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Curtis,J.L.,Freeman,C.M.&Hogg,J.C.Theimmunopathogenesisofchronicobstructivepulmonarydisease:insightsfromrecentresearch.Proc.Am.Thorac.Soc.4,512-521

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DOI:10.1513/pats.200701-002FM·Source:PubMed

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The Immunopathogenesis of Chronic ObstructivePulmonary DiseaseInsights from Recent Research

Jeffrey L. Curtis1,2,3, Christine M. Freeman2, and James C. Hogg4,5

1Pulmonary and Critical Care Medicine Section, Medical Service, Department of Veterans Affairs Health System, Ann Arbor, Michigan; 2Divisionof Pulmonary and Critical Care Medicine, Department of Internal Medicine, and 3Graduate Program in Immunology, University of MichiganHealth System, Ann Arbor, Michigan; and 4University of British Columbia, Centre for Cardiovascular and Pulmonary Research, and 5St. Paul’sHospital, Vancouver, British Columbia, Canada

Chronic obstructive pulmonary disease (COPD) progression is char-acterized by accumulation of inflammatory mucous exudates in thelumens of small airways, and thickening of their walls, which be-come infiltrated by innate and adaptive inflammatory immune cells.Infiltration of the airways by polymorphonuclear and mononuclearphagocytes and CD4 T cells increases with COPD stage, but thecumulative volume of the infiltrate does not change. By contrast,B cells and CD8 T cells increase in both the extent of their distribu-tion and in accumulated volume, with organization into lymphoidfollicles. This chronic lung inflammation is also associated with atissue repair and remodeling process that determines the ultimatepathologic phenotype of COPD. Why these pathologic abnormali-ties progress in susceptible individuals, even after removal of theoriginal noxious stimuli, remains mysterious. However, importantclues are emerging from analysis of pathologic samples from pa-tients with COPD and from recent discoveries in basic immunology.We consider the following relevant information: normal limitationson the innate immune system’s ability to generate adaptive pulmo-nary immune responses and how they might be overcome by to-bacco smoke exposure; the possible contribution of autoimmunityto COPD pathogenesis; and the potential roles of ongoing lympho-cyte recruitment versus in situ proliferation, of persistently activatedresident lung T cells, and of the newly described T helper 17 (Th17)phenotype. We propose that the severity and course of acute exac-erbations of COPD reflects the success of the adaptive immuneresponse in appropriately modulating the innate response to patho-gen-related molecular patterns (“the Goldilocks hypothesis”).

Keywords: adaptive immunity; adhesion molecules; chemokines;cytokines; innate immunity

The defining feature of chronic obstructive pulmonary disease(COPD) is irreversible airflow limitation measured during forcedexpiration (1, 2). This reduction in maximum expiratory flow mayresult from either an increase in the resistance of the conductingairways and/or an increase in lung compliance due to emphyse-matous destruction of the lung’s elastic recoil force (3). Airwayresistance is measured in units of cm H2O/L/second, and compli-ance is measured in units of L/cm H2O, and their product (time)

(Received in original form January 2, 2007; accepted in final form March 20, 2007 )

Supported by National Heart Lung and Blood Institute, United States Public HealthService grants RO1 HL082480, T32 HL07749, and RO1 HL063117; Merit Reviewfunding; a Research Enhancement Award Program grant from the Biomedical andLaboratory Research and Development Service, Department of Veterans Affairs;and by Canadian Institutes of Health Research grant 7246.

Correspondence and requests for reprints should be addressed to Jeffrey L. Curtis,M.D., Pulmonary and Critical Care Medicine Section (506/111G), Department ofVeterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, MI 48105-2303.E-mail: jlcurtis@umich.edu

Proc Am Thorac Soc Vol 4. pp 512–521, 2007DOI: 10.1513/pats.200701-002FMInternet address: www.atsjournals.org

determines the time required to empty the lung. FEV1 and itsratio to FVC (FEV1/FVC) are the standard spirometric teststhat are used to screen for the presence of airflow limitation andto classify the severity of COPD (1, 2).

PATHOLOGIC FEATURES OF COPD

The etiology of the airway obstruction and emphysematous de-struction that cause airflow limitation is the persistent lung tissueinjury produced by the chronic inhalation of toxic particles andgases (1). Figure 1 is modified from a seminal study of the naturalhistory of chronic bronchitis and emphysema conducted byFletcher and his associates (4), with the more recently introducedGlobal Initiative for Chronic Obstructive Lung Disease (GOLD)categories of COPD severity superimposed as horizontal lines(1). The data of Fletcher and colleagues establish that only aminority of the smoking population develop the rapid declinein FEV1 leading to severe (GOLD-3) and very severe (GOLD-4)COPD. In contrast, everyone who smokes has some evidenceof lung inflammation (5), and this response appears to be ampli-fied in the minority of smokers that reach the more advancedlevels of COPD (6, 7). The mechanism for this amplificationstep is poorly understood, but probably involves both geneticand/or epigenetic features of the host response, as well as differ-ences in the dose of inhaled particles and gases.

