Immunology of asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are both very common and their incidence is increasing globally, placing an increasing burden on health services in industrialized and developing countries1–3. Both diseases are characterized by airway obstruction, which is variable and reversible in asthma but is progressive and largely irreversible in COPD. In both diseases, there is chronic inflammation of the respiratory tract, which is mediated by the increased expression of multiple inflammatory proteins, including cytokines, chemokines, adhesion molecules, inflamma-tory enzymes and receptors. In both diseases there are acute episodes or exacerbations, when the intensity of this inflammation increases. The similarity between these airway diseases prompted the suggestion in the 1960s that asthma and COPD are different forms of a common disease (chronic obstructive lung disease), and this came to be known as the ‘Dutch hypothesis’. This was countered by the ‘British hypothesis’, which maintained that these diseases were separate entities; the debate continues today, with evidence both for and against these two views4,5.

Despite the similarity of some clinical features of asthma and COPD, there are marked differences in the pattern of inflammation that occurs in the respiratory tract, with different inflammatory cells recruited, dif-ferent mediators produced, distinct consequences of inflammation and differing responses to therapy. In addition, the inflammation seen in asthma is mainly located in the larger conducting airways, and although small airways can also be affected in more severe forms

of the disease, the lung parenchyma is not affected. By contrast, COPD predominantly affects the small airways and the lung parenchyma, although similar inflamma-tory changes can also be found in larger airways6,7. These differences in disease distribution may partly reflect the distribution of inhaled inciting agents, such as allergens in asthma and tobacco smoke in COPD. In both dis-eases, there are different clinical phenotypes recognized. Most patients with asthma are atopic (extrinsic asthma), but a few patients are non-atopic (intrinsic asthma), and these patients often have a more severe form of the dis-ease8. There is a range of asthma severity, which tends to be maintained throughout life9. Approximately 5% of patients have severe asthma that is difficult to con-trol with maximal inhaler therapy and for whom new therapeutic approaches are needed. The main types of COPD are the development of small-airway obstruction and emphysema, which can occur alone or together, but which both involve progressive airflow limitation and are usually caused by tobacco smoke.

The differences in inflammation between asthma and COPD are linked to differences in the immuno-logical mechanisms that underlie these two diseases (FIGS 1,2). There have been several recent important advances in our understanding of the immunopathol-ogy of asthma and COPD, and these are discussed in this Review. T cells have a crucial role in both asthma and COPD and it is now recognized that different sub-sets are involved in orchestrating inflammation in these two diseases, resulting in different inflammatory and structural consequences. B cells also have an important

Airway Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. e-mail: [email protected]:10.1038/nri2254Published online15 February 2008

Chronic obstructive pulmonary disease(COPD). A group of diseases characterized by the pathological limitation of airflow in the airway, including chronic obstructive bronchitis and emphysema. It is most often caused by tobacco smoking, but can also be caused by other airborne irritants, such as coal dust, and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.

Atopic (extrinsic) asthmaThe commonest form of asthma in which the patients are atopic (as indicated by a positive skin-prick test and the presence of IgE to common inhalant allergens, such as house-dust mites) and have allergic inflammation of the airways.

Immunology of asthma and chronic obstructive pulmonary diseasePeter J. Barnes

Abstract | Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive airway diseases that involve chronic inflammation of the respiratory tract, but the type of inflammation is markedly different between these diseases, with different patterns of inflammatory cells and mediators being involved. As described in this Review, these inflammatory profiles are largely determined by the involvement of different immune cells, which orchestrate the recruitment and activation of inflammatory cells that drive the distinct patterns of structural changes in these diseases. However, it is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations. This has important implications for the development of new therapies.

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f o c u S o n a l l E R g Y a n d a S t h m a

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Nature Reviews | Immunology

Eosinophilic inflammation

Dendritic cell

Epithelial cells

Mast cell

Inhaled allergens

CCL11

B cell

TSLP

TH2 cell

CCR4

CCR3

Bronchoconstriction

CCL17 andCCL22

↓ TReg cells?

IgE

Histamine, cysteinyl leukotrienes and prostaglandin D2

IL-13

IL-9

IL-5

SCF

Antibody production

Smooth-muscle cell

Eosinophil

IL-4

Non-atopic (intrinsic) asthmaAn uncommon form of asthma that is more likely to be severe and characterized by negative skin-prick tests. The airway inflammation is similar to that of atopic asthma and may be mediated by local rather than systemic IgE production.

EmphysemaDestruction 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 are involved in both asthma and COPD has important implications for the development of new therapies for these troublesome diseases.

Inflammatory cells and mediatorsThere are many differences between mild asthma and COPD in the type of inflammation that occurs in the lungs, with a different range of inflammatory cells and mediators being implicated10,11. however, many of the cytokines and chemokines that are secreted in both asthma and COPD are regulated by the transcription factor nuclear factor-κB (nF-κB), which is activated in airway epithelial cells and macrophages in both diseases, and may have an important role in amplifying airway inflammation12,13.

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

at the airway surface and activated T cells. There are characteristic structural changes, with collagen deposi-tion under the epithelium that is sometimes described as basement-membrane thickening and is found in all patients with asthma, and thickening of the airway smooth-muscle cell layer as a result of hyperplasia and hypertrophy, which is more commonly seen in patients with severe asthma14. epithelial cells are often shed from asthmatic patient biopsies compared to normal control biopsies, as they are friable and more easily detach from the 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 from asthmatic patients, with an increase in the number of mucus-secreting goblet cells in the epithelium and an increase in the size of submucosal glands16.

