire Specific
Immunological memory No Yes
Ontology Ancient Recent
Cellular component
Haematopoietic Neutrophils, macrophages, T lymphocytes, B lymphocytes
dendritic cells, eosinophils,
natural killer cells
Structural Epithelial cells Follicular dendritic cells
Effector molecules Acute phase proteins, B cells: immunoglobulins (antibodies)
complement, cytokines, CD4+ T cells: Th1,Th2, Th17, Treg cytokines
chemokines, growth factors, CD8+ T cells: perforins, granzymes
antimicrobial peptides (cytotoxicity)
CD=cluster of differentiation. 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 pro-
gresses 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 classified 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-specific cell
surface receptors.31 Natural killer cells act as cytolytic
effector 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 γ and TNFα.32
Dendritic cells and innate and adaptive immunity
Dendritic cells are specialised antigen-presenting cells
that link innate and adaptive immune responses (figure 1
and webappendix p 3).33 By the integration of many
signals of the microenvironment dendritic cells promote
CD4+ T helper (Th) cell differentiation and CD8+

www.thelancet.com Vol 378 September 10, 2011 1017

 Series

Sensing cigarette smoke and danger signals

Bacteria Viruses Autophagy

ROS

Cell death
(autophagic,
apoptotic,
necrotic)
RAGE PAMPs DAMPs

,...

Interle
B1 , HA

LPS,...
MG

P
,H

AT
HSP

ukin 1α
cid
Uric a
P2X7
P2Y2 TLRs
TLRs Interleukin 1R

P2X7
NF-κB
NLRPs

Pro
caspase-1

Inflammasome

caspase-1

TNFα Pro
CXCL8 interleukin 1β
Effector phase Mature
interleukin 1β

Pro-inflammatory ROS Proteolytic enzymes

cytokines and chemokines (NE, MMP-9, MMP-12,...)
(TNFα, interleukin 1β, CXCL8,...)
Interleukin 1β secretion

Figure 2: Afferent and efferent 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 dying—autophagic death, apoptotic or necrotic—cells. Viral and bacterial respiratory tract infections amplify the chronic
inflammation in COPD by triggering PRRs via pathogen-associated molecular patterns (PAMPs). On activation, the innate immune cells release
pro-inflammatory 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) inflammasomes in chronic obstructive
pulmonary disease. HSP=heat shock protein. HMGB1=high-mobility group box 1. HA=hyaluronic acid. NF-κB=nuclear factor κB. CXCL=chemokine (c-x-c motif)
ligand. RAGE=Receptor for Advanced Glycation End products.

cytotoxicity (figure 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 fluid 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
fluid of smokers compared with never-smokers.
In COPD, several dendritic cell subsets in the
lung parenchyma showed significant 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 (figure 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-specific
intracellular adhesion molecule 3–grabbing non-integrin,
which is located in the lamina propria and adventitia and
does not increase in patients with COPD (figure 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
airflow limitation and emphysema.23 The expression of
the chemokine receptor CXCR3, preferentially

1018 www.thelancet.com Vol 378 September 10, 2011

 Series

expressed on type 1 T lymphocytes, and its ligand

Receptor (cellular [soluble])
interferon-induced protein 10 (also known as CXCL10)
(table 3) is increased in peripheral airways of smokers Cigarette smoke components

