inmunology of epoc.pdf

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Eosinophilic inflammation

Dendriticcell

Epithelial cells

Mast cell

Inhaled allergens

CCL11

B cell

TSLP

TH2 cell

CCR4

CCR3

Bronchoconstriction

CCL17 andCCL22

TRegcells?

IgE

Histamine, cysteinylleukotrienes andprostaglandin D2

IL-13

IL-9

IL-5

SCF

Antibodyproduction

Smooth-musclecell

Eosinophil

IL-4

Non-atopic (intrinsic)

asthma

An uncommon form of asthma

that is more likely to be severe

and characterized by negativeskin-prick tests. The airway

inflammation is similar to that

of atopic asthma and may be

mediated by local rather than

systemic IgE production.

Emphysema

Destruction of the alveolar

walls, resulting in decreased

gas exchange and contributing

to airflow limitation by loss of

alveolar attachments to the

small airways that serve to

keep the airways open during

expiration.

role, although this remains poorly understood in COPD.The appreciation that similar immune mechanisms areinvolved in both asthma and COPD has importantimplications for the development of new therapies forthese troublesome diseases.

Inflammatory cells and mediators

There are many differences between mild asthma andCOPD in the type of inflammation that occurs in the lungs,

with a different range of inflammatory cells and mediatorsbeing implicated10,11. However, many of the cytokines andchemokines that are secreted in both asthma and COPDare regulated by the transcription factor nuclear factor-B(NF-B), which is activated in airway epithelial cells andmacrophages in both diseases, and may have an importantrole in amplifying airway inflammation12,13.

Histopathology.The histological appearance of airwaysfrom asthmatic individuals is very different from thechanges that are observed in patients with COPD (FIG. 3).Bronchial biopsies from asthmatic subjects reveal aninfiltration of eosinophils, activated mucosal mast cells

at the airway surface and activated T cells. There arecharacteristic structural changes, with collagen deposi-tion under the epithelium that is sometimes describedas basement-membrane thickening and is found inall patients with asthma, and thickening of the airwaysmooth-muscle cell layer as a result of hyperplasia andhypertrophy, which is more commonly seen in patientswith severe asthma14. Epithelial cells are often shed fromasthmatic patient biopsies compared to normal controlbiopsies, as they are friable and more easily detach fromthe basement membrane during the biopsy procedure.In addition, there is an increase in the number of blood

vessels (angiogenesis) in response to increased secre-tion of vascular-endothelial growth factor (VEGF)15.Mucus hyperplasia is commonly seen in biopsies fromasthmatic patients, with an increase in the number ofmucus-secreting goblet cells in the epithelium and anincrease in the size of submucosal glands16.

In biopsies of the bronchial airways, small airways andlung parenchyma from patients with COPD, there is noevidence for mast-cell activation, but there is an infiltra-

tion of T cells and increased numbers of neutrophils,particularly in the airway lumen17. Subepithelial fibrosisis not apparent, but fibrosis does occur around small air-ways and is thought to be a main factor that contributesto the irreversible airway narrowing that is characteristicof this disease18. The airway smooth-muscle cell layer isnot usually increased in COPD patients compared withnormal airways, and airway epithelial cells may showpseudostratificationas a result of chronic irritationfrominhaled cigarette smoke or other irritants and the releaseof epithelial-cell growth factors. As in biopsies fromasthma patients, there is mucus hyperplasia and increasedexpression of mucin genes in biopsies from patientswith COPD19. A marked difference between COPD andasthma is the destruction of alveolar walls (emphysema)that occurs in COPD as a result of protease-mediateddegradation of connective tissue elements, particularlyelastin, and apoptosis of type I pneumocytesand pos-sibly endothelial cells20,21. In addition, the productionof elastolytic enzymes, such as neutrophil elastase andparticularly several matrix metalloproteinases (MMPs),is increased in the lungs of COPD patients22, and theremay be a reduction in the levels of antiproteinases, suchas

1-antitrypsin, as seen in a rare form of emphysema

caused by a congenital deficiency of 1-antitrypsin23.

Mast cells.Mast cells have a key role in asthma through

the release of several bronchoconstrictors, includinghistamine, which is preformed and stored in granules,and the lipid mediators leukotriene C

4, leukotriene D

4,

leukotriene E4and prostaglandin D

2, which are synthe-

sized following mast-cell activation. The release of thesemediators may account for the variable bronchocon-striction seen in asthma, as these mediators are releasedby various environmental triggers, such as allergens, andan increase in plasma osmolality as a result of increased

ventilation during exerc ise. Mucosal mast cells arerecruited to the surface of the airways by stem-cell factor(SCF; also known as KIT ligand) released from epithelialcells, which acts on KIT receptors expressed by the

Figure 1 |Inflammatory and immune cells involved in asthma. Inhaled allergens

activate sensitized mast cells by crosslinking surface-bound IgE molecules to release

several bronchoconstrictor mediators, including cysteinyl leukotrienes and

prostaglandin D2. Epithelial cells release stem-cell factor (SCF), which is important for

maintaining mucosal mast cells at the airway surface. Allergens are processed by myeloid

dendritic cells, which are conditioned by thymic stromal lymphopoietin (TSLP) secreted

by epithelial cells and mast cells to release the chemokines CC-chemokine ligand 17

(CCL17) and CCL22, which act on CC-chemokine receptor 4 (CCR4) to attract T helper 2

(TH2) cells. T

H2 cells have a central role in orchestrating the inflammatory response in

allergy through the release of interleukin-4 (IL-4) and IL-13 (which stimulate B cells to

synthesize IgE), IL-5 (which is necessary for eosinophilic inflammation) and IL-9 (which

stimulates mast-cell proliferation). Epithelial cells release CCL11, which recruitseosinophils via CCR3. Patients with asthma may have a defect in regulatory T (TReg

) cells,

which may favour further TH2-cell proliferation.