The innate defense system of the lung includes the mucocili-ary clearance apparatus (8) and epithelial barrier (9), as well asthe coagulation and inflammatory cascades that stop the micro-scopic bleeding associated with tissue injury and bring an exudateof plasma and migrating inflammatory immune cells into thedamaged site (10). This innate defense system provides a rapidinitial response that can be triggered by a variety of mechanisms,but lacks specificity, has very limited diversity, and has no mem-ory. The tobacco smoking habit interferes with the innate hostdefense system by increasing mucus production and reducingmucociliary clearance, by disrupting the epithelial barrier andstimulating the migration of polymorphonuclear neutrophils(PMNs), monocyte/macrophages (Mø), CD4�, CD8�, andB-cell lymphocytes, and smaller numbers of dendritic cells (DCs)and natural killer (NK) cells, into the damaged tissue (7, 11).The tobacco smoking habit also stimulates the humoral andcellular components of the adaptive immune response to providea much more specific and very diverse reaction that has exquisitememory for previous exposures to foreign material introducedinto the lung.

The histologic hallmark of the presence of an adaptive im-mune response is the presence of lymphoid follicles with germi-nal centers that are usually found in regional lymph nodes. How-ever, bronchus-associated lymphoid tissue (BALT) collections,which are rarely found in the lungs of healthy nonsmokers (7),have been reported in about 5% of smokers with normal lungfunction (GOLD-0), as well as those with COPD of mild

Curtis, Freeman, and Hogg: COPD Immunopathogenesis 513

Figure 1. Correlation between the onset of pathologic pro-cesses in chronic obstructive pulmonary disease (COPD)and Global Initiative for Chronic Obstructive Lung Disease(GOLD) severity stage. The natural history of the declinein FEV1 in the working men followed by Fletcher and col-leagues (4) is shown with the GOLD categories superim-posed as dotted horizontal lines. Note that only a minorityof the smoking population (estimated to be approximately20% of the total) experienced the rapid decline in lungfunction that leads to severe (GOLD-3) and very severe(GOLD-4) COPD. Data from Reference 7 confirmed thatthe populations of macrophage, neutrophil, and lympho-cyte subtypes infiltrate the peripheral lung tissue of symp-tomatic smokers with normal lung function (GOLD-0). Inaddition, they confirmed that this infiltration increased inboth extent (number of airways involved) and severity (ac-cumulated volume of cell type) as COPD progressedthrough mild, moderate, severe, and very severe disease(GOLD-1 through GOLD-4). These data also showed that

the remodeling process (thickening of the small airways wall and occlusion of their lumen by inflammatory exudates containing mucus) increasesfrom moderate (GOLD-2) to very severe (GOLD-4) COPD, and that the formation of lymphoid follicles, which provides histologic evidence for anadaptive immune response, increased sharply in severe (GOLD-3) and very severe (GOLD-4) COPD. A multivariate analysis of these data indicatedthat measurements of the remodeling process explained more of the variance in the relationship between pathology in the small airways and FEV1

than either the extent or the severity of the infiltration of the airway tissue by any of the migrating inflammatory immune cells. Modified bypermission from Reference 4.

(GOLD-1) and moderate (GOLD-2) severity (7, 12, 13). Inter-estingly, these collections of BALT (Figure 2) appear to increasesharply in severe (GOLD-3) and very severe (GOLD-4) COPD,possibly because of an increased adaptive response to the coloni-zation and infection of the lower airways that is known to occurin the advanced stages of COPD (7). However, the increase inBALT may also serve as a marker for an immune response tosomething in the tobacco smoke itself; to microorganisms andother foreign materials that gain entry into the lower respiratorytract because of depression of the innate defenses; or to autoanti-gens that develop in repetitively damaged lung tissue (14).

The chronic inflammatory immune process found in lungtissue repetitively damaged by tobacco smoke is also associatedwith a tissue repair and remodeling process that determines theultimate pathologic phenotype of COPD. Their presence in theepithelial lining of the larger bronchi and their associated mucusglands produces the structural and functional changes associatedwith chronic bronchitis (15, 16). When present in the smallerbronchi and bronchioles that become the major site of airwayobstruction in COPD, this remodeling process results in occlu-sion of the lumen by inflammatory exudates containing mucus,thickening of the walls, and narrowing of the lumen of theseairways (7). In contrast, the extension of this inflammatory im-mune process to respiratory bronchioles and alveolar ducts andsacs is associated with emphysematous destruction (6) ratherthan tissue proliferation seen in the conducting airway tissue(7).