with COPD, suggesting that the axis between CXCL10 Endotoxin (lipopolysaccharide) TLR4 and CD14, [lipopolysaccharide-binding protein]
and chemokine (c-x-c motif ) receptor (CXCR) 3 might Nicotine nAChR, TRPA1
be implicated in CD8+ T-cell recruitment in COPD.38 Reactive oxygen species, free radicals NLRP3
On activation, CD8+ T cells release proteolytic enzymes Acrolein TRPA1
such as perforin and granzymes, which cause cell death Polycyclic aromatic hydrocarbon AhR
of structural cells by apoptosis or necrosis11,24 (figure 5). DAMP released from stressed, apoptotic, and necrotic cells
Numbers of CD4+ T cells are raised in the airways and ATP P2XR, P2YR
lungs of smokers with COPD. At least two different types Uric acid NLRP3
of effector CD4+ Th cells accumulate in the lungs of High-mobility group box 1 TLR2, TLR4, TLR9, RAGE, CD24
patients with stable COPD: Th1 cells and Th17 cells.39,40 Th1 S100 molecules TLR9, RAGE
cells expressing chemokine receptors CCR5 and CXCR3 Heat shock proteins TLR2, TLR4, CD91, CD24, CD14, CD40
produce interferon γ and promote accumulation of β defensins TLR4, CCR6
inflammatory cells to the lungs. Lung lymphocytes in Interleukin 1α Interleukin 1R
patients with COPD and emphysema have higher DNA (mitochondrial) TLR9
percentages of CD4+ Th1 cells and secrete more interferon Formyl peptides (mitochondrial) FPR1
γ than in control smokers.39 Interleukin 18, which promotes DAMP released from breakdown of ECM
Th1 cell development, is strongly expressed in alveolar Hyaluronic acid TLR2 , TLR4, CD44
macrophages, CD8+ T cells, and both bronchiolar and Fibronectin TLR4, α5β1 integrin, αVβ3 integrin
alveolar epithelia in lungs of patients with severe COPD.41 Heparan sulphate TLR4
Th17 cells are a distinct lineage of activated CD4+ Versican TLR2
T cells, regulating tissue inflammation by producing Biglycan TLR2, TLR4, P2XR
interleukin 17A and interleukin 17F.42 They mediate N-acetyl-proline-glycine-proline CXCR1, CXCR2
immunity against extracellular pathogens, but have also
been implicated in autoimmunity.42 Th17 cytokines TLR=Toll-like receptor. CD=cluster of differentiation. nAChR=nicotinic acetylcholine receptor. TRPA1=transient
receptor potential A1. AhR=aryl hydrocarbon receptor. P2XR=purinergic receptor P2XR. P2YR=purinergic receptor
induce epithelial cells to produce antimicrobial peptides P2YR. NLRP3=NOD-like receptor family, pyrin domain containing 3. RAGE=receptor for advanced glycation end
(such as β defensins), chemokines, and the granulocyte products; FPR1=formyl peptide receptor 1. ECM=extracellular matrix. CXCR=chemokine (c-x-c motif) receptor.
growth factors G-CSF and GM-CSF to promote neutrophil
Table 2: Sensing of cigarette smoke components and Damage Associated Molecular patterns (DAMP) by
accumulation at the site of tissue injury. Patients with Pattern Recognition Receptors (PRR) and other receptors of the innate immune system
COPD have increased numbers of interleukin 23+
immunoreactive cells in the bronchial epithelium and
interleukin 17A+ cells in the bronchial submucosa.40 smokers with normal lung function compared with people
However, because interleukin 17A production is linked to who had never smoked and patients with moderate COPD
structural cells such as endothelial cells, sources other in one study,45 whereas bronchoalveolar lavage CD4+
than T cells might be important.40 CD25-bright cells were increased in smokers and patients
Regulatory T cells (Treg) are subsets of CD4+ T cells with with COPD compared with healthy people who had never
immunoregulatory functions, which inhibit autoimmunity smoked in another study.46 Because these cells encompass
and suppress inflammation. The two most abundant both FOXP3+ Treg and non-regulatory activated Th cells,
subsets of Treg are the natural Treg and the adaptive or additional multicolour flowcytometric and functional
inducible Treg. Natural Treg leave the thymus as effector studies of bronchoalveolar lavage fluid and lung digests
cells and are essential in maintaining self-tolerance, are warranted to resolve this discrepancy. T cells that are
whereas induced Treg mature in the periphery and are FOXP3+ and CD4+ are raised in lymphoid follicles of
activated by exogenous antigens. Treg exert their patients with moderate COPD compared with control
suppressive effect on other T cells or on antigen-presenting smokers,47 suggesting that Treg might regulate inflam-
dendritic cells via contact-dependent mechanisms or the matory responses to prevent autoimmunity.11 Treg that are
production of anti-inflammatory cytokines such as inter- CD4+, CD25+, and FOXP3+ resolve experimental lung
leukin 10 and transforming growth factor β (TGFβ).43 They injury in mice after intratracheal lipopolysaccharide
are characterised by expression of the transcription factor administration and are present in the bronchoalveolar
FOXP3 (forkhead box P3) and bright expression of the lavage fluid of patients with acute lung injury, suggesting
surface marker CD25, the interleukin 2 receptor α chain. that Treg modify innate immune responses during
Smokers with COPD and emphysema had significantly resolution of lung injury.48
fewer Treg cells in the lungs, less messenger RNA (mRNA)
for FOXP3, and less interleukin 10 secretion from the B cells
whole lung than controls.44 CD4+ CD25-bright cells were B cells are increased in large airways of patients with
significantly increased in bronchoalveolar lavage fluid in COPD, as shown in central bronchial biopsy specimens.