In biopsies of the bronchial airways, small airways and lung parenchyma from patients with COPD, there is no evidence for mast-cell activation, but there is an infiltra-tion of T cells and increased numbers of neutrophils, particularly in the airway lumen17. subepithelial fibrosis is not apparent, but fibrosis does occur around small air-ways and is thought to be a main factor that contributes to the irreversible airway narrowing that is characteristic of this disease18. The airway smooth-muscle cell layer is not usually increased in COPD patients compared with normal airways, and airway epithelial cells may show pseudostratification as a result of chronic irritation from inhaled cigarette smoke or other irritants and the release of epithelial-cell growth factors. As in biopsies from asthma patients, there is mucus hyperplasia and increased expression of mucin genes in biopsies from patients with COPD19. A marked difference between COPD and asthma is the destruction of alveolar walls (emphysema) that occurs in COPD as a result of protease-mediated degradation of connective tissue elements, particularly elastin, and apoptosis of type I pneumocytes and pos-sibly endothelial cells20,21. In addition, the production of elastolytic enzymes, such as neutrophil elastase and particularly several matrix metalloproteinases (MMPs), is increased in the lungs of COPD patients22, and there may be a reduction in the levels of antiproteinases, such as α1-antitrypsin, as seen in a rare form of emphysema caused by a congenital deficiency of α1-antitrypsin23.

Mast cells. Mast cells have a key role in asthma through the release of several bronchoconstrictors, including histamine, which is preformed and stored in granules, and the lipid mediators leukotriene C4, leukotriene D4, leukotriene e4 and prostaglandin D2, which are synthe-sized following mast-cell activation. The release of these mediators may account for the variable bronchocon-striction seen in asthma, as these mediators are released by various environmental triggers, such as allergens, and an increase in plasma osmolality as a result of increased ventilation during exercise. Mucosal mast cells are recruited to the surface of the airways by stem-cell factor (sCF; also known as KIT ligand) released from epithelial cells, which acts on KIT receptors expressed by the

Figure 1 |inflammatoryandimmunecellsinvolvedinasthma.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. TH2 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 recruits eosinophils via CCR3. Patients with asthma may have a defect in regulatory T (TReg) cells, which may favour further TH2-cell proliferation.

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Epithelial cells Macrophage

Airwayepithelialcell

Fibroblast Neutrophil Monocyte

Cigarette smoke(and other irritants)

CXCL9, CXCL10 and CXCL11

TH1 cell TC1 cell

CXCR3

TGFβ

CCL2

CCR2

Proteases (such as neutrophil elastase and MMP9)

Alveolar wall destruction(emphysema)

Mucus gland

Mucus hypersecretion

CXCL1and CXCL8

CXCR2

Fibrosis(small airways)

Smooth-musclecell

Alveoli Gobletcell

Mucus

PseudostratificationIncreased 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 pneumocytesFlat 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.

BronchoconstrictorAn 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 are linked to allergic inflammation, including interleukin-4 (Il-4), Il-5 and Il-13 (REF. 25). The presence of mast cells in the airway smooth muscle has been linked to airway hyper-responsiveness in asthma26, as patients with eosinophilic bronchitis have a similar degree of eosino-philic inflammation to that found in asthmatics and also have subepithelial fibrosis, but they do not show airway hyper-responsiveness, which is the physiological hallmark of asthma. By contrast, mast cells do not seem to have a role in COPD, which may explain the lack of variable bronchoconstriction in this disease.

Granulocytes. The inflammation that occurs in asthma is often described as eosinophilic, whereas that occurring in COPD is described as neutrophilic. These differences reflect the secretion of different chemotactic factors in these diseases. In asthma, eosinophil chemotactic factors, such as CC-chemokine ligand 11 (CCl11; also known as eotaxin-1) and related CC-chemokines, are mainly secreted by airway epithelial cells. The functional role of

eosinophils in asthma is not clear and the evidence that links their presence to airway hyper-responsiveness has been questioned by the finding that the administration of Il-5-specific blocking antibodies that markedly reduce the number of eosinophils in the blood and sputum does not reduce airway hyper-responsiveness or asthma symptoms27,28. As discussed above, eosinophilic bronchi-tis is not associated with airway hyper-responsiveness, but subepithelial fibrosis does occur, which suggests a role for eosinophils in airway fibrosis. Interestingly, the presence of eosinophils seems to be a good marker of steroid responsiveness29.

neutrophils are increased in the sputum of patients with COPD and this correlates with disease severity30. The increase in neutrophils is related to an increase in the production of CXC-chemokines, such as CXC-chemokine ligand 1 (CXCl1; also known as GROα) and CXCl8 (also known as Il-8), which act on CXCR2 that is 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, which migrate to the lungs in response to chemoattractants such as CCl2 (also known as MCP1) acting on CCR2, and CXCl1 acting on CXCR2 (REF. 31). There is increasing evidence that lung macrophages orchestrate the inflam-mation of COPD through the release of chemokines that attract neutrophils, monocytes and T cells and the release of proteases, particularly MMP9 (REF. 32).

The pattern of inflammatory cells found in the res-piratory tract therefore differs in patients with asthma and those with COPD and some of these contrasts may be explained by differences in the immunological mechanisms that drive these two diseases.

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

T cells. In asthmatic patients, there is an increase in the number of CD4+ T cells in the airways and these are pre-dominantly T helper 2 (TH2) cells, whereas in normal air-ways TH1 cells predominate33. 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 and drives the differentiation of mast cells34, Th2 cells have a central role in allergic inflammation and therefore their regulation is an area of intense research.

The transcription factor GATA3 (GATA-binding pro-tein 3) is crucial for the differentiation of uncommitted naive T cells into Th2 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 | inflammatoryandimmunecellsinvolvedinchronicobstructivepulmonarydisease(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 (TC1) 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-β (TGFβ), which stimulates fibroblast proliferation, resulting in fibrosis in the small airways.

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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3565&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum







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-responsivenessIncreased 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 of TH1–TH2-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-γ 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-presenting cells, T-cell GATA3 is phosphorylated and activated by the mitogen-activated protein kinase (MAPK) p38. Activated GATA3 then translocates from the cytoplasm to the nucleus, where it activates gene transcription39. GATA3 expression in T cells is regulated by the tran-scription factor sTAT6 (signal transducer and activator of transcription 6), which is in turn regulated by Il-4 receptor activation.