A multivariate analysis of the components of this inflamma-tory immune repair process conducted to determine the relation-ship between their presence in the small conducting airways andthe decline in FEV1 has shown that more of the variance in FEV1

decline is explained by occlusion of the lumen and thickening ofthe airway wall than by either the extent (number of airwaysinvolved) or severity (accumulated volume of cells) in theseairways of any of the inflammatory immune cells present in thetissue (7). These and other studies indicate that the remodelingprocess is a critical feature of the pathogenesis of the lesionsthat define the pathology of COPD, but much of the detailconcerning the links between the innate and adaptive immune

processes and peripheral lung remodeling remain to be workedout.

DISCOVERING THE MOLECULAR BASIS FOR LUNGINFLAMMATION IN COPD

Why is COPD characterized, even after removal of the originalnoxious insults, by progressive accumulation of cells of the innateand adaptive immune systems in and around the airways, byperibronchial fibrosis, and by mucus hypersecretion? Subse-quently here, we offer suggestions based on known immunologicmechanisms, but it must be appreciated that the understandingof how they might apply to COPD is still in its infancy. Emphasisis on recent discoveries, areas requiring further study, and cluesfrom experimental studies that may be less well known to clinicalresearchers. We examine two types of evidence, each with strengthsand limitations. Analysis of human samples discloses associationsbetween clinical outcomes and cell types, inflammatory mediators,or other gene products. This type of inquiry is essential but inevita-bly limited by sample availability and ethical constraints on defini-tive experimentation. An alternative method is to seek candidatemechanisms and molecules from animal models, an approach cur-rently hobbled by the chronicity of COPD and the relative resis-tance of mice to cigarette smoke–induced injury. Current murinemodels have been more successful for studying emphysema (17)than chronic bronchitis. The relative merits of these two approachesin asthma have been argued recently (18, 19). We continue to seethem as complementary elements in a dialog in which the resultsof animal experiments are used to develop cogent mechanistichypotheses to be examined for relevance to human diseases.

“Prometheus Bound”: The Unique Constraints on LungMononuclear Phagocytes

A first approach to the question posed above is to consider howpulmonary immune response generation is normally constrainedto preserve gas exchange despite the daily onslaught of inhaledand aspirated stimuli. Alveolar macrophage (AMø) activation

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Figure 2. (A ) The migration of a population of predomi-nantly acute inflammatory cells (white arrows) migratingthrough the airway epithelium of an animal in responseto an acute exposure to tobacco smoke inhalation. (B ) Thelamina propria and adventitia of the airways are suppliedby separate sets of bronchial vessels (black arrows) thatinterconnect (black arrowhead) with each other. (C ) Acollection of bronchus-associated lymphocytes (BALT) witha germinal center (GC) which is supplied by bronchialvessels from the adventitial set of bronchial vessels. (D ) Adrawing of a lymph node for comparison to (C ). The blackarrowheads indicate the limits of the specialized epitheliumoverlying BALT. Note that the BALT structure has neitherthe capsule nor the afferent lymphatics that supply thelymph node. Reprinted by permission from Reference 3.

is tonically inhibited by transforming growth factor-�1 boundto �v�6-integrin on alveolar epithelial cells; in murine models,loss of this inhibition induces matrix metalloproteinase-12 andemphysema (20, 21). Control of AMø production of proinflam-matory mediators also comes from their distinct regulation ofDNA binding by the transcription factors, Ref-1 and activatorprotein-1 (AP-1) (22), and by their abundant expression ofperoxisome proliferator–activated receptor-� (23). AMø can

Figure 3. The Goldilocks hypothe-sis of acute exacerbations of COPDpathogenesis. In some cases, theinnate and adaptive immune re-sponse successfully eliminates theinfection, and the response is mildand transient (middle panel, “justright”). Lung inflammation can beexcessive and/or prolonged whenthe adaptive pulmonary immuneresponse is inappropriate in eitherof two ways: adaptive immunitycould fail when needed to controlcertain infections (left panel, “toolittle”), or it could excessively am-plify or prolong lung inflammationthrough its regulatory effects oninnate immunity (depicted here bythe T cell products IFN-� andIL-17A) (right panel, “too much”).AMø � alveolar macrophage;DC � dendritic cells; iDC � imma-ture DC.

migrate to regional nodes (24), but have limited ability to activatenaive T cells. Collectively, these properties imply that the AMøis highly evolved to survey the alveolar environment withoutinducing excessive inflammation.

