B Russell e 2011
B Russell e 2011
B Russell e 2011
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.
Introduction
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
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Series
Macrophage
Neutrophil
Lumen
Goblet cell
Epithelium
Lymphoid follicle
Mucosa
Dendritic cell
B cell
Mast cell
CD4+ T cell
CD8+ T cell
Innate immune 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 inammation. CD=cluster of dierentiation.
1016
Series
Innate immunity
Adaptive immunity
Recognition
Receptors
Molecules
Pathogen-associated molecular
patterns; damage-associated
molecular patterns
Onset
Immediate
Specicity
Fixed repertoire
Specic
Response
Immunological memory
No
Yes
Ontology
Ancient
Recent
Neutrophils, macrophages,
dendritic cells, eosinophils,
natural killer cells
T lymphocytes, B lymphocytes
Cellular component
Haematopoietic
Structural
Eector molecules
Epithelial cells
Series
Autophagy
Viruses
ROS
Cell death
(autophagic,
apoptotic,
necrotic)
RAGE
DAMPs
PAMPs
Interle
AT
P
cid
Uric a
,H
HSP
P2X7
TLRs
ukin 1
LPS,...
P2Y2
,...
, HA
B1
MG
Interleukin 1R
TLRs
P2X7
NF-B
NLRPs
Pro
caspase-1
Inammasome
caspase-1
TNF
CXCL8
Eector phase
Pro-inammatory
cytokines and chemokines
(TNF, interleukin 1, CXCL8,...)
ROS
Pro
interleukin 1
Mature
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.
Series
Nicotine
nAChR, TRPA1
NLRP3
Acrolein
TRPA1
AhR
P2XR, P2YR
Uric acid
NLRP3
S100 molecules
TLR9, RAGE
defensins
TLR4, CCR6
Interleukin 1
Interleukin 1R
DNA (mitochondrial)
TLR9
FPR1
Fibronectin
Heparan sulphate
TLR4
Versican
TLR2
Biglycan
N-acetyl-proline-glycine-proline
CXCR1, CXCR2
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
B cells
B cells are increased in large airways of patients with
COPD, as shown in central bronchial biopsy specimens.
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CXCR3
CD8+ cytotoxic T cell
MHCI TCR
Perforins, granzymes
CD8
CD80 CD28
CD86
CD4+ T helper cell
MHCII TCR
CD4
CD80 CD28
CD86
18
, IL
12 in
IL lept
IL 4 2A
P
virus
rhino
TGF
IL
1
, IL RA
6,
TG
F
; IL
23
IL 12R
IL 18R
Th1
CXCR3
T-bet
CCR5
IL 4R
CCR3
Th2
CCR4
GATA-3 CCR8
CD25
CTLA4
Treg
GITR
FOXP3
CCR7
Th17
RORyT
IL 23R
CCR4
CCR6
INF, TNF
IL 4, IL 5, IL 13
IL 10, TGF
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.
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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100 m
100 m
100 m
100 m
Target cells
CCL2/MCP-1
CCR5
CCR6
CCL20/MIP-3
CCR7
CCL19/MIP-3, CCL21/SLC
CXCL8/IL 8
CXCR2
CXCL8/IL 8, CXCL1/GRO-
Neutrophils, monocytes
Neutrophils, monocytes
CXCR3
T cells
CXCR5
CXCL13/BCA-1
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)
Series
slgA
Antigen
Epithelium
Lymphoid follicle
IgA
IL 1
CXCL9,10,11
Plasma cell
CCL3,4,5
IL 18/IL 23
CXCR3
CCR5 IL 18R
IgM, IgG
IL 23R
Antibody
CD8+ cytotoxic
T cell
LTR
BAFF
BAFF-R
Th17 cell
Th1 cell
CXCL12
CXCL13
B cell
T cell
LT12
CXCR5
CCL19
CCL21
Perforins
Granzymes
CCR7
IFN
TNF
IL 17A
IL 17F
IL 21
IL 22
HEV
Smooth muscle cell
Dendritic cell
Series
PAMP
Streptococcus pneumoniae
Haemophilus inuenzae
LPS
OMP P6, OMP P2
Peptidoglycan
Moraxella catarrhalis
LPS
Usp A1
Usp A2
Pseudomonas aeruginosa
LPS
Flagellin
Bacteria
Viruses
Rhinovirus
dsRNA
TLR3, MDA5
Inuenza
dsRNA
ssRNA
Table 4: Microbial pathogens, pathogen associated molecular patterns (PAMP), and pattern recognition
receptors (PRR) in chronic obstructive pulmonary disease
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
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