www.thelancet.com Vol 378 September 10, 2011 1019

 Series

The compartmentalisation of lymphoid follicles in

CXCR3
MHCI TCR CD8+ cytotoxic T cell B-cell and T-cell areas is—as in lymph nodes—regulated
CD8 Perforins, granzymes by homoeostatic chemokines, which dictate homing and
motility of lymphocytes and dendritic cells in lymphoid
CD80 CD28
CD86 tissues.55 CCL19 and CCL21 attract naive T lymphocytes
CD4+ T helper cell IL 12R expressing CCR7 and mature dendritic cells into the
IL 18R T-cell areas, whereas the CXC chemokine CXCL13
Th1 CXCR3 INFγ, TNFα
T-bet CCR5 attracts B cells expressing CXCR5 (table 3). Whereas in
lymph nodes lymphotoxin α induces the expression of
18 IL 4R
, IL CCR3
the chemokines CCL19 and CXCL13, interleukin 17 is
12 in
IL lept Th2 CCR4 needed for the induction of these chemokines in iBALT.56
IL 4, IL 5, IL 13
GATA-3 CCR8
MHCII TCR IL 4 2A Once formed, iBALT is longlasting and participates in
P
virus
CD4 rhino CD25 local immune responses.52
TGFβ
IL
1β CTLA4 In these lymphoid follicles—especially in germinal
CD80 CD28 , IL RA Treg GITR
CD86 6,
TG FOXP3 CCR7
IL 10, TGFβ centres of secondary lymphoid follicles—antigen
Fβ retention, immunoglobulin class switching, and affinity
; IL
23
IL 23R maturation occur.52 The B cells are oligoclonal in nature,
CCR4
Th17 CCR6 suggesting antigen-specific induction of the B-cell
IL 17A, IL 17F, IL 21, IL 22
RORyT follicles.50 Which antigens might be involved is not
known, but microbial antigens, cigarette smoke-derived
Figure 3: Dendritic cells driving CD4+ T helper cell differentiation and CD8+ T-cell cytotoxicity antigens, breakdown products from extracellular matrix,
MHC I-restricted dendritic cells present antigenic peptides to CD8+ T cells, whereas MHC II-restricted dendritic and autoantigens have been suggested.51 Therefore, the
cells drive the differentiation of naive CD4+ T cells towards T helper (Th) 1, Th2, Th17 cells or regulatory T cells pathogenic role of the follicular B-cell response is
(Treg) depending on the cytokine balance in the local microenvironment. The different Th cell subsets and
Treg cells are characterised by different transcription factors and membrane-bound receptors (eg, chemokine
controversial; it might be beneficial, if protective against
receptors) and produce different cytokines. IL=interleukin. CXCR=chemokine (c-x-c motif) receptor. microbial colonisation and infection of the lower
CCR=chemokine (c-c motif) receptor. INF=interferon. TNFα=tumour necrosis factor α. GATA-3=GATA binding respiratory tract; or by contrast, it could be detrimental, if
protein 3. GITR=glucocorticoid-induced tumour necrosis factor-related protein. CD=cluster of differentiation. directed against lung tissue antigens, suggesting an
CTLA=cytotoxic T-lymphocyte antigen. TGFβ=transforming growth factor β. FOXP3=forkhead box P3.
RORγT=retinoid related orphan receptor gamma T.
autoimmune component in the pathogenesis of COPD
and especially emphysema.11

Moreover, B cells organised into lymphoid follicles have Infection in COPD

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
affected by chronic inflammation, 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 inflammation 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 specific 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 airflow limitation and hypoxia, two important
markers of disease severity.
Infections of the respiratory tract contribute to the
pathogenesis and course of COPD in at least two different
ways.57 First, viral and bacterial infections are the most
important cause of acute exacerbations of COPD. As
airflow 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 inflam-
mation in stable COPD. The frequency of chronic
bacterial colonisation and infection increases progres-
sively with disease severity.59,60
Importantly, in COPD, phagocytosis of bacteria such
as Haemophilus influenzae and Streptococcus pneumoniae
by alveolar macrophages is impaired.61,62 Monocyte-
derived macrophages and alveolar macrophages from
patients with COPD showed significantly decreased
phagocytic responses to bacteria compared with non-
smokers 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 influenzae, 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 inflammation, as a

1020 www.thelancet.com Vol 378 September 10, 2011

 Series

result of direct effects of bacteria and of the host response.57 A B

Several PAMPs of bacteria, including lipopolysaccharides,
peptidoglycans, and outer-membrane proteins, are sensed
by specific PRRs on epithelial cells and innate immune
cells (table 4), triggering the nuclear factor-κB pathway
and other signal transduction pathways such as p38
mitogen-activated protein kinase and interferon regulatory
factors, resulting in the production of pro-inflammatory
cytokines and chemokines (figure 2). TLR signalling in
100 μm 100 μm
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 C D
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, exacer-
bations can be caused by Pseudomonas aeruginosa.
Viruses can be detected in 10–15% of sputum samples
in patients with stable COPD, and in 30–60% of those
with COPD exacerbations, dependent on the sensitivity of 100 μm 100 μm
the detection method.68 Rhinoviruses and influenza virus
are the respiratory viruses that are most frequently 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
associated with exacerbations of COPD. Rhinoviruses are
human lung tissue cryosections of (A) a smoker without COPD and (B) a patient with stage II COPD according to the
isolated from nasal and lung fluid from patients with global initiative for chronic obstructive lung disease (GOLD) scale. (C) Immunohistochemical double staining for
acute exacerbations of COPD,69 indicating that rhino- dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin+ (DC-SIGN+) interstitial-type
viruses infect upper and lower airway epithelial cells. 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.
In induced rhinovirus infection in volunteers with There are no double positive cells, confirming the segregation of these two dendritic cell subsets in human lung.
COPD, Johnston and colleagues70 showed a causal relation (D) Identification of plasmacytoid dendritic cells in a lymphoid follicle of a patient with COPD GOLD stage II. Triple
between rhinovirus infection and COPD exacerbations. staining of a cryosection of human lung tissue for CD3 (blue colour indicates the T-cell zone), CD20 (red-pink colour
After rhinovirus infection, patients with COPD developed 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.
lower respiratory symptoms, airflow obstruction, and
systemic and airway inflammation that were greater and
Ligands Target cells
lengthier than in controls; virus load was higher in
patients with COPD, whereas interferon production by CC-motif chemokine receptors

bronchoalveolar lavage cells was impaired.70 CCR2 CCL2/MCP-1 Monocytes, immature dendritic cells, T cells