For Th1-cell differentiation and secretion of the Th1-type cytokine interferon-γ (IFnγ), the crucial transcrip-tion factor is T-bet. Consistent with the prominent role of Th2 cells in asthma, T-bet expression is reduced in T cells from the airways of asthmatic patients compared with non-asthmatic subjects40. when phosphorylated, T-bet can associate with and inhibit the function of GATA3, by preventing it from binding to its DnA target sequences41. T-bet-deficient mice show increased expres-sion of GATA3 and production of Th2-type cytokines, confirming that T-bet is an important regulator of GATA3 (REF. 40). GATA3 expression is also regulated by Il-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 Th1-type cytokines by inhibiting sTAT4, the key transcription factor activated by the T-bet-inducing cytokine Il-12 (REF. 43) (FIG. 4). nuclear factor of activated T cells (nFAT) is a T-cell-specific transcription factor and appears to enhance the transcriptional activation of GATA3 by targeting the IL4 promoter44. Finally, Il-33, a newly discovered member of the Il-1 family of cytokines, seems to promote Th2-cell differentiation by translocat-ing to the nucleus and regulating transcription through an effect on chromatin structure45, but it also acts as a selective chemoattractant of Th2 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 are mainly Th1 cells. Th1 cells express the chemokine recep-tor CXCR3 (REF. 47) and may be attracted to the lungs by the IFnγ-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 present at high levels in COPD airways48,49. however, there is some evidence that Th2 cells are also increased in lavage fluid of patients with COPD50; likewise, in patients with more severe asthma, Th1 cells are activated, as well as

Figure 3 | Contrastinghistopathologyofasthmaandchronicobstructivepulmonarydisease(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; TH1, 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 IFNγ)

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

STAT6

GATA3

Allergic inflammation

Regulatory T cellsA 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 rhinitisAllergic 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 RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

Invariant natural killer T (iNKT) cellsLymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα (joining) gene segment to yield T-cell receptor α-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 α-galactosylceramide is bound in the groove of CD1d.

Type 1 cytotoxic T (TC1) and TC2 cellsA designation that is used to describe subsets of CD8+ cytotoxic T cells. TC1 cells typically secrete interferon-γ 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 Th-cell patterns in these two diseases less clear.

Other subtypes of CD4+ T cells that may have an important role in airway diseases are regulatory T cells, which have a suppressive effect on other CD4+ T cells and may have a role in regulating Th2-cell function in asthma33,52. There is evidence that the numbers of CD4+CD25+ regulatory T cells that express the tran-scription factor forkhead box P3 (FOXP3) are reduced in individuals with allergic rhinitis (hay fever) compared with non-atopic individuals, and this may be important in enabling high numbers of Th2 cells to develop in aller-gic disease53. however, by contrast, asthmatic patients seem to have an increase in FOXP3-expressing regula-tory T cells compared with patients with mild asthma, at least among circulating cells54. Analysis of sputum from COPD patients suggests that the numbers of CD4+CD25+FOXP3+ regulatory T cells are reduced, but similar changes are also seen in people who smoke but do not have airflow obstruction55. so, the role of regulatory T cells in asthma and COPD remains unclear and fur-ther research is therefore needed, particularly in defining the 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 an important role in inflammatory and autoimmune dis-eases57,58. little is known about the role of Th17 cells in asthma or COPD, but increased concentrations of Il-17 (the predominant product of Th17 cells) have been reported in the sputum of asthma patients59. Il-17 and the closely related cytokine Il-17F have been linked to neutrophilic inflammation by inducing the release of CXCl1 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 and thus acts as a positive autoregulatory mechanism, but it also inhibits FOXP3 expression and regulatory T-cell development61,62. Another cytokine Il-22 is also released by these cells and stimulates the production of Il-10 and acute-phase proteins63. however, more work is needed to understand the role and regulation of Th17 cells in asthma and COPD, as they may represent important new 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 shown to account for 60% of all CD4+ T cells in bronchial biop-sies from asthmatic patients64, but this has been disputed in another study that failed to show any increase in inKT-cell numbers in bronchial biopsies, bronchoalveolar lavage or sputum of either asthma or COPD patients65. The role of inKT cells in asthma is currently uncertain as there appears to be a discrepancy between the data from murine models of asthma and humans with the disease33.

CD8+ T cells predominate over CD4+ T cells in the airways and lung parenchyma of patients with COPD66, but their role in disease pathogenesis is not yet certain. Type 1 cytotoxic T (TC1) cells, which secrete IFnγ, predomi-nate and express CXCR3, suggesting that they are attracted to the lungs by CXCR3-binding chemokines47,49. These CXCR3 ligands suppress signalling through CCR3, the receptor 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 COPD patients compared with controls and may also be involved in T-cell recruitment49. TC1 cells release granzyme B and perforins, which are also present at higher levels in the sputum of COPD patients than normal control subjects who also smoke68, and may induce apoptosis of type 1 pneumocytes, thereby contributing to the development of emphysema20. TC1- and Th1-cell-driven inflammation is likely to be self-perpetuating as IFnγ stimulates the release of CXCR3 ligands, which then attract more Th1 and TC1 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 disease and irreversible airflow obstruction69 and these cells may be of either the TC1 or TC2 type70.

B cells. B cells have an important role in allergic diseases, including asthma, through the release of allergen-specific Ige which binds to high-affinity Fc receptors for Ige (FcεRI) expressed by mast cells and basophils, and to low-affinity Fc receptors for Ige (FcεRII) expressed by other inflammatory cells, including B cells, macrophages and possibly eosinophils71. The Th2-type cytokines Il-4 and Il-13 induce B cells to undergo immunoglobulin class switching to produce Ige. Blocking Ige with the mono-clonal antibody omalizumab reduces the response to allergens, airway inflammation and asthma exacerba-tions, indicating that Ige drives allergic inflammation in asthma72. 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 patients with COPD, but in the peripheral airways of patients with more severe disease there is a marked increase in the number of B cells, which are organized into lym-phoid follicles that are surrounded by T cells18. The class of immunoglobulin they secrete and how they

Figure 4 | interactionsbetweenTH1andTH2cellsinasthma.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-γ (IFNγ) and also has an inhibitory action on GATA3. 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 cellsNeutrophils

IL-23

IL-17 andIL-17F

IL-21

IL-22

IL-6

IL-6

TGFβ

TH17 cell

TNF

CD8+ T cell

?