R E V I E W S

184 |MARCH 2008 |VOLUME 8 www.nature.com/reviews/immunol

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Epithelial cells Macrophage

Airwayepithelialcell

Fibroblast Neutrophil Monocyte

Cigarette smoke(and other irritants)

CXCL9, CXCL10and CXCL11

TH1 cell TC1 cell

CXCR3

TGF

CCL2

CCR2

Proteases (such as neutrophilelastase and MMP9)

Alveolar wall destruction(emphysema)

Mucus gland

Mucushypersecretion

CXCL1and CXCL8

CXCR2

Fibrosis(small airways)

Smooth-musclecell

AlveoliGobletcell

Mucus

Pseudostratification

Increased proliferation of

airway epithelial cells in chronic

obstructive pulmonary disease,

as a result of the release of

epithelial-cell growth factors,

which lead to increased

thickness of the epithelial-cell

layer.

Type I pneumocytes

Flat alveolar cells that make up

most of the epithelial-cell layer

of the alveolar wall and that are

responsible for gas exchange in

the alveoli.

Bronchoconstrictor

An agent that induces

contraction of airway smooth

muscle and thereby narrows

the airways, thus reducing the

flow of air.

mast cells24. Mast cells also release cytokines that arelinked to allergic inflammation, including interleukin-4(IL-4), IL-5and IL-13(REF. 25). The presence of mastcells in the airway smooth muscle has been linked toairway hyper-responsivenessin asthma26, as patients witheosinophilic bronchitis have a similar degree of eosino-philic inflammation to that found in asthmatics andalso have subepithelial fibrosis, but they do not showairway hyper-responsiveness, which is the physiologicalhallmark of asthma. By contrast, mast cells do not seemto have a role in COPD, which may explain the lack of

variable bronchoconstriction in this disease.

Granulocytes.The inflammation that occurs in asthma isoften described as eosinophilic, whereas that occurringin COPD is described as neutrophilic. These differencesreflect the secretion of different chemotactic factors inthese diseases. In asthma, eosinophil chemotactic factors,such as CC-chemokine ligand 11 (CCL11; also knownas eotaxin-1) and related CC-chemokines, are mainlysecreted by airway epithelial cells. The functional role of

eosinophils in asthma is not clear and the evidence thatlinks their presence to airway hyper-responsiveness hasbeen questioned by the finding that the administration ofIL-5-specific blocking antibodies that markedly reducethe number of eosinophils in the blood and sputumdoes not reduce airway hyper-responsiveness or asthmasymptoms27,28. As discussed above, eosinophilic bronchi-tis is not associated with airway hyper-responsiveness,but subepithelial fibrosis does occur, which suggests arole for eosinophils in airway fibrosis. Interestingly, thepresence of eosinophils seems to be a good marker ofsteroid responsiveness29.

Neutrophils are increased in the sputum of patientswith COPD and this correlates with disease severity30.The increase in neutrophils is related to an increasein the production of CXC-chemokines, such as CXC-chemokine ligand 1 (CXCL1; also known as GRO) andCXCL8 (also known as IL-8), which act on CXCR2thatis expressed predominantly by neutrophils.

Macrophages.Macrophage numbers are increased in the

lungs of patients with asthma and COPD, but their num-bers are far greater in COPD than in asthma. These mac-rophages are derived from circulating monocytes, whichmigrate to the lungs in response to chemoattractants suchas CCL2 (also known as MCP1) acting on CCR2, andCXCL1 acting on CXCR2 (REF. 31). There is increasingevidence that lung macrophages orchestrate the inflam-mation of COPD through the release of chemokines thatattract neutrophils, monocytes and T cells and the releaseof proteases, particularly MMP9 (REF. 32).

The pattern of inflammatory cells found in the res-piratory tract therefore differs in patients with asthmaand those with COPD and some of these contrastsmay be explained by differences in the immunologicalmechanisms that drive these two diseases.

Immune responses

The immune mechanisms that drive the different inflam-matory processes of asthma and COPD are mediated bydifferent types of immune cell, in particular by differentT-cell subsets. An understanding of which immune cellsare involved is now emerging and may lead to the devel-opment of new and more-specific therapies for airwaydiseases in the future (FIGS 1,2).

T cells.In asthmatic patients, there is an increase in thenumber of CD4+T cells in the airways and these are pre-

dominantly T helper 2 (TH2) cells, whereas in normal air-ways T

H1 cellspredominate33. By secreting the cytokines

IL-4 and IL-13, which drive IgE production by B cells,IL-5, which is solely responsible for eosinophil differen-tiation in the bone marrow, and IL-9, which attracts anddrives the differentiation of mast cells34, T

H2 cells have a

central role in allergic inflammation and therefore theirregulation is an area of intense research.

The transcription factor GATA3(GATA-binding pro-tein 3) is crucial for the differentiation of uncommittednaive T cells into T

H2 cells and it also regulates the secre-

tion of TH2-type cytokines35,36. Accordingly, there is an

increase in the number of GATA3+T cells in the airways

Figure 2 | Inflammatory and immune cells involved in chronic obstructive

pulmonary disease (COPD). Inhaled cigarette smoke and other irritants activate

epithelial cells and macrophages to release several chemotactic factors that attract

inflammatory cells to the lungs, including CC-chemokine ligand 2 (CCL2), which acts on

CC-chemokine receptor 2 (CCR2) to attract monocytes, CXC-chemokine ligand 1

(CXCL1) and CXCL8, which act on CCR2 to attract neutrophils and monocytes (which

differentiate into macrophages in the lungs) and CXCL9, CXCL10 and CXCL11, which act

on CXCR3 to attract T helper 1 (TH1) cells and type 1 cytotoxic T (T

C1) cells. These

inflammatory cells together with macrophages and epithelial cells release proteases,

such as matrix metalloproteinase 9 (MMP9), which cause elastin degradation and

emphysema. Neutrophil elastase also causes mucus hypersecretion. Epithelial cells and

macrophages also release transforming growth factor-(TGF), which stimulatesfibroblast proliferation, resulting in fibrosis in the small airways.