Severe COPD exacerbations needing hospitalisation CCR5 CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES Monocytes, immature dendritic cells, T cells
were associated with increased sputum neutrophilia, CCR6 CCL20/MIP-3α Immature dendritic cells, T cells
irrespective of viral or bacterial infections, whereas CCR7 CCL19/MIP-3β, CCL21/SLC Mature dendritic cells, T cells, B cells
sputum eosinophils were increased during viral CXC-motif chemokine receptors
exacerbations.71 CD4+ T cells from bronchoalveolar lavage CXCR1 CXCL8/IL 8 Neutrophils, monocytes
fluid from patients with COPD showed a mixed Th1 and CXCR2 CXCL8/IL 8, CXCL1/GRO-α Neutrophils, monocytes
Th2 cell cytokine phenotype during acute rhinovirus CXCR3 CXCL9/Mig, CXCL10/IP-10, CXCL11/I-TAC T cells
infection.69 Human rhinovirus-encoded proteinase 2A CXCR5 CXCL13/BCA-1 B cells
induced strong Th1 and Th2 immune responses from
Simplified and non-limiting table of chemokines and chemokine receptors implicated in COPD. CCL=chemokine
CD4+ T cells, implicating this microbial proteinase as an (c-c motif) ligand. CXCL=chemokine (c-x-c motif) ligand. MCP 1=monocyte chemoattractant protein 1.
adjuvant factor during respiratory tract infections in MIP=macrophage inflammatory protein. RANTES=regulated on activation normal T-cell expressed and secreted.
patients with COPD69 (figure 3). SLC=secondary lymphoid tissue chemokine. IL 8=interleukin 8. GRO-α=growth related oncogene α. Mig=monokine
induced by interferon γ. IP-10=interferon-γ inducible protein of 10 kDa. I-TAC=interferon-inducible T-cell-α
Studies of sputum and bronchoalveolar lavage showed chemoattractant. BCA-1=B-cell attracting chemokine.
increased concentrations of neutrophils, CXCL8, TNFα,
and proteases (neutrophil elastase and MMP-9) in Table 3: Chemokines and chemokine receptors in chronic obstructive pulmonary disease (COPD)
COPD patients and bacterial colonisation compared
with those without bacterial pathogens.57 The locally to the development of B-cell lymphoid follicles
colonisation-induced triggering of PRR by microbial and mucosal IgA production, and systemically to the
PAMPs thus amplifies the chronic neutrophilic airway production of IgG antibodies in serum. Strain-specific
inflammation in COPD. Patients with COPD develop immunoglobulin responses reduce the risk of
specific adaptive immune responses to colonising exacerbation after acquisition of a new bacterial strain
bacteria. These adaptive immune responses contribute and contribute to clearance of the pathogen.72

www.thelancet.com Vol 378 September 10, 2011 1021

 Series

slgA
Antigen

Epithelium

Lymphoid follicle
IgA
Plasma cell
IL 1β CCL3,4,5
CXCL9,10,11 IL 18/IL 23 ECM breakdown fragments
FDC
CXCR3
CCR5 IL 18R

IL 23R IgM, IgG

Antibody
CD8+ cytotoxic BAFF
LTβR
T cell
BAFF-R
Th17 cell
Th1 cell CXCL12
B cell CXCL13
CXCR5 LTα1β2
T cell CCL19
CCL21
Perforins
Granzymes CCR7
IFNγ
TNFα
IL 17A
IL 17F
IL 21 HEV
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 follicles—which belong to the inducible Bronchus-Associated Lymphoid Tissue—local immunoglobulin production, including production of protective mucosal
immunoglobulin (Ig) A, occurs rapidly and efficiently. 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. TNFα=tumour necrosis factor α. CD=cluster of differentiation.