CXCL1 andCXCL8

↑ IL-10↑ Acute-phase proteins

STAT3RORγt

Immunoglobulin class switchingThe somatic-recombination process by which the class of immunoglobulin expressed by activated B cells is switched from IgM to IgG, IgA or IgE.

CorticosteroidsAnti-inflammatory drugs that are derived from cortisol secreted 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 be activated by bacterial or viral antigens as a consequence of the chronic bacterial colonization or latent viral infec-tion in the airways of these patients. Alternatively, it has been suggested that COPD might have an autoimmune component characterized by the development of new antigenic epitopes as a result of the tissue damage induced by cigarette smoking, oxidative stress or chronic bacte-rial infection21,74. CD4+ T cells isolated from the lungs of patients with severe emphysema are oligoclonal, which is consistent with antigenic stimulation by infective organ-isms or autoimmunity75. Indeed, in a mouse model of emphysema induced by tobacco smoke, an autoimmune mechanism 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 Th2 cells and in the presentation of processed peptides from inhaled allergens to Th2 cells77. They are not only involved in the initial sensitization to allergens, but also in driving the chronic inflammatory response in the lungs, and therefore provide a link between allergen exposure and allergic inflammation in asthma. The cytokine thymic stromal lymphopoietin (TslP), which is secreted in large amounts by epithelial cells and mast cells of asthmatic patients78,79, 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 as TARC) and CCl22 (also known as MDC), which bind to CCR4 that is selectively expressed by Th2 cells80.

Cigarette smoking is associated with an expansion of the DC population and with a marked increase in the number of mature DCs in the airways and alveolar walls of people who smoke81. however, the role of DCs in COPD is currently unclear as there are no obvious antigenic stimulants, apart from α-glycoprotein, which is isolated from tobacco and known to have a powerful immunostimulatory effect82. however, a recent electron microscopy study has demonstrated a decrease in DCs in the airways of patients with COPD who smoke com-pared to smokers without airway obstruction, suggesting that they do not have a key role in COPD83.

Similarities between asthma and COPDAlthough the inflammatory and immune mechanisms of asthma and COPD described above are markedly differ-ent, there are several situations where they become more similar and the distinction between asthma and COPD becomes blurred (TABLE 1).

Severe asthma. Although only about 5% of the asthmatic population develop severe disease, such cases account for more than half of the healthcare spending in asthma and they are poorly controlled by currently available thera-pies84. The inflammatory pattern that occurs in cases of severe asthma, contrary to mild asthma, is more similar to that which occurs in COPD, with increased numbers of neutrophils in the sputum and increased amounts of CXCl8 and tumour-necrosis factor85, increased oxidative stress and a poor response to corticosteroids as is observed in patients with COPD (TABLE 1). Moreover, whereas in mild asthma Th2 cells predominate, in more severe asthmatic disease there is a mixture of Th1 and Th2 cells present in bronchial biopsies, as well as more CD8+ T cells and this more closely resembles the immune-cell infiltration seen in COPD51,69,70. The neutrophilic inflam-mation seen in cases of severe asthma may be induced by Il-17 production by Th17 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 sputum of asthmatic individuals who smoke86. similar to patients with severe disease or COPD, these individuals also have a poor response to corticosteroids, even if given orally at high doses.

Reversible COPD. Approximately 10% of patients with COPD have a reversibility of bronchoconstriction, show-ing greater than 12% improvement in lung function as assessed by forced expiratory volume in 1 second (FEV1), and therefore behave more like asthmatics. Furthermore, compared with most patients with COPD, these patients more frequently have eosinophils in their sputum, an increase in exhaled nitric oxide and respond better to corticosteroid treatment, all of which are characteristic features of asthma87,88. It therefore seems likely that these patients have concomitant asthma and COPD.

Figure 5 | TH17cellsandairwayinflammation.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, and IL-6, which enhances the activation of TH17 cells. TH17 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-γt (RORγt), whereas transforming growth factor-β (TGFβ) may have an inhibitory effect in human cells. TNF, tumour-necrosis factor.

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Epithelial cells Macrophage

IFNγ

CXCL9, CXCL10 and CXCL11

TH1 cell TC1 cell

CXCR3

Emphysema (apoptosis of type Ipneumocytes)

Perforin andgranzyme B

TheophyllineA 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 tacrolimusCalcineurin inhibitors that are used to prevent transplant rejection and that function by inhibiting nuclear factor of activated T cells (NFAT).

RapamycinAn immunosuppressive drug that, in contrast to calcineurin inhibitors, does not prevent T-cell activation but blocks interleukin-2-mediated clonal expansion by blocking mTOR (mammalian target of rapamycin).

Mycophenolate mofetilAn 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 of symptoms) occur in patients with asthma and COPD, and are a major cause of patient suffering and medical expenditure89,90. exacerbations in asthmatic individuals are usually triggered by upper respiratory tract infections, such as with rhinoviruses, and less commonly by inhaled allergens and air pollutants, whereas exacerbations in patients with COPD are usually triggered by either bacte-rial or viral infections. In both diseases, exacerbations are associated with a further increase in airway inflamma-tion, increased numbers of cells infiltrating the lungs and higher concentrations of inflammatory mediators than are present in the steady state. however, there may also be changes in the pattern of inflammation. In exacerbations of asthma triggered by viruses, there can be increases in the numbers of neutrophils, as well as of eosinophils89, 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 of inflammation becomes similar in COPD and asthma.

Implications for therapyIn view of the different inflammatory and immune patterns of asthma and COPD, it is not surprising that they should respond differently to anti-inflammatory therapies.