Stimulating AMø via any of the known Toll-like receptorsreleases them from transforming growth factor-�–mediated inhi-bition (25), and vigorously induces inflammatory cytokines andchemokines. However, because AMø lack the feed-forward

Curtis, Freeman, and Hogg: COPD Immunopathogenesis 515

amplification mediated in other mononuclear phagocyte sub-types by autocrine secretion of IFN-� and signal transducer andactivator of transcription 1 activation, AMø require exogenousIFN to mount a second phase of host defense (26, 27). Thus,the normal AMø response is rapid, yet restrained from producingdamaging effector molecules without additional signals. AMøare responsive to IFN produced by multiple lung cell types duringviral respiratory infections. IFN-� converts the normally weaklystimulatory outer membrane proteins of nontypeable Haemo-philus influenzae into potent inducers of IL-6 production by bothmurine and human AMø (28). Given the importance of IL-6,which is outlined subsequently here, this finding may help toexplain the association of viral respiratory infections with acuteexacerbations of COPD (AECOPD).

Cigarette smoke induces a distinctive pattern of AMø geneexpression not seen in nonsmokers or patients with asthma (29).Interestingly, although AMø of smokers strongly express matrixmetalloproteinase-12, shown to be essential for emphysema ina murine model of cigarette smoke exposure (30), most of the72 genes up-regulated in smokers relative to healthy nonsmokingcontrol subjects were not identified in two transgenic murinemodels of emphysema (29). The lack of global comparisons ofgene expression between human smokers and mice exposed tocigarette smoke makes it uncertain whether murine modelsmight accelerate understanding of COPD immunopathogenesis,even if they so far fail to mimic human pathology completely.

The normal lung contains potent antigen-presenting cells inthe form of DCs (31), the best described function of which isto migrate in a CC chemokine receptor (CCR) 7–dependentfashion to regional lymph nodes, where they activate naive Tcells to proliferate. All four types of DC previously identifiedin peripheral blood (32, 33) have been identified in the lungs.These are: myeloid DC types 1 and 2, which are blood DCantigen 1� (BDCA1�) and BDCA3�, respectively; plasmacytoidDCs, positive for both the IL-3 receptor (CD123) and BDCA2;and CD1a� DCs (32, 34). DCs and NK cells appear to regulateone another’s maturation reciprocally (35). Thus, NK cells ex-posed to DC-produced IL-12 enhance DC maturation and theircapacity to secrete IL-12 (and, hence, to foster type 1 responses),whereas NK cells exposed to IL-4 favor DCs that are tolerogenicor inducers of type 2 responses (36). DC-activated NK cells alsokill immature DCs (37), presumably to reinforce local immuneresponse polarization to the most recently encountered pathogens.

Conflicting data exist on how cigarette smoke exposure af-fects DC number and immune function. In mice, smoke exposurehas been reported to increase (38) or decrease lung DC numbers,to impair antiviral host defenses (39), and to increase (40) ordecrease (41) lung DC expression of costimulatory molecules.One study found that smoke exposure increased numbers ofLangerhans-type DCs in mice and induced changes resemblingeosinophilic granulomatosis (42), a disease strongly associatedwith smoking. The reason for these disparate results is not imme-diately apparent, but standardization of smoke exposures in mu-rine models is clearly needed to facilitate comparison betweenresults from different laboratories. Ex vivo exposure to cigarettesmoke extract skewed the priming ability of human monocyte-derived DCs from a Th1 to a Th2 phenotype (43). The effecton lung DC numbers and function of exposure to tobacco smokeor other oxidants, or of varying COPD severities and pheno-types, has not been studied systematically, and is an important,unmet research goal.

Could COPD Be an Autoimmune Disease?

From the onset, investigators of COPD pathogenesis have de-bated the relative contributions of direct toxic effects of cigarettesmoke (“the American hypothesis”) and the role of chronic

infection (“the British hypothesis”). A novel twist, that an ac-quired immune response to newly created or altered epitopesis an essential component of COPD pathogenesis, has been ad-vanced by several groups (14, 44). A possible autoimmune com-ponent to COPD is supported by the marked oligoclonality ofCD4� T cells isolated from resected emphysematous humanlung tissue (45), but this finding might also reflect retention ofclones specific for exogenous antigens (e.g., E1A protein) dueto latent adenoviral infection (6). Additional support comes froman intriguing animal model system devised by Taraseviciene-Stewart and associates (46). Adult rats immunized with humanpulmonary vein endothelial cells or pulmonary artery smoothmuscle cells plus adjuvant develop significant emphysema. Oneelusive key point is whether autoantibodies in patients withemphysema are etiologic or are a result of tissue damage (i.e.,cause vs. effect), but the entire autoimmune hypothesis does notrest on that result. That the immunologic mechanisms drivingpannus formation in rheumatoid arthritis could be shared insome way with COPD is a tantalizing possibility.