R E V I E W S

NATURE REVIEWS |IMMUNOLOGY VOLUME 8 |MARCH 2008 |185

F OC US ON A LLE R G Y A N D A S THMA
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Airway smooth muscle

Airway smooth muscle

|

Inflammation

Inflammation

Basement membrane

Basement membrane

Fibrosis

Fibrosis

Alveolar disruption

Alveolar disruption

Airway vessels

Mast cells

Dendritic cells

Eosinophils

Neutrophils

Lymphocytes

Epithelium

Goblet cells

+++ (peribronchiolar)

+++

+++

+

++

++

Normal

Normal

TH1 and TC1 type

+++

+++

++

+ (subepithelial)

++

++

++

++

++ (and activated)

Normal

TH2 type

Often shed

No change

ND

Pseudostratified

Asthma COPD

Airway hyper-

responsiveness

Increased narrowing of the

airways, initiated by exposure

to a defined stimulus that

usually has little or no effect

on airway function in normal

individuals. This is a defining

physiological characteristic of

asthma.

TH2 cells

(T helper 2 cells). The definition

of a CD4+T cell that has

differentiated into a cell that

produces the cytokines

interleukin-4 (IL-4), IL-5 and

IL-13, thereby supporting

humoral immunity and

counteracting TH1-cell

responses. An imbalance ofT

H1T

H2-cell responses is

thought to contribute to the

pathogenesis of various

infections, allergic responses

and autoimmune diseases.

TH1 cells

(T helper 1 cells). The definition

of a CD4+T cell that has

differentiated into a cell that

produces the cytokines

interferon-and tumour-

necrosis factor, thereby

promoting cell-mediated

immunity.

of asthmatic subjects compared with normal subjects37,38.Following simultaneous ligation of the T-cell receptor(TCR) and co-receptor CD28 by antigen-presentingcells, T-cell GATA3 is phosphorylated and activatedby the mitogen-activated protein kinase (MAPK) p38.Activated GATA3 then translocates from the cytoplasmto the nucleus, where it activates gene transcription39.GATA3 expression in T cells is regulated by the tran-scription factor STAT6 (signal transducer and activatorof transcription 6), which is in turn regulated by IL-4receptor activation.

For TH1-cell differentiation and secretion of the T

H1-

type cytokine interferon-(IFN), the crucial transcrip-

tion factor is T-bet. Consistent with the prominent roleof T

H2 cells in asthma, T-bet expression is reduced in

T cells from the airways of asthmatic patients comparedwith non-asthmatic subjects40. When phosphorylated,T-bet can associate with and inhibit the function ofGATA3, by preventing it from binding to its DNA targetsequences41. T-bet-deficient mice show increased expres-sion of GATA3 and production of T

H2-type cytokines,

confirming that T-bet is an important regulator ofGATA3 (REF. 40). GATA3 expression is also regulated byIL-27, a recently identified member of the IL-12 family,which downregulates GATA3 expression and upregu-lates T-bet expression, thereby favouring the production

TH1-type cytokines, which then act to further inhibit

GATA3 expression42.

In turn, GATA3 inhibits the pro-duction of T

H1-type cytokines by inhibiting STAT4, the

key transcription factor activated by the T-bet-inducingcytokine IL-12 (REF. 43)(FIG. 4). Nuclear factor of activatedT cells (NFAT) is a T-cell-specific transcription factorand appears to enhance the transcriptional activation ofGATA3 by targeting the IL4promoter44. Finally, IL-33, anewly discovered member of the IL-1 family of cytokines,seems to promote T

H2-cell differentiation by translocat-

ing to the nucleus and regulating transcription throughan effect on chromatin structure45, but it also acts as aselective chemoattractant of T

H2 cells by binding the sur-

face receptor IL-1-receptor-like 1 (also known as ST2),which is specifically expressed by these cells46.

In contrast to asthma, the CD4+T cells that accumu-late in the airways and lungs of patients with COPD aremainly T

H1 cells. T

H1 cells express the chemokine recep-

tor CXCR3(REF. 47)and may be attracted to the lungs bythe IFN-induced release of the CXCR3 ligands CXCL9(also known as MIG), CXCL10 (also known as IP-10)and CXCL12 (also known as I-TAC), which are presentat high levels in COPD airways48,49. However, there issome evidence that T

H2 cells are also increased in lavage

fluid of patients with COPD50; likewise, in patients withmore severe asthma, T

H1 cells are activated, as well as

Figure 3 | Contrasting histopathology of asthma and chronic obstructive pulmonary disease (COPD). A small airway

from a patient who died from asthma and a similar sized airway from a patient with severe COPD are shown. There is an

infiltration of inflammatory cells in both diseases. The airway smooth-muscle cell layer is thickened in asthma but only to

a minimal degree in COPD. The basement membrane is thickened in asthma due to collagen deposition (subepithelial

fibrosis) but not in COPD, whereas in COPD collagen is deposited mainly around the airway (peribronchiolar fibrosis). The

alveolar attachments are intact in asthma, but disrupted in COPD as a result of emphysema. Images courtesy of Dr J. Hogg

(Vancouver, Canada). Other differences in the cellular infiltrate in the two diseases are also shown. ND, not determined;

TC1, type 1 cytotoxic T; T

H1, T helper 1.