Corticosteroid responsiveness. Asthma is usually highly responsive to corticosteroid therapy and inhaled cor-ticosteroids have become the mainstay of disease management. Corticosteroids suppress inflammation by inducing the recruitment of the nuclear enzyme histone deacetylase 2 (hDAC2) to multiple activated inflammatory genes, which leads to deacetylation of the hyperacetylated genes, thereby suppressing inflamma-tion92. By contrast, patients with COPD respond poorly to corticosteroid treatment, and even high doses of inhaled or oral corticosteroids fail to suppress inflam-mation. This appears to be related to decreased activity and expression of hDAC2 in the inflammatory cells and peripheral lungs of COPD patients93. This is the result of increased oxidative and nitrative stress, which together generate peroxynitrite that nitrates tyrosine residues in hDAC2, impairing enzyme activity and decreasing expression93,94. The poor response to corticosteroid treat-ment seen in patients with severe asthma, in asthmatics who smoke and during acute exacerbations may also reflect a reduction in hDAC2 protein levels and func-tion, as oxidative and nitrative stress are also increased in these situations95. so, patients with severe asthma have a relative corticosteroid resistance, and this is linked to impaired hDAC2 function96,97. Reversal of corticosteroid resistance may therefore be a useful therapeutic strategy in 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 to restore hDAC2 activity in vitro to normal levels and have been shown to reverse corticosteroid resistance in cells from COPD patients, so may provide a means of restoring corticosteroid responsiveness clinically98.

Immunomodulation. specific immunotherapy to inhibit allergic 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 proved to be very effective for treating asthma and, because it is potentially dangerous through triggering anaphylactic responses, it is not recommended in current treatment guidelines. More effective and safer immunotherapy for asthma using DnA vaccines, T-cell peptides and sublin-gual immunotherapy is currently under investigation99.

suppression of T cells may be a useful therapeutic approach in the treatment of asthma and COPD, given their role in driving inflammation in both diseases. Cyclosporin A, a non-selective inhibitor of T cells, although early studies showed it had some clinical benefit100, it has subsequently been found to be of little benefit to asthmat-ics in several clinical trials and is now not recommended as a therapy, particularly in view of its toxicity101. less-toxic immunomodulators, such as tacrolimus, rapamycin and mycophenolate mofetil (CellCept; Roche), which are currently used in the prevention of transplantation rejec-tion, have not been tested in clinical studies of asthma and there are no studies assessing the efficacy of immuno-suppressants in patients with COPD. More specific immunomodulators that selectively inhibit Th2 cells have been sought for the treatment of asthma, as yet without success. suplatast tosilate (IPD; Taiho Pharmaceutical) is a drug that apparently inhibits Th2 cells and Th2-type cytokine release102, but its mechanisms of action are not known. It has only weak clinical effects and is currently only available in Japan. In COPD patients, treatments that target CD8+ T cells might be more appropriate.

Figure 6 | CD8+Tcellsinchronicobstructivepulmonarydisease(CoPD).Epithelial cells and macrophages are stimulated by interferon-γ (IFNγ) to release 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 (TC1) 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. IFNγ released 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 autoimmune diseases103. however, there are concerns about the safety of using rituximab, particularly in COPD patients who are susceptible to recurrent bacterial infections, as the airways of patients with more severe disease are often colonized by bacteria.

Other novel therapeutic approaches. several novel therapeutic approaches are currently in development for 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 in these diseases106. In both airway diseases, nF-κB acti-vation appears to be important for activating multiple but different inflammatory genes, so inhibition of this transcription factor using small molecule inhibitors of IKK2 (inhibitor of nF-κB kinase 2) would be a logical approach. For the treatment of asthma, inhibition of GATA3 function and therefore Th2-type cytokine pro-duction may be a more specific approach and this might be possible using inhibitors of the GATA3-activating kinase p38 MAPK39. Indeed, downregulation of p38 MAPK expression using an antisense oligonucleotide has proved to be effective in inhibiting Th2-type cytokine production in a mouse model of asthma107. For the treat-ment of COPD, inhibition of the Th1-cell-inducing tran-scription factor T-bet would be more appropriate and

this could be achieved by blocking sTAT4 activity, but no such drugs have so far been developed.

Given that chemokines are crucial mediators in the recruitment of inflammatory cells to the lungs of patients with asthma and COPD, antagonism of spe-cific chemokine receptors would be a logical approach for treating these diseases108,109. In asthma, chemokine receptors on eosinophils (CCR3) and Th2 cells (CCR4, CCR8 and CXCR4) are the main targets, whereas in COPD, receptors on neutrophils (CXCR2), monocytes (CXCR2 and CCR2), Th1 cells (CXCR3) and TC1 cells (CXCR3) are the major foci of drug development. small molecule inhibitors for all of these receptors are now in development.

Conclusions and future perspectivesAlthough both COPD and asthma involve chronic inflammation of the respiratory tract, the pattern of inflammation is markedly different between these two diseases. Mild asthma is characterized by eosinophilic inflammation driven by Th2 cells and DCs, and is asso-ciated with mast-cell sensitization by Ige, and by the release of multiple bronchoconstrictors. By contrast, COPD is characterized by neutrophilic inflammation that can be driven by a marked increase in the number of 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 released following lung injury. Mast cells and DCs, which have such 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

mastcells ++ +++ +++? 0 0 ? 7,26,112

macrophages + + ? +++ ++++ ++++ 113

Tcells TH2 cells: ++ iNKT cells: ?

TH1 cells: + TH2 cells: + TC1 cells: + TC2 cells: +?TH17 cells: ?

? TC1 cells: + TC1 cells: +++ TH1 cells: +++ TH17 cells: ?

? 18,66,114

Bcells IgE producing IgE producing ? + +++ ? 18,73

Dendriticcells + ? ? +? +? ? 115

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

CXCL8: ++ CXCL8: +++ 116

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

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

lipidmediators LTD4: ++ PGD2: +

LTB4: ++ PGD2: +

? LTB4: + LTB4: ++ LTB4: +++ 10,11

oxidativestress 0 ++ +++ ++ +++ ++++ 119–122

Steroidresponse ++++ ++ + 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; LTB4, leukotriene B4; LTD4, leukotriene D4; PGD2, prostaglandin D2; TC1, type 1 cytotoxic T; TH, T helper; TNF, tumour-necrosis factor.

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involvement in COPD. however, these distinctions between asthma and COPD may not be as clear as previously believed, as in patients with severe asthma and in asthmatic individuals who smoke there is a neutrophilic pattern of inflammation, and acute exac-erbations of asthma and of COPD have similar inflam-matory features. The role of Th17 cells in severe asthma and COPD as a driving mechanism of neutrophilic inflammation is not yet fully understood and deserves more research; understanding these mechanisms may lead to new therapeutic approaches.

new therapeutic approaches may also stem from a greater understanding and appreciation of the similarities between asthma and COPD. Although there are highly effective treatments for mild asthma, severe asthma and asthma 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 that are effective in COPD may also be effective in refractory asthma. whether therapies based on the immune mecha-nisms will be safe and effective in treating airway diseases also deserves further research.