The growing literature on apoptosis as a driving force inemphysema pathogenesis (47–49) is directly germane. In sys-temic lupus erythematosus, defective apoptotic cell clearanceprovides the self-antigens essential for autoantibody formation;whether this could be the case in COPD is unknown. NormalAMø show a markedly reduced capacity to ingest apoptotic cellsrelative to their avid ingestion of pathogen or inert particles(50–52). This capacity appears to be further reduced in COPD,with attendant increased apoptotic cell accumulation (52, 53).Because apoptotic cell recognition typically induces a uniqueantiinflammatory state in Mø (54–56), defective clearance mightbe one factor encouraging lung inflammation.

Lung Inflammation in COPD: Ongoing Recruitment VersusIn Situ Proliferation?

Peripheral immune responses typically require recruitment ofmultiple types of hematopoietic cells from the bloodstream. Thisprocess has been demonstrated in asthma by acute bronchialchallenge, and is clearly the case in pneumonia. Whether thechronic infiltration of the lung parenchyma in COPD also de-pends heavily on recruitment, or, once initiated, can be sustainedby local proliferation, is largely unstudied. Defining the balancebetween these two processes is crucial to designing novel thera-peutic strategies—antirecruitment strategies are worth devel-oping only if continuous recruitment is essential for lung in-flammation to persist.

Leukocyte recruitment is regulated by endothelial cell displayof distinct combinations of adhesion receptors and chemokines,with the exact combinations varying between organs and hema-topoietic cell types. Recruitment of lymphocytes to the promi-nent BALT of the nonobese diabetic mouse strain depends onlymphocyte L-selectin (CD62L), �4�1-integrin (CD29/CD49d),and lymphocyte function–associated antigen-1 (CD18/CD11a)interacting with their respective endothelial ligands (57). In mu-rine models of acute antigen-driven lung recruitment, the endo-thelial selectins E-selectin (CD62E) and P-selectin (CD62P) arerequired by CD8 T cells, Th1 CD4 T cells and B cells, but notby monocytes, immature DCs, �� T cells, or Th2 CD4 T cells(58–62). However, the finding that T-cell recruitment and evengerminal center formation in the lungs of mice infected withMycobacterium tuberculosis are independent of selectin ligandexpression (63) implies that chronic infection might induce alter-native mechanisms of lung leukocyte recruitment. Expressionof selectins and other adhesion molecules on the lung vasculaturein COPD is unreported, but important to define, given the immi-nent availability of therapeutic agents to block this adhesivepathway (64).

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Cigarette smoke or other airway irritants have been postu-lated to induce AMø, alveolar epithelial cells, or DCs to secretechemotactic factors for inflammatory cells. Correlations betweenchemokine levels in sputum, bronchoalveolar lavage (BAL)fluid, and lungs of patients with COPD and lung function orinflammatory cell numbers help to identify potential mediatorsof cellular influx in COPD. A modest number of reports havedescribed chemokine and chemokine receptor expression inCOPD. CC chemokine ligand (CCL) 2, a known chemoattrac-tant for human monocytes/Mø and T cells, was increased insputum, BAL fluid, and lungs of patients with COPD (65–67),whereas expression of its receptor, CCR2, was increased in AMøof subjects with COPD. These findings suggest that CCL2 andCCR2 may be involved in the recruitment of monocytes andimmature DCs into the airways in COPD (67), roles supportedby murine data (62, 68, 69). CCR5 has also been implicated inCOPD immunopathogenesis. Numbers of airway CCR5� T cellswere increased in patients with COPD with mild to moderatedisease severity, but not in those with severe COPD (70, 71).Likewise, CCL4, a ligand for CCR5, was increased in BAL fluidof patients with mild to moderate airflow limitation and chronicbronchitis (66). CCL5, a ligand for CCR5, CCR3, and CCR1,was increased in the airways and sputum of patients with COPD,but only during exacerbations (72).

Members of the CXC chemokine family attract a variety ofleukocyte types. CXCL1 and CXCL8, ligands for CXCR1 andCXCR2, are elevated in induced sputum and BAL fluid frompatients with COPD as compared with normal smokers andnonsmokers (65, 73, 74). CXCL8 (previously known as IL-8) isa potent PMN chemoattractant; unsurprisingly, CXCL8 concen-trations in sputum and BAL fluid correlate with increased PMNaccumulation (75). In rodent models of cigarette smoke expo-sure, a small molecule inhibitor of CXCR2 reduced PMN influxto the lungs (76, 77). Several CXCR2 inhibitors are now inclinical development for COPD (78). Numbers of CXCR3� cells(chiefly, CD8� T cells) in the epithelium and submucosa wereincreased in smokers with COPD, as compared with nonsmokers(79). Furthermore, CXCL10, a CXCR3 ligand, was expressedin bronchiolar epithelial cells and airway smooth muscle cells,suggesting that CXCR3/CXCL10 interactions may be involvedin T-cell recruitment or retention in COPD. Although chemo-taxis is the signature feature of chemokines and chemokine re-ceptors, investigation should also focus on their other effectson inflammatory cells, including proliferation, differentiation,retention, and survival.