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IL-27 IL-12 IL-4 IL-33

STAT1 STAT4

T-betTH1 cells TH2 cells

TH1-type cytokines(IL-2 and IFN)

TH2-type cytokines(IL-4, IL-5, IL-9 and IL-13)

STAT6

GATA3

Allergic inflammation

Regulatory T cells

A specialized type of CD4+

T cells that can suppress the

responses of other T cells.

These cells provide a crucial

mechanism for the

maintenance of peripheral self-

tolerance and a subset of these

cells is characterized by

expression of CD25 and the

transcription factor forkhead

box P3 (FOXP3).

Allergic rhinitis

Allergic inflammation that is

caused by the pollen of specific

seasonal plants, such as

grasses (causing hay fever), and

house dust (causing perennial

rhinitis) in people who are

allergic to these substances. It

is characterized by sneezing,and a runny and blocked nose.

TH17 cells

(T helper 17 cells). A subset of

CD4+T helper cells that

produce interleukin-17 (IL-17)

and that are thought to be

important in inflammatory and

autoimmune diseases. Their

generation involves IL-23 and

IL-21,as well as the

transcription factors RORt

(retinoic-acid-receptor-related

orphan receptor-t) and STAT3

(signal transducer and activator

of transcription 3).

Invariant natural killer T

(iNKT) cells

Lymphocytes that express

a particular variable gene

segment, V14 (in mice) and

V24 (in humans), precisely

rearranged to a particular J

(joining) gene segment to yield

T-cell receptor -chains with an

invariant sequence. Typically,

these cells co-express cell-

surface markers that are

encoded by the natural killer

(NK) locus, and they are

activated by recognition of

CD1d, particularly when-galactosylceramide is bound

in the groove of CD1d.

Type 1 cytotoxic T (TC1) and

TC2 cells

A designation that is used to

describe subsets of CD8+

cytotoxic T cells. TC1 cells

typically secrete interferon-

and granulocyte/macrophage

colony-stimulating factor, and

have strong cytotoxic capacity,

whereas TC2 cells secrete

interleukin-4 (IL-4) and IL-10

and are less effective killers.

TH2 cells51, making the distinction between the T

H-cell

patterns in these two diseases less clear.Other subtypes of CD4+T cells that may have an

important role in airway diseases areregulatory T cells,which have a suppressive effect on other CD4+T cellsand may have a role in regulating T

H2-cell function

in asthma33,52. There is evidence that the numbers ofCD4+CD25+regulatory T cells that express the tran-scription factor forkhead box P3 (FOXP3) are reducedin individuals with allergic rhinitis(hay fever) comparedwith non-atopic individuals, and this may be importantin enabling high numbers of T

H2 cells to develop in aller-

gic disease53. However, by contrast, asthmatic patientsseem to have an increase in FOXP3-expressing regula-tory T cells compared with patients with mild asthma,at least among circulating cells54. Analysis of sputumfrom COPD patients suggests that the numbers ofCD4+CD25+FOXP3+regulatory T cells are reduced, butsimilar changes are also seen in people who smoke but donot have airflow obstruction55. So, the role of regulatoryT cells in asthma and COPD remains unclear and fur-

ther research is therefore needed, particularly in definingthe role of different types of regulatory T cells56.

Another subset of CD4+T cells, known as TH17 cells,

has recently been described and shown to have animportant role in inflammatory and autoimmune dis-eases57,58. Little is known about the role of T

H17 cells in

asthma or COPD, but increased concentrations ofIL-17(the predominant product of T

H17 cells) have been

reported in the sputum of asthma patients59. IL-17 andthe closely related cytokine IL-17F have been linked toneutrophilic inflammation by inducing the release ofCXCL1 and CXCL8 from airway epithelial cells60(FIG. 5).As well as IL-17,

TH17 cells also produce IL-21, which

is important for the differentiation of these cells andthus acts as a positive autoregulatory mechanism, butit also inhibits FOXP3 expression and regulatory T-celldevelopment61,62. Another cytokine IL-22 is also releasedby these cells and stimulates the production of IL-10 andacute-phase proteins63. However, more work is neededto understand the role and regulation of T

H17 cells in

asthma and COPD, as they may represent importantnew targets for future therapies.

A subset of CD4+T cells termed invariant natural killer T(iNKT) cells, which secrete IL-4 and IL-13, has been shownto account for 60% of all CD4+T cells in bronchial biop-sies from asthmatic patients64, but this has been disputedin another study that failed to show any increase in iNKT-

cell numbers in bronchial biopsies, bronchoalveolar lavageor sputum of either asthma or COPD patients65.The roleof iNKT cells in asthma is currently uncertain as thereappears to be a discrepancy between the data from murinemodels of asthma and humans with the disease33.

CD8+T cells predominate over CD4+T cells in theairways and lung parenchyma of patients with COPD66,but their role in disease pathogenesis is not yet certain.Type 1 cytotoxic T (T

C1) cells, which secrete IFN, predomi-

nate and express CXCR3, suggesting that they are attractedto the lungs by CXCR3-binding chemokines47,49. TheseCXCR3 ligands suppress signalling through CCR3, thereceptor for CCL11, suggesting that they might suppress

eosinophilic inflammation67. The production of CCL5(also known as RANTES), which attracts CD4+and CD8+T cells via CCR5, is also increased in the sputum of COPDpatients compared with controls and may also be involvedin T-cell recruitment49. T

C1 cells release granzyme B and

perforins, which are also present at higher levels in thesputum of COPD patients than normal control subjectswho also smoke68, and may induce apoptosis of type 1pneumocytes, thereby contributing to the development ofemphysema20. T

C1- and T

H1-cell-driven inflammation is

likely to be self-perpetuating as IFNstimulates the releaseof CXCR3 ligands, which then attract more T

H1 and T

C1

cells into the lungs (FIG. 6). TC2 cells, which secrete IL-4,

have also been described in COPD50. In asthma, CD8+T cells are present in patients with more severe diseaseand irreversible airflow obstruction69and these cells maybe of either the T

C1 or T

C2 type70.