1. Barnes, P. J. Chronic obstructive pulmonary disease: a growing but neglected epidemic. PLoS Med. 4, e112 (2007).

2. Mannino, D. M. & Buist, A. S. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 370, 765–773 (2007).A comprehensive recent review of the various risk factors involved in COPD and the current global prevalence of the disease.

3. Pearce, N. et al. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 62, 758–766 (2007).This paper provides the most recent data showing the worldwide prevalence of asthma.

4. Kraft, M. Asthma and chronic obstructive pulmonary disease exhibit common origins in any country! Am. J. Respir. Crit. Care Med. 174, 238–240 (2006).

5. Barnes, P. J. Against the Dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases. Am. J. Respir. Crit. Care. Med. 174, 240–243 (2006).

6. Barnes, P. J. Mechanisms in COPD: differences from asthma. Chest 117, 10S–14S (2000).

7. Jeffery, P. K. Comparison of the structural and inflammatory features of COPD and asthma. Chest 117, 251S–260S (2000).

8. Wenzel, S. E. Asthma: defining of the persistent adult phenotypes. Lancet 368, 804–813 (2006).This paper provides a discussion of the different phenotypes of asthma that are discussed in this Review.

9. Phelan, P. D., Robertson, C. F. & Olinsky, A. The Melbourne Asthma Study: 1964–1999. J. Allergy Clin. Immunol. 109, 189–194 (2002).

10. Barnes, P. J., Chung, K. F. & Page, C. P. Inflammatory mediators of asthma: an update. Pharmacol. Rev. 50, 515–596 (1998).

11. Barnes, P. J. Mediators of chronic obstructive pulmonary disease. Pharm. Rev. 56, 515–548 (2004).

12. Hart, L. A., Krishnan, V. L., Adcock, I. M., Barnes, P. J. & Chung, K. F. Activation and localization of transcription factor, nuclear factor-κB, in asthma. Am. J. Respir. Crit. Care Med. 158, 1585–1592 (1998).

13. Caramori, G. et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax 58, 348–351 (2003).

14. Benayoun, L., Druilhe, A., Dombret, M. C., Aubier, M. & Pretolani, M. Airway structural alterations selectively associated with severe asthma. Am. J. Respir. Crit. Care Med. 167, 1360–1368 (2003).This study quantifies the changes in airway smooth muscle that occur in asthmatic patients.

15. Siddiqui, S. et al. Vascular remodeling is a feature of asthma and nonasthmatic eosinophilic bronchitis. J. Allergy Clin. Immunol. 120, 813–819 (2007).

16. Ordonez, C. L. et al. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am. J. Respir. Crit. Care Med. 163, 517–523 (2001).

17. Hogg, J. C. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364, 709–721 (2004).

18. Hogg, J. C. et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350, 2645–2653 (2004).An important study quantifying the inflammation in small airways in patients with differing severity of COPD.

19. Caramori, G. et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology 45, 477–484 (2004).

20. Majo, J., Ghezzo, H. & Cosio, M. G. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur. Respir. J. 17, 946–953 (2001).A demonstration of increased numbers of CD8+ T cells in the lung parenchyma of patients with COPD and their relationship to apoptosis of type I pneumocytes.

21. Taraseviciene-Stewart, L. et al. Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease? Proc. Am. Thorac. Soc. 3, 687–690 (2006).

22. Ohnishi, K., Takagi, M., Kurokawa, Y., Satomi, S. & Konttinen, Y. T. Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab. Invest. 78, 1077–1087 (1998).

23. Tuder, R. M., Yoshida, T., Arap, W., Pasqualini, R. & Petrache, I. State of the art. Cellular and molecular mechanisms of alveolar destruction in emphysema: an evolutionary perspective. Proc. Am. Thorac. Soc. 3, 503–510 (2006).

24. Reber, L., Da Silva, C. A. & Frossard, N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur. J. Pharmacol. 533, 327–340 (2006).

25. Galli, S. J. et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005).

26. Brightling, C. E. et al. Mast-cell infiltration of airway smooth muscle in asthma. N. Engl. J. Med. 346, 1699–1705 (2002).This paper shows that mast-cell numbers are present in the airway smooth muscle of asthmatic patients, whereas this is not seen in non-asthmatic subjects or patients with eosinophilic bronchitis who do not have asthma.

27. Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 356, 2144–2148 (2000).This study reports a surprising finding that blocking IL-5 in asthmatic patients does not reduce the response to allergen or airway hyper-responsiveness despite a profound reduction in circulating and sputum eosinophils.

28. Flood-Page, P. et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176, 1062–1071 (2007).

29. Green, R. H. et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57, 875–879 (2002).

30. Keatings, V. M., Collins, P. D., Scott, D. M. & Barnes, P. J. Differences in interleukin-8 and tumor necrosis factor-α in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 153, 530–534 (1996).

31. Traves, S. L., Smith, S. J., Barnes, P. J. & Donnelly, L. E. Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2. J. Leukoc. Biol. 76, 441–450 (2004).

32. Barnes, P. J. Macrophages as orchestrators of COPD. COPD 1, 59–70 (2004).

33. Meyer, E. H., DeKruyff, R. H. & Umetsu, D. T. T cells and NKT cells in the pathogenesis of asthma. Annu. Rev. Med. 59, 281–292 (2008).

34. Kay, A. B. The role of T lymphocytes in asthma. Chem. Immunol. Allergy. 91, 59–75 (2006).

35. Ho, I. C. & Pai, S. Y. GATA-3 — not just for Th2 cells anymore. Cell Mol. Immunol. 4, 15–29 (2007).

36. Barnes, P. J. Role of GATA-3 in allergic diseases. Curr. Mol. Med. (in the press) (2008).

37. Caramori, G. et al. Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies. Eur. Respir. J. 18, 466–473 (2001).

38. Nakamura, Y. et al. Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J. Allergy Clin. Immunol. 103, 215–222 (1999).