To date, no chemotactic factors have been shown to be uniqueto COPD, as opposed to lung inflammation due to other causes,or indeed, to inflammation in other organs. However, severalinstances of tissue-specific lymphocyte homing have been dem-onstrated, and the molecular basis for two, the gut and the skin,is increasingly becoming understood. The ability to home to thesmall intestine depends on high levels of �4�7-integrin and CCR9-mediated responsiveness to the gut-specific chemokine, CCL25(TECK). Only DCs from Peyer’s patches induced murine CD8�

T cells to express high levels of �4�7-integrin and CCR9, and tohome to the gut in vivo, even though DCs from Peyer’s patches,peripheral lymph nodes, or spleen all induced equivalent activa-tion markers and effector activity (80). This induction of guttropism by Peyer’s patch DCs is mediated by retinoic acid (81).Similarly, skin DCs can produce another retinoid, 1,25(OH)2

vitamin D3, that imprints skin tropism on T cells by inducingCCR10-mediated responsiveness to the skin-specific chemokineCCL27 (82). Whether analogous lung-specific lymphocyte tro-pism exists, and if so, whether lung-draining DCs can similarlyinduce it, are currently unknown.

The presence of well-developed lymphoid follicles containinggerminal centers in GOLD-3 to GOLD-4 COPD argues for atleast a component of local proliferation. Lymphoid follicles arealso a feature of severe chronic inflammation in several organ-specific autoimmune diseases, including rheumatoid arthritis,Sjogren’s syndrome, and Hashimoto thyroiditis. Developmentof such structures, termed lymphoneogenesis, typically dependson lymphotoxin-� and the chemokine, CXCL13, the same factorsthat are crucial for formation of secondary lymphoid structuresduring ontogeny (83–85). Neither of these factors has been exam-ined in COPD. However, this paradigm may not apply com-pletely to the lungs, based on the results of experimental influ-enza infection in gene-targeted mice devoid of lymphotoxin-�(86). These mice, which lack spleen, lymph nodes, and Peyer’spatches, show very abnormal primary response to antigen andallografts, but do develop intrapulmonary antigen-specific T- andB-cell responses to respiratory viruses (with delayed kinetics).Organized peribronchovascular lymphoid aggregates also de-velop in double-transgenic mice expressing both IL-6 and theIL-6 receptor (87). However, because these mice also develophepatosplenomegaly, systemic lymphadenopathy, and glomeru-lonephritis, it is unclear to what degree this model system isrelevant to advanced COPD. In addition to being the most im-portant inducer of acute-phase protein synthesis, IL-6 also medi-ates T-cell activation, growth, differentiation, and survival. IL-6expression is elevated in BAL fluid in COPD, appears to corre-late with disease severity (74), and increases during exacerba-tions (88). In vivo evidence supports a role for IL-6 in amplifyingleukocyte recruitment to sites of inflammation (89).

“Locked and Loaded”: Persistently Activated Lung T Cells andHeterologous Immunity

In COPD, CD4 and CD8 T cells accumulate in the alveolarwalls, with CD8� cells predominating. The stimulus for this accu-mulation is largely unknown, but one plausible contributor isthe immune response to respiratory viral infections, common inpatients with COPD. After viral infections, both CD4 and CD8memory T cells persist at stable frequencies in peripheral organswithout any obvious reexposure in mice (90–96), and for 4–18years in peripheral blood in humans (97–99). Effector memoryT cells can be harbored in the lung tissue and airways; murinemodels of both influenza and Sendai virus infections show thatmemory CD4 and CD8 T cells can be recovered from the lungfor many months after the initial infection has resolved (91, 92).The absolute number of antigen-specific effector memory CD8�

T cells remaining in the airways after viral infections is initiallyquite high, and comprises two population (100). A proliferatingminority population probably accounts for the long-term stabili-zation of airway T-cell numbers. The majority population doesnot proliferate, leading to a decline in absolute numbers overthe next 6 months (a substantial percentage of the life of amouse), with a half-life of approximately 40 days (91). The netloss of airway memory T cells correlates with reduced efficacyof the immune response to respiratory viral challenges, despitestable numbers of memory T cells in the spleen (101). Thisfinding suggests that lung effector memory T cells help mediateimmune responses to recall viral infections, possibly throughtheir production of cytokines, including IFN-�, which may limitviral replication and dissemination (102, 103).