B cells.B cells have an important role in allergic diseases,including asthma, through the release of allergen-specificIgE which binds to high-affinity Fc receptors for IgE

(FcRI) expressed by mast cells and basophils, and tolow-affinity Fc receptors for IgE (FcRII) expressed byother inflammatory cells, including B cells, macrophagesand possibly eosinophils71. The T

H2-type cytokines IL-4

and IL-13 induce B cells to undergo immunoglobulin classswitchingto produce IgE. Blocking IgE with the mono-clonal antibody omalizumab reduces the response toallergens, airway inflammation and asthma exacerba-tions, indicating that IgE drives allergic inflammation inasthma72. In both atopic asthma and non-atopic asthma,IgE may be produced locally by B cells in the airways73.

Interestingly, IgE secretion is not observed in patientswith COPD, but in the peripheral airways of patientswith more severe disease there is a marked increase inthe number of B cells, which are organized into lym-phoid follicles that are surrounded by T cells18. Theclass of immunoglobulin they secrete and how they

Figure 4 | Interactions between TH1 and T

H2 cells in

asthma. The transcription factorGATA3 (GATA-binding

protein 3) is regulated by interleukin-4 (IL-4) via STAT6

(signal transducer and activator of transcription 6) and

regulates the expression of IL-4, IL-5, IL-9 and IL-13 from

T helper 2 (TH2) cells and also inhibits the expression of

T-bet via inhibition of STAT4. IL-33 enhances the actions of

GATA3. T-bet regulates T helper 1 (TH1)-cell secretion of IL-2

and interferon-(IFN) and also has an inhibitory action onGATA3. T-bet is regulated by IL-12 via STAT4 and by IL-27

via STAT1. This demonstrates the complex interplay of

cytokines and transcription factors in asthma.

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Epithelial cells

Neutrophils

IL-23

IL-17 andIL-17F

IL-21

IL-22

IL-6

IL-6

TGF

TH17 cell

TNF

CD8+T cell

?

CXCL1 andCXCL8

IL-10Acute-phase

proteins

STAT3

RORt

Immunoglobulin class

switching

The somatic-recombination

process by which the class of

immunoglobulin expressed by

activated B cells is switched

from IgM to IgG, IgA or IgE.

Corticosteroids

Anti-inflammatory drugs that

are derived from cortisolsecreted by the adrenal cortex

and that are effective in

suppressing inflammation

in asthma but not in chronic

obstructive pulmonary disease.

FEV1

(Forced expiratory volume in

1 second). The amount of air

that can be forcibly exhaled in

1 second, measured in litres.

It is used as a measurement of

airway obstruction in asthma

and chronic obstructive

pulmonary disease.

are regulated is currently unknown, but they might beactivated by bacterial or viral antigens as a consequenceof the chronic bacterial colonization or latent viral infec-tion in the airways of these patients. Alternatively, it hasbeen suggested that COPD might have an autoimmunecomponent characterized by the development of newantigenic epitopes as a result of the tissue damage inducedby cigarette smoking, oxidative stress or chronic bacte-rial infection21,74. CD4+T cells isolated from the lungs ofpatients with severe emphysema are oligoclonal, which isconsistent with antigenic stimulation by infective organ-isms or autoimmunity75. Indeed, in a mouse model ofemphysema induced by tobacco smoke, an autoimmunemechanism has been proposed with a role for antibodies

specific for neutrophil elastase76.

Dendritic cells.Dendritic cells (DCs) have an impor-tant role in asthma as regulators of T

H2 cells and in

the presentation of processed peptides from inhaledallergens to T

H2 cells77. They are not only involved in

the initial sensitization to allergens, but also in drivingthe chronic inflammatory response in the lungs, andtherefore provide a link between allergen exposure andallergic inflammation in asthma. The cytokine thymicstromal lymphopoietin (TSLP), which is secreted in largeamounts by epithelial cells and mast cells of asthmaticpatients78,79, might have a critical role in the maturation

of myeloid DCs and the recruitment of TH2 cells to the

airways by inducing the release of CCL17 (also known asTARC) and CCL22 (also known as MDC), which bind toCCR4that is selectively expressed by T

H2 cells80.

Cigarette smoking is associated with an expansionof the DC population and with a marked increase inthe number of mature DCs in the airways and alveolarwalls of people who smoke81. However, the role of DCsin COPD is currently unclear as there are no obviousantigenic stimulants, apart from -glycoprotein, whichis isolated from tobacco and known to have a powerfulimmunostimulatory effect82. However, a recent electronmicroscopy study has demonstrated a decrease in DCsin the airways of patients with COPD who smoke com-pared to smokers without airway obstruction, suggestingthat they do not have a key role in COPD83.

Similarities between asthma and COPD

Although the inflammatory and immune mechanisms ofasthma and COPD described above are markedly differ-ent, there are several situations where they become more

similar and the distinction between asthma and COPDbecomes blurred (TABLE 1).

Severe asthma. Although only about 5% of the asthmaticpopulation develop severe disease, such cases account formore than half of the healthcare spending in asthma andthey are poorly controlled by currently available thera-pies84. The inflammatory pattern that occurs in cases ofsevere asthma, contrary to mild asthma, is more similarto that which occurs in COPD, with increased numbersof neutrophils in the sputum and increased amounts ofCXCL8 and tumour-necrosis factor85, increased oxidativestress and a poor response to corticosteroidsas is observedin patients with COPD (TABLE 1). Moreover, whereas inmild asthma T

H2 cells predominate, in more severe

asthmatic disease there is a mixture of TH

1 and TH

2cells present in bronchial biopsies, as well as more CD8+T cells and this more closely resembles the immune-cellinfiltration seen in COPD51,69,70. The neutrophilic inflam-mation seen in cases of severe asthma may be induced byIL-17 production by T

H17 cells, which induces the release

of the neutrophilic chemokine CXCL8 from airway epi-thelial cells59,60. A neutrophilic pattern of inflammation,with high levels of CXCL8, is also found in the sputumof asthmatic individuals who smoke86. Similar to patientswith severe disease or COPD, these individuals also havea poor response to corticosteroids, even if given orally at

high doses.