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 auto-
immune 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
significant differences in the levels of antielastin or
anti-N-acetylated proline-glycine-proline (Pro-Gly-Pro)
autoantibodies in three groups of patients with chronic
inflammatory lung disease (cystic fibrosis, α1-antitrypsin
deficiency, 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 muscle-
antigen antibodies, were present in a fifth of patients with
COPD with a recent history of hospitalisation for
exacerbation of COPD, and correlated with the severity of
airflow 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 inflammation persist
despite smoking cessation?
Airway inflammation in patients with COPD persists
after smoking cessation.76 Although autoimmunity might
contribute to the perpetuation of pulmonary inflammation
in a subgroup of patients with advanced COPD and

1022 www.thelancet.com Vol 378 September 10, 2011

 Series

emphysema, several other mechanisms are likely to be

PAMP PRR (cellular [soluble])
involved in persistence of the inflammatory response
despite smoking cessation. These mechanisms are not Bacteria

mutually exclusive and encompass self-perpetuating Streptococcus pneumoniae Lipoteichoic acid, pneumolysin TLR2, TLR4, PAFR
Peptidoglycan NOD1, NOD2, [LBP]
innate immune responses, airway wall remodelling, CpG dinucleotides TLR9
impaired macrophage clearance, chronic colonisation Phosphorylcholine [CRP]
and infection of the lower airways, oxidative stress, tissue Haemophilus influenzae LPS TLR4 and CD14, [LBP]
hypoxia, genetic susceptibility, and epigenetic changes.21 OMP P6, OMP P2 TLR2
Peptidoglycan NOD1, NOD2
First, destruction of extracellular matrix (collagen,
Moraxella catarrhalis LPS TLR4 and CD14, [LBP]
elastin, and hyaluronan), releases proinflammatory
Usp A1 NOD1, NOD2, CAECAM1
fragments that are chemotactic for neutrophils and Usp A2 PAFR
monocytes, sustaining inflammation even when the Pseudomonas aeruginosa LPS TLR4 and CD14, [LBP]
initial stimulus is gone.77 CXC chemokines mediate Flagellin TLR5
neutrophil attraction to sites of tissue injury, and matrix Viruses
fragments of collagen—including the tripeptide N-acetyl Rhinovirus dsRNA TLR3, MDA5
Pro-Gly-Pro—are important neutrophil chemoattrac- Influenza dsRNA TLR3, RIG-I, MDA5
tants.78 Furthermore, fragments of elastin have major ssRNA TLR7, TLR8
chemotactic activity, inducing recruitment of monocytes TLR=Toll-like receptor. PAFR=plateled-activating factor receptor. NOD=nucleotide-binding oligomerisation
and macrophages in experimental models of emphysema. domain-containing protein. LBP=lipopolysaccharide-binding protein. CRP=C-reactive protein. LPS=lipopolysaccharide.
Additionally, other constituents or fragments of the 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
extracellular matrix such as tenascin C, biglycan, and low
differentiation-associated gene 5. RIG-I=retinoic acid-inducible gene I.
molecular weight hyaluronan contribute to the
perpetuation of the inflammatory response, partly Table 4: Microbial pathogens, pathogen associated molecular patterns (PAMP), and pattern recognition
through activation of TLR2, or TLR4, or both (table 2). receptors (PRR) in chronic obstructive pulmonary disease

Second, the removal of apoptotic cells (termed

efferocytosis) is a highly conserved process, and is
essential for the resolution of inflammation and the
maintenance of lung integrity.13 In COPD, apoptotic cells
are increased because of enhanced induction of apoptosis
and deficient phagocytosis of apoptotic cells by alveolar
macrophages, which lead to impaired resolution of
inflammation. In a murine model of COPD, acute and
subacute cigarette exposure suppresses efferocytosis by
alveolar macrophages.79 Moreover, apoptosis of neutrophils
followed by efferocytosis not only prevents damage, but
also induces an anti-inflammatory macrophage phenotype
(M2 or alternatively activated macrophages). By contrast,
failed efferocytosis of apoptotic neutrophils leads to
secondary necrosis, which results in the release of
DAMPs, neutrophil elastase, and other toxic components
into the extracellular space (figure 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 amplifies
chronic inflammation and perpetuates microbial
infections that are characteristic of severe COPD.57 Fourth,
local tissue hypoxia in patients with COPD can perpetuate
lung inflammation, because of an important bidirectional
communication between hypoxia and inflammation.80 In
hypoxic conditions, hypoxia-inducible factor 1α (HIF1α)
translocates frFom the cytoplasm to the nucleus, inducing
transcription of multiple genes, including those of TLRs
and nuclear factor-κB. HIF-1α prolongs the lifespan of
neutrophils by inhibiting apoptosis. Conversely, inflamed
tissues often become hypoxic and activation of the
nuclear factor-κB pathway leads to the transcription of
inflammatory genes and HIF-1α.80 Fifth, expression of
several microRNAs—which negatively regulate protein
expression (webappendix p 4)—is significantly 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 inflammatory 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 inflammation (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 Nrf2-
mediated antioxidant defences and epigenetic changes
induced by reactive oxygen species (eg, histone
modifications) 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 inflammatory
cells in the bronchial mucosa are much the same as in
former smokers and in persistent smokers.76 How-
ever, analysis of bronchoalveolar lavage fluid of
COPD patients suggests that smoking cessation
partly changes the macrophage polarisation from a