39. Maneechotesuwan, K. et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3..J. Immunol. 178, 2491–2498 (2007).This study shows that in human T cells GATA3 translocates to the nucleus after phosphorylation by p38 MAPK, which is activated by TCR and co-receptor activation.

40. Finotto, S. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295, 336–338 (2002).This paper shows that the lack of T-bet results in eosinophilic inflammation in mouse lungs and a reduction in T cells expressing T-bet in the airways of asthmatic patients.

41. Hwang, E. S., Szabo, S. J., Schwartzberg, P. L. & Glimcher, L. H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307, 430–433 (2005).

42. Yoshimoto, T., Yoshimoto, T., Yasuda, K., Mizuguchi, J. & Nakanishi, K. IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells: a novel therapeutic way for Th2-mediated allergic inflammation. J. Immunol. 179, 4415–4423 (2007).

43. Usui, T. et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J. Exp. Med. 203, 755–766 (2006).

44. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002).

45. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282–287 (2007).

46. Komai-Koma, M. et al. IL-33 is a chemoattractant for human Th2 cells. Eur. J. Immunol. 37, 2779–2786 (2007).

47. Grumelli, S. et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 1, 75–83 (2004).This study shows that the numbers of TH1 and TC1 cells, both of which express CXCR3, are increased in the lung parenchyma of patients with COPD.

48. Saetta, M. 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. 165, 1404–1409 (2002).

49. Costa, C. et al. CXCR3 and CCR5 chemokines in the induced sputum from patients with COPD. Chest 133, 26–33 (2008).

50. Barczyk, A. et al. Cytokine production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 117, 1484–1492 (2006).

51. Kurashima, K. et al. Asthma severity is associated with an increase in both blood CXCR3+ and CCR4+ T cells. Respirology 11, 152–157 (2006).

R E V I E W S




52. Larche, M. Regulatory T cells in allergy and asthma. Chest 132, 1007–1014 (2007).

53. Ling, E. M. et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–615 (2004).

54. Lee, J. H. et al. The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin. Exp. Immunol. 148, 53–63 (2007).

55. Smyth, L. J., Starkey, C., Vestbo, J. & Singh, D. CD4-regulatory cells in COPD patients. Chest 132, 156–163 (2007).

56. Wan, Y. Y. & Flavell, R. A. Regulatory T cells, transforming growth factor-β, and immune suppression. Proc. Am. Thorac. Soc. 4, 271–276 (2007).

57. Stockinger, B. & Veldhoen, M. Differentiation and function of Th17 T cells. Curr. Opin. Immunol. 19, 281–286 (2007).

58. Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

59. Bullens, D. M. et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir. Res. 7, 135 (2006).

60. Laan, M., Lotvall, J., Chung, K. F. & Linden, A. IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br. J. Pharmacol. 133, 200–206 (2001).

61. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).

62. Spolski, R. & Leonard, W. J. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 8 November 2007 (doi:10.1146/annurev.immunol.26.021607.090316).

63. Wolk, K. & Sabat, R. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 17, 367–380 (2006).

64. Akbari, O. et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 1117–1129 (2006).

65. Vijayanand, P. et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N. Engl. J. Med. 356, 1410–1422 (2007).A careful study showing that there is no increase in iNKT cells in asthma or COPD in contrast to reference 64.

66. Saetta, M. et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 157, 822–826 (1998).

67. Xanthou, G., Duchesnes, C. E., Williams, T. J. & Pease, J. E. CCR3 functional responses are regulated by both CXCR3 and its ligands CXCL9, CXCL10 and CXCL11. Eur. J. Immunol. 33, 2241–2250 (2003).

68. Chrysofakis, G. et al. Perforin expression and cytotoxic activity of sputum CD8+ lymphocytes in patients with COPD. Chest 125, 71–76 (2004).

69. van Rensen, E. L. et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am. J. Respir. Crit. Care Med. 172, 837–841 (2005).

70. Cho, S. H., Stanciu, L. A., Holgate, S. T. & Johnston, S. L. Increased interleukin-4, interleukin-5, and interferon-γ in airway CD4+ and CD8+ T cells in atopic asthma. Am. J. Respir. Crit. Care Med. 171, 224–230 (2005).

71. Gould, H. J., Beavil, R. L. & Vercelli, D. IgE isotype determination: epsilon-germline gene transcription, DNA recombination and B-cell differentiation. Br. Med. Bull. 56, 908–924 (2000).

72. Avila, P. C. Does anti-IgE therapy help in asthma? Efficacy and controversies. Annu. Rev. Med. 58, 185–203 (2007).

73. Takhar, P. et al. Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma. J. Allergy Clin. Immunol. 119, 213–218 (2007).An important study demonstrating that IgE is produced locally in the airways of patients with non-atopic (intrinsic) asthma.

74. Agusti, A., Macnee, W., Donaldson, K. & Cosio, M. Hypothesis: does COPD have an autoimmune component? Thorax 58, 832–834 (2003).

75. Sullivan, A. K. et al. Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema. Am. J. Respir. Crit. Care Med. 172, 590–596 (2005).

76. Lee, S. H. et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nature Med. 13, 567–569 (2007).

77. Hammad, H. & Lambrecht, B. N. Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. J. Allergy Clin. Immunol. 118, 331–336 (2006).

78. Ying, S. et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol. 174, 8183–8190 (2005).

79. Allakhverdi, Z. et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J. Exp. Med. 204, 253–258 (2007).This study highlights an important role for TSLP released from airway epithelial cells in the activation of mast cells, providing a link between environmental factors and mast-cell activation in asthma.

80. Liu, Y. J. Thymic stromal lymphopoietin: master switch for allergic inflammation. J. Exp. Med. 203, 269–273 (2006).

81. Soler, P., Moreau, A., Basset, F. & Hance, A. J. Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells. Am. Rev. Respir. Dis. 139, 1112–1117 (1989).