Reversible COPD.Approximately 10% of patients withCOPD have a reversibility of bronchoconstriction, show-ing greater than 12% improvement in lung function asassessed by forced expiratory volume in 1 second(FEV

1),

and therefore behave more like asthmatics. Furthermore,compared with most patients with COPD, these patientsmore frequently have eosinophils in their sputum, anincrease in exhaled nitric oxide and respond better tocorticosteroid treatment, all of which are characteristicfeatures of asthma87,88. It therefore seems likely that thesepatients have concomitant asthma and COPD.

Figure 5 | TH17 cells and airway inflammation. T helper 17

(TH17) cells are a newly described subset of CD4+T cells

that may have a role in chronic obstructive pulmonary

disease (COPD) and severe asthma. These cells release

interleukin-17 (IL-17) and IL-17F, which act on airway

epithelial cells to release CXC-chemokine ligand 1 (CXCL1)and CXCL8, which attract neutrophils, andIL-6, which

enhances the activation of TH17 cells. T

H17 cells also release

IL-21, which promotes TH17-cell differentiation via a

positive autoregulatory loop involving the transcription

factor STAT3 (signal transducer and activator of

transcription 3) and IL-22, which induces the release of

IL-10 and acute-phase proteins. The regulation of TH17 cells

is predominantly via IL-23 through the activation of the

transcription factor retinoic-acid-receptor-related orphan

receptor-t (RORt), whereas transforming growth factor-(TGF) may have an inhibitory effect in human cells.TNF, tumour-necrosis factor.

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Epithelial cells Macrophage

IFN

CXCL9, CXCL10 and CXCL11

TH1 cell TC1 cell

CXCR3

Emphysema

(apoptosis of type Ipneumocytes)Perforin andgranzyme B

Theophylline

A drug that is used at high

doses as a bronchodilator in

the treatment of asthma and

chronic obstructive pulmonary

disease. However, it is now less

widely used as the high doses

can have side effects, including

nausea, headaches, cardiac

arrhythmias and seizures.

More recently, it has been

shown to have anti-

inflammatory effects at lower

doses and may reverse

corticosteroid resistance by

increasing the activity of

histone deacetylase.

Cyclosporin A and

tacrolimus

Calcineurin inhibitors that are

used to prevent transplant

rejection and that function by

inhibiting nuclear factor of

activated T cells (NFAT).

Rapamycin

An immunosuppressive drug

that, in contrast to calcineurininhibitors, does not prevent

T-cell activation but blocks

interleukin-2-mediated clonal

expansion by blocking mTOR

(mammalian target of

rapamycin).

Mycophenolate mofetil

An immunosuppressant that

inhibits purine synthesis and

has an inhibitory effect on

T cells and B cells. It is

currently used to treat

transplant rejection and

rheumatoid arthritis.

Acute exacerbations.Acute exacerbations (worsening ofsymptoms) occur in patients with asthma and COPD,and are a major cause of patient suffering and medicalexpenditure89,90. Exacerbations in asthmatic individualsare usually triggered by upper respiratory tract infections,such as with rhinoviruses, and less commonly by inhaledallergens and air pollutants, whereas exacerbations inpatients with COPD are usually triggered by either bacte-rial or viral infections. In both diseases, exacerbations areassociated with a further increase in airway inflamma-tion, increased numbers of cells infiltrating the lungs andhigher concentrations of inflammatory mediators than arepresent in the steady state. However, there may also bechanges in the pattern of inflammation. In exacerbationsof asthma triggered by viruses, there can be increases inthe numbers of neutrophils, as well as of eosinophils 89,whereas in COPD exacerbations, particularly those due to

viruses, there may be an increase in eosinophil numbers91.So, during episodes of disease exacerbation, the pattern ofinflammation becomes similar in COPD and asthma.

Implications for therapyIn view of the different inflammatory and immunepatterns of asthma and COPD, it is not surprising thatthey should respond differently to anti-inflammatorytherapies.

Corticosteroid responsiveness.Asthma is usually highlyresponsive to corticosteroid therapy and inhaled cor-ticosteroids have become the mainstay of diseasemanagement. Corticosteroids suppress inflammationby inducing the recruitment of the nuclear enzymehistone deacetylase 2 (HDAC2) to multiple activatedinflammatory genes, which leads to deacetylation of thehyperacetylated genes, thereby suppressing inflamma-tion92. By contrast, patients with COPD respond poorlyto corticosteroid treatment, and even high doses ofinhaled or oral corticosteroids fail to suppress inflam-mation. This appears to be related to decreased activityand expression of HDAC2 in the inflammatory cells andperipheral lungs of COPD patients93. This is the result ofincreased oxidative and nitrative stress, which togethergenerate peroxynitrite that nitrates tyrosine residuesin HDAC2, impairing enzyme activity and decreasingexpression93,94. The poor response to corticosteroid treat-ment seen in patients with severe asthma, in asthmaticswho smoke and during acute exacerbations may alsoreflect a reduction in HDAC2 protein levels and func-

tion, as oxidative and nitrative stress are also increasedin these situations95. So, patients with severe asthma havea relative corticosteroid resistance, and this is linked toimpaired HDAC2 function96,97. Reversal of corticosteroidresistance may therefore be a useful therapeutic strategyin the future for patients with COPD and severe asthma.Interestingly, low concentrations of the drug theophylline,which was previously used at high doses as a bronchodi-lator in the treatment of asthma and COPD, are able torestore HDAC2 activity in vitroto normal levels andhave been shown to reverse corticosteroid resistance incells from COPD patients, so may provide a means ofrestoring corticosteroid responsiveness clinically98.

