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Chronic obstructive pulmonary disease (COPD) progression is characterized by accumulation of inflammatory mucous exudates in the lumens of small airways, and thickening of their walls, which become infiltrated by innate and adaptive inflammatory immune cells. Infiltration of the airways by polymorphonuclear and mononuclear phagocytes and CD4 T cells increases with COPD stage, but the cumulative volume of the infiltrate does not change. By contrast, B cells and CD8 T cells increase in both the extent of their distribution and in accumulated volume, with organization into lymphoid follicles. This chronic lung inflammation is also associated with a tissue repair and remodeling process that determines the ultimate pathologic phenotype of COPD. Why these pathologic abnormalities progress in susceptible individuals, even after removal of the original noxious stimuli, remains mysterious. However, important clues are emerging from analysis of pathologic samples from patients with COPD and from recent discoveries in basic immunology. We consider the following relevant information: normal limitations on the innate immune system's ability to generate adaptive pulmonary immune responses and how they might be overcome by tobacco smoke exposure; the possible contribution of autoimmunity to COPD pathogenesis; and the potential roles of ongoing lymphocyte recruitment versus in situ proliferation, of persistently activated resident lung T cells, and of the newly described T helper 17 (Th17) phenotype. We propose that the severity and course of acute exacerbations of COPD reflects the success of the adaptive immune response in appropriately modulating the innate response to pathogen-related molecular patterns (“the Goldilocks hypothesis”).
The defining feature of chronic obstructive pulmonary disease (COPD) is irreversible airflow limitation measured during forced expiration (1, 2). This reduction in maximum expiratory flow may result from either an increase in the resistance of the conducting airways and/or an increase in lung compliance due to emphysematous destruction of the lung's elastic recoil force (3). Airway resistance is measured in units of cm H2O/L/second, and compliance is measured in units of L/cm H2O, and their product (time) determines the time required to empty the lung. FEV1 and its ratio to FVC (FEV1/FVC) are the standard spirometric tests that are used to screen for the presence of airflow limitation and to classify the severity of COPD (1, 2).
The etiology of the airway obstruction and emphysematous destruction that cause airflow limitation is the persistent lung tissue injury produced by the chronic inhalation of toxic particles and gases (1). Figure 1 is modified from a seminal study of the natural history of chronic bronchitis and emphysema conducted by Fletcher and his associates (4), with the more recently introduced Global 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 a minority of the smoking population develop the rapid decline in FEV1 leading to severe (GOLD-3) and very severe (GOLD-4) COPD. In contrast, everyone who smokes has some evidence of lung inflammation (5), and this response appears to be amplified in the minority of smokers that reach the more advanced levels of COPD (6, 7). The mechanism for this amplification step is poorly understood, but probably involves both genetic and/or epigenetic features of the host response, as well as differences in the dose of inhaled particles and gases.
The innate defense system of the lung includes the mucociliary clearance apparatus (8) and epithelial barrier (9), as well as the coagulation and inflammatory cascades that stop the microscopic bleeding associated with tissue injury and bring an exudate of plasma and migrating inflammatory immune cells into the damaged site (10). This innate defense system provides a rapid initial response that can be triggered by a variety of mechanisms, but lacks specificity, has very limited diversity, and has no memory. The tobacco smoking habit interferes with the innate host defense system by increasing mucus production and reducing mucociliary clearance, by disrupting the epithelial barrier and stimulating the migration of polymorphonuclear neutrophils (PMNs), monocyte/macrophages (Mø), CD4+, CD8+, and B-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 and cellular components of the adaptive immune response to provide a much more specific and very diverse reaction that has exquisite memory for previous exposures to foreign material introduced into the lung.
The histologic hallmark of the presence of an adaptive immune response is the presence of lymphoid follicles with germinal centers that are usually found in regional lymph nodes. However, 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 lung function (GOLD-0), as well as those with COPD of mild (GOLD-1) and moderate (GOLD-2) severity (7, 12, 13). Interestingly, these collections of BALT (Figure 2) appear to increase sharply in severe (GOLD-3) and very severe (GOLD-4) COPD, possibly because of an increased adaptive response to the colonization and infection of the lower airways that is known to occur in the advanced stages of COPD (7). However, the increase in BALT may also serve as a marker for an immune response to something in the tobacco smoke itself; to microorganisms and other foreign materials that gain entry into the lower respiratory tract because of depression of the innate defenses; or to autoantigens that develop in repetitively damaged lung tissue (14).