www.thelancet.com Vol 378 September 10, 2011 1023

 Series
For more on clinical trials for
COPD see http://clinicaltrials.
gov/ct2/results?term=COPD
1024
proinflammatory M1 towards an anti-inflammatory
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 effects of pharma-
cological treatment on the underlying bronchial and
pulmonary inflammation.90–92 3-month treatment with the
inhaled corticosteroid fluticasone-propionate did not
reduce numbers of CD8+ T cells, macrophages, or
neutrophils in bronchial biopsy samples,91 whereas
combination therapy of salmeterol xinafoate and
fluticasone was associated with a reduction in CD8+ cells
on biopsy samples.92 Whereas—especially mild to
moderate—asthma is usually highly responsive to inhaled
corticosteroid therapy, COPD patients respond poorly to
such treatment. The differences 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 off inflammatory gene expression.85,93 Additionally,
differences in the type of the underlying immune responses
between asthma and COPD, might contribute to
differential corticosteroid responsiveness.93,94 The Th2-
driven eosinophilic airway inflammation 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 inflammation in COPD is resistant to steroids.95
Short-term courses of oral corticosteroids are effective 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 specific phosphodiesterase-4
inhibitor roflumilast significantly reduced the absolute
number of neutrophils in sputum and the concentrations
of CXCL8 and neutrophil elastase in sputum super-
natants.97 This anti-inflammatory effect of roflumilast
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 significant reductions in the rate of
exacerbations compared with placebo.99 Low dose
macrolide treatment shows much the same benefits in
other chronic neutrophilic airway diseases, including
diffuse panbronchiolitis, bronchiolitis obliterans
syndrome after lung transplantation, cystic fibrosis, and
non-cystic fibrosis bronchiectasis. The anti-inflammatory
mechanisms of macrolides need to be fully elucidated,
but probably encompass pleiotropic inhibitory effects 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 differentiation towards Treg instead of
Th17 cells). However, specific targeted anti-inflammatory
therapy with the anti-TNFα monoclonal antibody
infliximab 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-specific
therapies need to be investigated, encompassing anti-
oxidants, theophylline, or kinase inhibitors such as
mitogen-activated protein kinase inhibitors or phos-
phatidylinositol-3 kinase inhibitors.86,102,103
Contributors
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 figures, and reviewed and edited the report.
Conflicts 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 speaker’s fees from
AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck,
Novartis, Pfizer, 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 speaker’s fees from Almirall, AstraZeneca,
Boehringer-Ingelheim, GlaxoSmithKline, Merk Novartis, Pfizer, and
UCB. KRB declares that he has no conflicts of interest.
Acknowledgments
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 Scientific Research Flanders
and the Concerted Research Action of Ghent University for funding.
References
1 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: 1747–57.
2 Pauwels R, Rabe K. Burden and clinical features of chronic
obstructive pulmonary disease (COPD). Lancet 2004; 364: 613–20.
3 Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in
non-smokers. Lancet 2009; 374: 733–43.
4 Sinden NJ, Stockley RA. Systemic inflammation and comorbidity
in COPD: a result of ‘overspill’ of inflammatory mediators from the
lungs? Review of the evidence. Thorax 2010; 65: 930–36.
5 Wouters EF, Reynaert NL, Dentener MA, Vernooy JH. Systemic and
local inflammation in asthma and chronic obstructive pulmonary
disease: is there a connection? Proc Am Thorac Soc 2009; 6: 638–47.
6 Wouters EF, Groenewegen KH, Dentener MA, Vernooy JH.
Systemic inflammation in chronic obstructive pulmonary disease:
the role of exacerbations. Proc Am Thorac Soc 2007; 4: 626–34.
www.thelancet.com Vol 378 September 10, 2011