Lung effector memory CD8� T cells express high levels ofreceptors typically associated with acute activation, which distin-guishes them from memory T cells in secondary lymphoid organs(95, 100, 104, 105). For this reason, they have been called “persis-tently activated T cells.” The presence of these persistently acti-vated T cells in the lungs offers a potential but unproven explana-tion for the large numbers of lymphocytes seen in the airways

Curtis, Freeman, and Hogg: COPD Immunopathogenesis 517

of patients with COPD (106). Evidence supports the existenceof specific antiviral resident lung CD8� T cells in humans (107).However, it is unresolved whether effector memory T cells aresimply retained for long periods within lung parenchyma, asoriginally suggested, or depend on prolonged local antigen stimu-lation, as implied by some recent experimental data (108–110).

During a recall viral challenge, the T-cell receptor repertoiremay gain additional clones via a new primary T-cell responsethat develops in tandem with the existing memory response(111–113). However, repeated T-cell receptor stimulation, as inchronic infections, can actually decrease CD4 effector expansionand cytokine production, and impair migration. In mice lethallychallenged with influenza virus, repeatedly stimulated Th1 ef-fectors were unable to provide protective immune responses(114). Emulating the real world, in which people are exposedto multiple viruses, murine models have shown that antigen-specific memory T cells have a role in the response to unrelatedviruses, a phenomenon known as heterologous immunity (115,116). In mice sequentially infected with four different viruses,each successive infection reduced memory CD8 T cells to thepreviously encountered viruses (117, 118). These murine dataare generally interpreted to imply that there is a limit to the sizeof the total memory T-cell pool, but one human study contradictsthis view (119).

Experimentally, memory T-cell populations generated in re-sponse to one virus can actually alter the course of disease inresponse to an unrelated virus (120). Heterologous immunitycan skew Th1/Th2 responses and immunodominance, possiblyleading to a less effective or even potentially harmful T-cellresponse (121, 122). Direct support for the relevance of theseconcepts in humans is currently modest, but does come fromthe experience in dengue, and from recent analysis of Epstein-Barr infections (123). Thus, the repertoire of viruses to whichindividual patients have been exposed might result in an inappro-priately severe or weak immune response, and have an impacton the development or the course of COPD, a point to whichwe will return.

Is COPD a Type 1 Cytokine–mediated Disease?

The bulk of existing data indicate that lung lymphocytes inCOPD are type 1 cytokine-producing CD8 T cells (i.e., Tc1 cells)(49, 71, 79, 124) that may be identical to the persistently activatedmurine memory T cells. However, many AECOPD symptoms,such as mucus production, increased cough, and airway edema,are more typically linked in vivo to the type 2 cytokines, IL-13and IL-9 (125–127). Two recent studies suggest that Tc2 cytokinescould also be crucial in COPD (128, 129). Perhaps, as in asthma,both cytokine phenotypes contribute.

However, recent developments in cytokine biology imply thatCOPD might be better explained by the T helper 17 (Th17) pheno-type. IL-17A, the prototype of a new cytokine family, is a 20–30kD glycosylated homodimeric cytokine produced exclusively byT cells (130). IL-17 induces bronchial epithelial cells and fibro-blasts to release IL-6 (131); IL-6 and IL-17 are central to mucusproduction by airway epithelial goblet cells and submucosalglands, respectively. In fact, when primary human tracheobron-chial epithelial cells were stimulated using an extensive panelof cytokines, the MUC5AC and MUC5B genes were only in-duced by two cytokines: IL-6 and IL-17 (132). Additionally,IL-17 potently induces epithelial cells to secrete PMN attract-ants—notably, CXCL8 (133, 134). Finally, IL-17 family membersincrease the sensitivity of Mø to pathogen-associated molecularpattern (PAMPs), and may even directly induce tumor necrosisfactor-�, although it is uncertain whether human AMø expressthe IL-17 receptor.

IL-17A can be produced by CD4 and CD8 T cells of bothtype 1 and type 2 cytokine profiles. In mice, IL-17 can also beinduced by IL-15 in CD4 T cells, but not in CD8 T cells. IL-17has been implicated in rheumatoid arthritis and several modelsof autoimmunity. Transgenic overexpression in the alveoli ofIL-17 induces lung inflammation (135). IL-17 has been shownto be increased in the lungs in asthma, but there are little dataon IL-17A production in COPD (131, 136). IL-17A is itselfinduced by a product of the innate immune system, IL-23 (137–139), implying the possibility of positive-feedback loops. Thisand other recently identified cytokine-mediated interactions be-tween the innate and adaptive immune responses could explainvariability in the cardinal symptoms of AECOPD, as describedin the final section.