82. Francus, T., Klein, R. F., Staiano-Coico, L., Becker, C. G. & Siskind, G. W. Effects of tobacco glycoprotein (TGP) on the immune system. II. TGP stimulates the proliferation of human T cells and the differentiation of human B cells into Ig secreting cells. J. Immunol. 140, 1823–1829 (1988).

83. Rogers, A. V., Adelroth, E., Hattotuwa, K., Dewar, A. & Jeffery, P. K. Bronchial mucosal dendritic cells in smokers and ex-smokers with COPD: an electron microscopic study. Thorax 63,108–114 (2008).

84. Wenzel, S. E. & Busse, W. W. Severe asthma: lessons from the Severe Asthma Research Program. J. Allergy. Clin. Immunol. 119, 14–21 (2007).

85. Jatakanon, A. et al. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med. 160, 1532–1539 (1999).

86. Thomson, N. C., Chaudhuri, R. & Livingston, E. Asthma and cigarette smoking. Eur. Respir. J. 24, 822–833 (2004).

87. Papi, A. et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162, 1773–1777 (2000).

88. Brightling, C. E. et al. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 60, 193–198 (2005).

89. Wark, P. A. & Gibson, P. G. Asthma exacerbations. 3: pathogenesis. Thorax 61, 909–915 (2006).

90. Celli, B. R. & Barnes, P. J. Exacerbations of chronic obstructive pulmonary disease. Eur. Respir. J. 29, 1224–1238 (2007).

91. Papi, A., Luppi, F., Franco, F. & Fabbri, L. M. Pathophysiology of exacerbations of chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 3, 245–251 (2006).

92. Barnes, P. J. How corticosteroids control inflammation. Br. J. Pharmacol. 148, 245–254 (2006).A review of the molecular mechanisms involved in the anti-inflammatory actions of corticosteroids and a discussion of the mechanisms of corticosteroid resistance in airway diseases.

93. Ito, K. et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352, 1967–1976 (2005).This paper shows that HDAC2 activity and expression are reduced in peripheral lungs, airways and alveolar macrophages of COPD patients, and that this is associated with an increase in inflammatory gene expression.

94. Barnes, P. J. Reduced histone deacetylase in COPD: clinical implications. Chest 129, 151–155 (2006).

95. Barnes, P. J., Ito, K. & Adcock, I. M. A mechanism of corticosteroid resistance in COPD: inactivation of histone deacetylase. Lancet 363, 731–733 (2004).

96. Cosio, B. G. et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood monocytes in asthma. Am. J. Respir. Crit. Care Med. 170, 141–147 (2004).

97. Hew, M. et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am. J. Respir. Crit. Care Med. 174, 134–141 (2006).

98. Barnes, P. J. Theophylline: new perspectives on an old drug. Am. J. Respir. Crit. Care Med. 167, 813–818 (2003).

99. Finegold, I. Allergen immunotherapy: present and future. Allergy Asthma Proc. 28, 44–49 (2007).

100. Alexander, A., Barnes, N. C. & Kay, A. B. Cyclosporin A in chronic severe asthma: a double-blind placebo-controlled trial. Am. Rev. Respir. Dis. 143, A633 (1991).

101. Evans, D. J., Cullinan, P. & Geddes, D. M. Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst. Rev. 2, CD002993 (2001).

102. Tamaoki, J. et al. Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Lancet 356, 273–278 (2000).

103. Edwards, J. C. & Cambridge, G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nature Rev. Immunol. 6, 394–403 (2006).

104. Barnes, P. J. New therapies for asthma. Trends Mol. Med. 12, 515–520 (2006).

105. Barnes, P. J. & Hansel, T. T. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet 364, 985–996 (2004).

106. Barnes, P. J. Transcription factors in airway diseases. Lab. Invest. 86, 867–872 (2006).

107. Duan, W. et al. Inhaled p38α mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am. J. Respir. Crit. Care Med. 171, 571–578 (2005).

108. Smit, J. J. & Lukacs, N. W. A closer look at chemokines and their role in asthmatic responses. Eur. J. Pharmacol. 533, 277–288 (2006).

109. Donnelly, L. E. & Barnes, P. J. Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol. Sci. 27, 546–553 (2006).

110. Saetta, M. et al. Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin. Exp. Allergy 26, 766–774 (1996).

111. Zhu, J. et al. Exacerbations of bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am. J. Respir. Crit. Care Med. 164, 109–116 (2001).

112. Gamble, E. et al. Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis. Eur. Respir. J. 30, 467–471 (2007).

113. Retamales, I. et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am. J. Respir. Crit. Care Med. 164, 469–473 (2001).

114. Humbert, M. et al. The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences. Immunol. Today 20, 528–533 (1999).

115. Jahnsen, F. L. et al. Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 56, 823–826 (2001).

116. Lukacs, N. W., Hogaboam, C. M. & Kunkel, S. L. Chemokines and their receptors in chronic pulmonary disease. Curr. Drug Targets Inflamm. Allergy 4, 313–317 (2005).

117. Chung, K. F. & Barnes, P. J. Cytokines in asthma. Thorax 54, 825–857 (1999).

118. Chung, K. F. Cytokines in chronic obstructive pulmonary disease. Eur. Respir. J. 34, 50S–59S (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, 216–220 (1999).

120. Paredi, P., Kharitonov, S. A. & Barnes, P. J. Elevation of exhaled ethane concentration in asthma. Am. J. Respir. Crit. Care Med. 162, 1450–1454 (2000).

121. Montuschi, P. et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 162, 1175–1177 (2000).

122. Rahman, I., Biswas, S. K. & Kode, A. Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 533, 222–239 (2006).

DATABASESEntrez gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneCCR2 | CCR3 | CCR4 | CXCR2 | CXCR3 | CXCR4 | GATA3 | IFNγ | IL-4 | IL-5 | IL-6 | IL-9 | IL-13 | IL-17 | IL-33 | p38 | TSLP

FURTHER INFORMATIONPeter Barnes’s homepage: http://www1.imperial.ac.uk/medicine/people/p.j.barnes.html

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

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


















http://www1.imperial.ac.uk/medicine/people/p.j.barnes.html

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Immunology of asthma and chronic obstructive pulmonary disease

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