7 Hogg JC, Timens W. The pathology of chronic obstructive
pulmonary disease. Annu Rev Pathol 2009; 4: 435–59.
8 Laurell CB ES. The electrophoretic alpha-1 globulin pattern of serum in
alpha-1 antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15: 132–40.
9 Rahman I, Adcock IM. Oxidative stress and redox regulation of lung
inflammation in COPD. Eur Respir J 2006; 28: 219–42.
10 Tsuji T, Aoshiba K, Nagai A. Cigarette smoke induces senescence
in alveolar epithelial cells. Am J Respir Cell Mol Biol 2004; 31: 643–49.
11 Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic
obstructive pulmonary disease. N Engl J Med 2009; 360: 2445–54.
12 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.
13 Vandivier RW, Henson PM, Douglas IS. Burying the dead: the
impact of failed apoptotic cell removal (efferocytosis) on chronic
inflammatory lung disease. Chest 2006; 129: 1673–82.
14 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: 1294–309.
15 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: 917–27.
16 Lommatzsch M, Cicko S, Muller T, et al. Extracellular adenosine
triphosphate and chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2010; 181: 928–34.
17 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: 482–90.
18 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: 688–97.
19 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.
20 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: 18880–85.
21 Chung KF, Adcock IM. Multifaceted mechanisms in COPD:
inflammation, immunity, and tissue repair and destruction.
Eur Respir J 2008; 31: 1334–56.
22 Demedts IK, Morel-Montero A, Lebecque S, et al. Elevated MMP-12
protein levels in induced sputum from patients with COPD. Thorax
2006; 61: 196–201.
23 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: 822–86.
24 Urbanowicz RA, Lamb JR, Todd I, Corne JM, Fairclough LC.
Enhanced effector function of cytotoxic cells in the induced sputum
of COPD patients. Respir Res 2010; 11: 76.
25 Fahy JV, Dickey BF. Airway mucus function and dysfunction.
N Engl J Med 2010; 363: 2233–47.
26 Shapiro SD. Transgenic and gene-targeted mice as models for chronic
obstructive pulmonary disease. Eur Respir J 2007; 29: 375–78.
27 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: 974–80.
28 D’Hulst 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.
29 Botelho FM, Gaschler GJ, Kianpour S, et al. Innate immune
processes are sufficient for driving cigarette smoke-induced
inflammation in mice. Am J Respir Cell Mol Biol 2010; 42: 394–403.
30 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: 206–17.
31 Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity?
The example of natural killer cells. Science 2011; 331: 44–49.
32 Degli-Esposti MA, Smyth MJ. Close encounters of different kinds:
dendritic cells and NK cells take centre stage. Nat Rev Immunol
2005; 5: 112–24.
www.thelancet.com Vol 378 September 10, 2011
Series
33 Lambrecht BN, Hammad H. The role of dendritic and epithelial
cells as master regulators of allergic airway inflammation. Lancet
2010; 376: 835–43.
34 Lommatzsch M, Bratke K, Knappe T, et al. Acute effects of tobacco
smoke on human airway dendritic cells in vivo. Eur Respir J 2010;
35: 1130–36.
35 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: 1179–88.
36 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: 998–1005.
37 Heath WR, Carbone FR. Dendritic cell subsets in primary and
secondary T cell responses at body surfaces. Nat Immunol 2009;
10: 1237–44.
38 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: 1404–09.
39 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.
40 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: 316–24.
41 Imaoka H, Hoshino T, Takei S, et al. Interleukin-18 production
and pulmonary function in COPD. Eur Respir J 2008; 31: 287–97.
42 Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper
T cells. N Engl J Med 2009; 361: 888–98.
43 Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all
trades, master of regulation. Nat Immunol 2008; 9: 239–44.
44 Lee SH, Goswami S, Grudo A, et al. Antielastin autoimmunity in
tobacco smoking-induced emphysema. Nat Med 2007; 13: 567–69.
45 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: 555–62.
46 Smyth LJ, Starkey C, Vestbo J, Singh D. CD4-regulatory cells
in COPD patients. Chest 2007; 132: 156–63.
47 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: 89–94.
48 D’Alessio 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: 2898–913.
49 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: 2645–53.
50 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: 751–58.
51 Brusselle GG, Demoor T, Bracke KR, Brandsma CA, Timens W.
Lymphoid follicles in (very) severe COPD: beneficial or harmful?
Eur Respir J 2009; 34: 219–30.
52 Randall TD. Bronchus-associated lymphoid tissue (BALT) structure
and function. Adv Immunol 2010; 107: 187–241.
53 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: 781–91.
54 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: 1011–19.
55 Mueller SN, Hosiawa-Meagher KA, Konieczny BT, et al. Regulation
of homeostatic chemokine expression and cell trafficking during
immune responses. Science 2007; 317: 670–74.
56 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: 639–46.
1025
 Series
57 Sethi S, Murphy TF. Infection in the pathogenesis and course
of chronic obstructive pulmonary disease. N Engl J Med 2008;
359: 2355–65.
58 Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway
inflammation and bronchial bacterial colonization in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2006;
173: 991–98.
59 Hurst JR, Vestbo Jr, Anzueto A, et al. Susceptibilty to exacerbation
in chronic obstructive pulmonary disease. N Engl J Med 2010;
363: 1128–38.
60 Hilty M, Burke C, Pedro H, et al. Disordered microbial
communities in asthmatic airways. PLoS One 2010; 5: e8578.