Why Are Some AECOPD Worse than Others? The“Goldilocks Hypothesis”

In many patients with COPD, the initially silent process of lunginflammation in early GOLD stages becomes punctuated byAECOPD, which accelerate the declines in lung function andfunctional status. Most, but certainly not all, AECOPD havebeen linked to specific infections, which can be bacterial, viral,both, or neither (reviewed elsewhere in this issue). The cardinalsymptoms of AECOPD—increased dyspnea, cough, and mucusproduction—can plausibly be linked to inflammatory cytokines,especially IL-6, which may in turn be driven by a positive-feedback loop between IL-17 and IL-23. Because these cytokinesare induced by a variety of infectious agents, AECOPD severityor duration might relate directly to the pathogenicity of specificorganism(s) infecting the lower respiratory tract.

An unproven alternative we find attractive is that AECOPDsymptom intensity relates to the success of the adaptive immuneresponse in controlling the innate response. We call this the“Goldilocks hypothesis” (Figure 3). Pathogens to which the pa-tient has optimal immunity are cleared rapidly with a minimumof inflammation (i.e., the pulmonary immune response is “justright”). By contrast, we hypothesize that severe, slowly resolving,or relapsing AECOPD result from excessive innate immuneresponses due to two types of inappropriate adaptive pulmonaryimmune responses.

One type of inappropriate adaptive response does not clearthe pathogen (“too little”), because it insufficiently activateslung macrophages, or fails in essential direct cytotoxic roles ofCD8� T cells or NK cells. Such a response could be a directconsequence of immunosuppressive viral products in AECOPDresulting either directly from viruses, or from mixed viral–bacterialinfection. Insufficient responses might also result if repetitiveviral infections have punched “holes” in the diversity of T mem-ory or if chronic colonization had induced T regulatory cellsthat excessively dampen antibacterial responses. In these cases,persistent stimulation of lung pathogen recognition receptorsby PAMPs induces excessive lung inflammation. In a secondtype of inappropriate adaptive response (“too much”), vigorousrecruitment of circulating lymphocytes and immature DCs leadsto excessive or relapsing inflammation. Such a response mightresult when a pathogen expresses antigens recognized by a dis-proportionate fraction of resident lung T cells or memory T cellselsewhere in the body, or from synergy between viral and bacte-rial PAMPs (28). Autoimmune cross-reaction between pathogenand host epitopes might also fuel lung inflammation in someAECOPD. It is important to stress that we do not postulate thatall AECOPD are directly infectious, as airway irritants such asozone might also induce an innate response to PAMPs of airwaycolonizers.

This hypothesis, which we are currently testing in a seriesof observational human trials, has important implications for

518 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 4 2007

AECOPD pathogenesis. For one thing, this model allows a rolefor genetic differences in the immune response to contributepowerfully to AECOPD pathogenesis (e.g., via polymorphismsregulating inflammatory cytokine production, and the effect ofmajor histocompatibility complex alleles on T-cell repertoire).However, based on the tenets of the heterologous response citedpreviously here, this model also predicts a substantial degree ofstochastic variation in response intensity driven by the uniquehistory of respiratory infections of each patient with COPD.

CONCLUSIONS

The first generation of the 21st century is at once a soberingand exciting time for researchers of COPD immunopathogen-esis. Even as COPD prevalence and morbidity continue to in-crease throughout the world, insights from basic immunobiologyand genetics provide myriad opportunities for possible intervention.We are beginning to define the unique “traffic signals” essentialfor recruitment of inflammatory cells to the lungs, and simultane-ously to appreciate the degree to which repeated infection canpopulate the lung with long-lasting sentries. Viral infections havebeen shown to have complex and potentially long-lasting effects,in part by synergizing with other stimuli of innate responseactivation. The intriguing possibility of an autoimmune compo-nent to lung destruction, especially in emphysema, requires, anddeserves, considerably greater investigation.

Conflict of Interest Statement : J.L.C. has been reimbursed by Sepracor for at-tending a conference and received $3,000 in speaker’s fees, and is an investigatorin an ongoing, multicenter clinical trial sponsored by Boehringer Ingelheim. C.M.F.does not have a financial relationship with a commercial entity that has an interestin the subject of this manuscript. J.C.H., during the calendar year 2006, servedas an advisor to Altana, GSK, and Sepracor. He has also given lectures at industry-sponsored events for GSK and Marck, and has received grants through a peer-reviewed Canadian Institutes of Health Research–industry sponsored program inwhich Merck and GlaxoSmithKline have served as industrial partners. He hasreceived less than Can $20,000 as compensation for this work.

Acknowledgment : The authors thank Drs. Fernando J. Martinez, AntonelloPunturieri, Ian Sabroe, Galen B. Toews, Moira K. B. Whyte, and all the membersof the Ann Arbor Veteran’s Affairs Research Enhancement Award Program forhelpful suggestions and discussion, and Joyce O’Brien and Rebecca Weeks forsecretarial support.

Note added in proof : Since submission of this manuscript, Lee and colleagueshave published direct evidence of antielastin autoimmunity in patients with em-physema (140).

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