Immunomodulation. Specific immunotherapy to inhibitallergic responses has been successful in treating individ-uals with hay fever, in which there is a single type of aller-gen involved, but so far such an approach has not provedto be very effective for treating asthma and, because itis potentially dangerous through triggering anaphylacticresponses, it is not recommended in current treatmentguidelines. More effective and safer immunotherapy forasthma using DNA vaccines, T-cell peptides and sublin-gual immunotherapy is currently under investigation99.

Suppression of T cells may be a useful therapeuticapproach in the treatment of asthma and COPD, giventheir role in driving inflammation in both diseases.Cyclosporin A, a non-selective inhibitor of T cells, althoughearly studies showed it had some clinical benefit100, it hassubsequently been found to be of little benefit to asthmat-ics in several clinical trials and is now not recommendedas a therapy, particularly in view of its toxicity101. Less-toxic immunomodulators, such as tacrolimus, rapamycinand mycophenolate mofetil (CellCept; Roche), which arecurrently used in the prevention of transplantation rejec-

tion, have not been tested in clinical studies of asthmaand there are no studies assessing the efficacy of immuno-suppressants in patients with COPD. More specificimmunomodulators that selectively inhibit T

H2 cells have

been sought for the treatment of asthma, as yet withoutsuccess. Suplatast tosilate (IPD; Taiho Pharmaceutical)is a drug that apparently inhibits T

H2 cells and T

H2-type

cytokine release102, but its mechanisms of action are notknown. It has only weak clinical effects and is currentlyonly available in Japan. In COPD patients, treatmentsthat target CD8+T cells might be more appropriate.

Figure 6 | CD8+T cells in chronic obstructive

pulmonary disease (COPD). Epithelial cells and

macrophages are stimulated by interferon-(IFN) torelease the chemokines CXC-chemokine ligand 9 (CXCL9),

CXCL10 and CXCL11, which together act on CXC-

chemokine receptor 3 (CXCR3) expressed on T helper 1

(TH1) cells and type 1 cytotoxic T (T

C1) cells to attract them

into the lungs. TC1 cells, through the release of perforin and

granzyme B, induce apoptosis of type I pneumocytes,

thereby contributing to emphysema. IFNreleased by TH1

and TC1 cells then stimulates further release of CXCR3

ligands, resulting in a persistent inflammatory activation.

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Given the role of B cells in both asthma and COPD,non-selective B-cell inhibitors, such as the CD20-specific monoclonal antibody rituximab (Rituxan;Genentech, Inc. and Biogen Idec) might be beneficial,as it is in rheumatoid arthritis and other autoimmunediseases103. However, there are concerns about the safetyof using rituximab, particularly in COPD patients whoare susceptible to recurrent bacterial infections, as theairways of patients with more severe disease are oftencolonized by bacteria.

Other novel therapeutic approaches.Several noveltherapeutic approaches are currently in developmentfor treating inflammation in asthma and COPD104,105,for example, one type of therapy involves targeting spe-cific transcription factors that are known to be active inthese diseases106. In both airway diseases, NF-B acti-

vation appears to be important for activating multiple

but different inflammatory genes, so inhibition of thistranscription factor using small molecule inhibitors ofIKK2 (inhibitor of NF-B kinase 2) would be a logicalapproach. For the treatment of asthma, inhibition ofGATA3 function and therefore T

H2-type cytokine pro-

duction may be a more specific approach and this mightbe possible using inhibitors of the GATA3-activatingkinase p38 MAPK39. Indeed, downregulation of p38MAPK expression using an antisense oligonucleotidehas proved to be effective in inhibiting T

H2-type cytokine

production in a mouse model of asthma107. For the treat-ment of COPD, inhibition of the T

H1-cell-inducing tran-

scription factor T-bet would be more appropriate and

this could be achieved by blocking STAT4 activity, butno such drugs have so far been developed.

Given that chemokines are crucial mediators inthe recruitment of inflammatory cells to the lungs ofpatients with asthma and COPD, antagonism of spe-cific chemokine receptors would be a logical approachfor treating these diseases108,109. In asthma, chemokinereceptors on eosinophils (CCR3) and T

H2 cells (CCR4,

CCR8 and CXCR4) are the main targets, whereas inCOPD, receptors on neutrophils (CXCR2), monocytes(CXCR2 and CCR2), T

H1 cells (CXCR3) and T

C1 cells

(CXCR3) are the major foci of drug development. Smallmolecule inhibitors for all of these receptors are nowin development.

Conclusions and future perspectives

Although both COPD and asthma involve chronicinflammation of the respiratory tract, the pattern of

inflammation is markedly different between these twodiseases. Mild asthma is characterized by eosinophilicinflammation driven by T

H2 cells and DCs, and is asso-

ciated with mast-cell sensitization by IgE, and by therelease of multiple bronchoconstrictors. By contrast,COPD is characterized by neutrophilic inflammationthat can be driven by a marked increase in the numberof lung-resident macrophages, which also attract CD4+and CD8+T cells to the lungs. This lymphocytic infil-tration can also be driven by chronic stimulation by

viral and bacterial antigens or by autoantigens releasedfollowing lung injury. Mast cells and DCs, which havesuch a key role in asthma, have little or no known

Table 1 | Comparison between patterns of inflammation in asthma and COPD

Asthma COPD Refs

Mild Severe Exacerbation Mild Severe Exacerbation

Neutrophils 0 ++ ++++ ++ +++ ++++ 7

Eosinophils + ++ +++ 0 0 + 110,111

Mast cells ++ +++ +++? 0 0 ? 7,26,112

Macrophages + + ? +++ ++++ ++++ 113

T cells TH2 cells: ++

iNKT cells: ?T

H1 cells: +

TH2 cells: +

TC1 cells: +

TC2 cells: +?