61 Berenson CS, Garlipp MA, Grove LJ, Maloney J, Sethi S. Impaired
phagocytosis of nontypeable Haemophilus influenzae by human
alveolar macrophages in chronic obstructive pulmonary disease.
J Infect Dis 2006; 194: 1375–84.
62 Taylor AE, Finney-Hayward TK, Quint JK, et al. Defective macrophage
phagocytosis of bacteria in COPD. Eur Respir J 2010; 35: 1039–47.
63 Rosell A, Monso E, Soler N, et al. Microbiologic determinants
of exacerbation in chronic obstructive pulmonary disease.
Arch Intern Med 2005; 165: 891–97.
64 Sanjuan MA, Dillon CP, Tait SW, et al. Toll-like receptor signalling
in macrophages links the autophagy pathway to phagocytosis.
Nature 2007; 450: 1253–57.
65 Levine B, Mizushima N, Virgin HW. Autophagy in immunity
and inflammation. Nature 2011; 469: 323–35.
66 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: 465–71.
67 Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory
viruses, symptoms, and inflammatory markers in acute
exacerbations and stable chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2001; 164: 1618–23.
68 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: 1369–78e2.
69 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: 734–42.
70 Papi A, Bellettato CM, Braccioni F, et al. Infections and airway
inflammation in chronic obstructive pulmonary disease severe
exacerbations. Am J Respir Crit Care Med 2006; 173: 1114–21.
71 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: 195–99.
72 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: 156–63.
73 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: 1025–31.
74 Greene CM, Low TB, O’Neill SJ, McElvaney NG.
Anti-proline-glycine-proline or antielastin autoantibodies are not
evident in chronic inflammatory lung disease.
Am J Respir Crit Care Med 2010; 181: 31–35.
75 Wood AM, de Pablo P, Buckley CD, Ahmad A, Stockley RA. Smoke
exposure as a determinant of autoantibody titre in {alpha}1-antitrypsin
deficiency and COPD. Eur Respir J 2011; 37: 32–38.
76 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: 101–07.
77 Gamble E, Grootendorst DC, Hattotuwa K, et al. Airway mucosal
inflammation in COPD is similar in smokers and ex-smokers:
a pooled analysis. Eur Respir J 2007; 30: 467–71.
78 Sorokin L. The impact of the extracellular matrix on inflammation.
Nat Rev Immunol 2010; 10: 712–23.
79 Weathington NM, van Houwelingen AH, Noerager BD, et al.
A novel peptide CXCR ligand derived from extracellular matrix
degradation during airway inflammation. Nat Med 2006; 12: 317–23.
80 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: 1011–21.
1026
81 Eltzschig HK, Carmeliet P. Hypoxia and inflammation.
N Engl J Med 2011; 364: 656–65.
82 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: 898–906.
83 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: 3753–56.
84 Mercado N, Thimmulappa R, Thomas CM, et al. Decreased histone
deacetylase 2 impairs Nrf2 activation by oxidative stress.
Biochem Biophys Res Commun 2011; 406: 292–98.
85 Ito K, Ito M, Elliott WM, et al. Decreased Histone Deacetylase
Activity in Chronic Obstructive Pulmonary Disease. N Engl J Med
2005; 352: 1967–76.
86 Adcock IM, Tsaprouni L, Bhavsar P, Ito K. Epigenetic regulation
of airway inflammation. Curr Opin Immunol 2007; 19: 694–700.
87 Fletcher C, Peto R. The natural history of chronic airflow
obstruction. BMJ 1977; 1: 1645–48.
88 Kohansal R, Martinez-Camblor P, Agusti A, Buist AS,
Mannino DM, Soriano JB. The natural history of chronic airflow
obstruction revisited: an analysis of the Framingham offspring
cohort. Am J Respir Crit Care Med 2009; 180: 3–10.
89 Kunz LI, Lapperre TS, Snoeck-Stroband JB, et al. Smoking status
and anti-inflammatory macrophages in bronchoalveolar lavage and
induced sputum in COPD. Respir Res 2011; 12: 34.
90 Lapperre TS, Snoeck-Stroband JB, Gosman MM, et al. Effect of
fluticasone with and without salmeterol on pulmonary outcomes
in chronic obstructive pulmonary disease: a randomized trial.
Ann Intern Med 2009; 151: 517–27.
91 Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC.
The effects of inhaled fluticasone on airway inflammation in chronic
obstructive pulmonary disease: a double-blind, placebo-controlled
biopsy study. Am J Respir Crit Care Med 2002; 165: 1592–96.
92 Barnes NC, Qiu YS, Pavord ID, et al. Antiinflammatory effects
of salmeterol/fluticasone propionate in chronic obstructive lung
disease. Am J Respir Crit Care Med 2006; 173: 736–43.
93 Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid
resistance. Chest 2008; 134: 394–401.
94 Barnes PJ. Immunology of asthma and chronic obstructive
pulmonary disease. Nat Rev Immunol 2008; 8: 183–92.
95 Vanaudenaerde BM, Verleden SE, Vos R, et al. Innate and Adaptive
Interleukin-17-producing Lymphocytes in Chronic Inflammatory
Lung Disorders. Am J Respir Crit Care Med 2011; 183: 977–86.
96 Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in
sputum neutrophil and eosinophil numbers by the PDE4 inhibitor
roflumilast in patients with COPD. Thorax 2007; 62: 1081–87.
97 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: 532–55.
98 Calverley PM, Rabe KF, Goehring UM, et al, for the M2-124
and M2-125 study groups. Roflumilast in symptomatic chronic
obstructive pulmonary disease: two randomised clinical trials.
Lancet 2009; 374: 685–94.
99 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: 1139–47.
100 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: 139–48.
101 Rennard SI, Fogarty C, Kelsen S, et al. The safety and efficacy
of infliximab in moderate to severe chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 2007; 175: 926–34.
102 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: 689–95.
103 Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ.
Treatment effects of low-dose theophylline combined with an
inhaled corticosteroid in COPD. Chest 2010; 137: 1338–44.
www.thelancet.com Vol 378 September 10, 2011