TH17 cells: ?

? TC1 cells: + T

C1 cells: +++

TH1 cells: +++

TH17 cells: ?

? 18,66,114

B cells IgE producing IgE producing ? + +++ ? 18,73

Dendritic cells + ? ? +? +? ? 115

Chemokines CCL11: + CXCL8: + CXCL8: ++ CXCL8: +CXCL1: +CCL2: +

CXCL8: ++ CXCL8: +++ 116

Cytokines IL-4: ++IL-5: ++IL-13: ++

TNF: ++ ? TNF: + TNF: ++ TNF: +++ 117,118

Lipid mediators LTD4: ++

PGD2: +

LTB4: ++

PGD2: +

? LTB4: + LTB

4: ++ LTB

4: +++ 10,11

Oxidative stress 0 ++ +++ ++ +++ ++++ 119122

Steroid response ++++ ++ + 0 0 0 92

0, no response; + to ++++, magnitude scale; ?, uncertain. CCL, CC-chemokine ligand; COPD, chronic obstructive pulmonary disease; CXCL, CXC-chemokine ligand;iNKT, invariant natural killer T; LTB

4, leukotriene B

4; LTD

4, leukotriene D

4; PGD

2, prostaglandin D

2; T

C1, type 1 cytotoxic T; T

H, T helper; TNF, tumour-necrosis factor.

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involvement in COPD. However, these distinctionsbetween asthma and COPD may not be as clear aspreviously believed, as in patients with severe asthmaand in asthmatic individuals who smoke there is aneutrophilic pattern of inflammation, and acute exac-erbations of asthma and of COPD have similar inflam-matory features. The role of T

H17 cells in severe asthma

and COPD as a driving mechanism of neutrophilicinflammation is not yet fully understood and deservesmore research; understanding these mechanisms maylead to new therapeutic approaches.

New therapeutic approaches may also stem from agreater understanding and appreciation of the similaritiesbetween asthma and COPD. Although there are highlyeffective treatments for mild asthma, severe asthma andasthma in people who smoke are poorly treated with cur-rent therapies and because of the similarities with COPD,it is likely that new anti-inflammatory treatments thatare effective in COPD may also be effective in refractoryasthma. Whether therapies based on the immune mecha-nisms will be safe and effective in treating airway diseasesalso deserves further research.

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for chronic obstructive pulmonary disease. Lancet

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protein kinase antisense oligonucleotide attenuatesasthma in mice.Am. J. Respir. Crit. Care Med.171,

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chemokines and their role in asthmatic responses.Eur. J. Pharmacol.533, 277288 (2006).

109. Donnelly, L. E. & Barnes, P. J. Chemokine receptors as

therapeutic targets in chronic obstructive pulmonarydisease. Trends Pharmacol . Sci.27, 546553

(2006).110. Saetta, M. et al.Airway eosinophilia and expression of

interleukin-5 protein in asthma and in exacerbationsof chronic bronchitis. Clin. Exp. Allergy26, 766774

(1996).111. Zhu, J. et al.Exacerbations of bronchitis: bronchial

eosinophilia and gene expression for interleukin-4,interleukin-5, and eosinophil chemoattractants.

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COPD is similar in smokers and ex-smokers: a pooledanalysis. Eur. Respir. J.30, 467471 (2007).

113. Retamales, I. et al.Amplification of inflammation in

emphysema and its association with latent adenoviralinfection.Am. J. Respir. Crit. Care Med.164,

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(atopic) and intrinsic (non-atopic) asthma: moresimilarities than differences. Immunol. Today20,

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the bronchial mucosa of patients with atopic asthmain response to local allergen challenge. Thorax56,

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Chemokines and their receptors in chronic pulmonarydisease. Curr. Drug Targets Inflamm. Allergy4,313317 (2005).

117. Chung, K. F. & Barnes, P. J. Cytokines in asthma.

Thorax54, 825857 (1999).118. Chung, K. F. Cytokines in chronic obstructive pulmonary

disease. Eur. Respir. J.34, 50S59S (2001).119. Montuschi, P. et al.Increased 8-Isoprostane, a marker

of oxidative stress, in exhaled condensates of

asthmatic patients.Am. J. Respir. Crit. Care Med.160, 216220 (1999).

120. Paredi, P., Kharitonov, S. A. & Barnes, P. J. Elevationof exhaled ethane concentration in asthma.Am. J.

Respir. Crit. Care Med.162, 14501454 (2000).121. Montuschi, P. et al.Exhaled 8-isoprostane as an

in vivobiomarker of lung oxidative stress in patientswith COPD and healthy smokers.Am. J. Respir. Crit.

Care Med.162, 11751177 (2000).122. Rahman, I., Biswas, S. K. & Kode, A. Oxidant and

antioxidant balance in the airways and airway

diseases. Eur. J. Pharmacol.533, 222239 (2006).

DATABASESEntrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

CCR2| CCR3| CCR4|CXCR2| CXCR3|CXCR4|GATA3|

IFN|IL-4|IL-5| IL-6| IL-9| IL-13|IL-17|IL-33|p38|TSLP

FURTHER INFORMATIONPeter Barness homepage:http://www1.imperial.ac.uk/

medicine/people/p.j.barnes.html

ALL LINKS ARE ACTIVE IN THE ONLINE PDF

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