The chronic inflammatory immune process found in lung tissue repetitively damaged by tobacco smoke is also associated with a tissue repair and remodeling process that determines the ultimate pathologic phenotype of COPD. Their presence in the epithelial lining of the larger bronchi and their associated mucus glands produces the structural and functional changes associated with chronic bronchitis (15, 16). When present in the smaller bronchi and bronchioles that become the major site of airway obstruction in COPD, this remodeling process results in occlusion of the lumen by inflammatory exudates containing mucus, thickening of the walls, and narrowing of the lumen of these airways (7). In contrast, the extension of this inflammatory immune process to respiratory bronchioles and alveolar ducts and sacs is associated with emphysematous destruction (6) rather than tissue proliferation seen in the conducting airway tissue (7).
A multivariate analysis of the components of this inflammatory immune repair process conducted to determine the relationship between their presence in the small conducting airways and the decline in FEV1 has shown that more of the variance in FEV1 decline is explained by occlusion of the lumen and thickening of the airway wall than by either the extent (number of airways involved) or severity (accumulated volume of cells) in these airways of any of the inflammatory immune cells present in the tissue (7). These and other studies indicate that the remodeling process is a critical feature of the pathogenesis of the lesions that define the pathology of COPD, but much of the detail concerning the links between the innate and adaptive immune processes and peripheral lung remodeling remain to be worked out.
Why is COPD characterized, even after removal of the original noxious insults, by progressive accumulation of cells of the innate and adaptive immune systems in and around the airways, by peribronchial fibrosis, and by mucus hypersecretion? Subsequently here, we offer suggestions based on known immunologic mechanisms, but it must be appreciated that the understanding of how they might apply to COPD is still in its infancy. Emphasis is on recent discoveries, areas requiring further study, and clues from experimental studies that may be less well known to clinical researchers. We examine two types of evidence, each with strengths and limitations. Analysis of human samples discloses associations between clinical outcomes and cell types, inflammatory mediators, or other gene products. This type of inquiry is essential but inevitably limited by sample availability and ethical constraints on definitive experimentation. An alternative method is to seek candidate mechanisms and molecules from animal models, an approach currently hobbled by the chronicity of COPD and the relative resistance of mice to cigarette smoke–induced injury. Current murine models have been more successful for studying emphysema (17) than chronic bronchitis. The relative merits of these two approaches in asthma have been argued recently (18, 19). We continue to see them as complementary elements in a dialog in which the results of animal experiments are used to develop cogent mechanistic hypotheses to be examined for relevance to human diseases.
A first approach to the question posed above is to consider how pulmonary immune response generation is normally constrained to preserve gas exchange despite the daily onslaught of inhaled and aspirated stimuli. Alveolar macrophage (AMø) activation is tonically inhibited by transforming growth factor-β1 bound to αvβ6-integrin on alveolar epithelial cells; in murine models, loss of this inhibition induces matrix metalloproteinase-12 and emphysema (20, 21). Control of AMø production of proinflammatory mediators also comes from their distinct regulation of DNA binding by the transcription factors, Ref-1 and activator protein-1 (AP-1) (22), and by their abundant expression of peroxisome proliferator–activated receptor-γ (23). AMø can migrate to regional nodes (24), but have limited ability to activate naive T cells. Collectively, these properties imply that the AMø is highly evolved to survey the alveolar environment without inducing excessive inflammation.
Stimulating AMø via any of the known Toll-like receptors releases them from transforming growth factor-β–mediated inhibition (25), and vigorously induces inflammatory cytokines and chemokines. However, because AMø lack the feed-forward amplification mediated in other mononuclear phagocyte subtypes by autocrine secretion of IFN-β and signal transducer and activator of transcription 1 activation, AMø require exogenous IFN to mount a second phase of host defense (26, 27). Thus, the normal AMø response is rapid, yet restrained from producing damaging effector molecules without additional signals. AMø are responsive to IFN produced by multiple lung cell types during viral respiratory infections. IFN-β converts the normally weakly stimulatory outer membrane proteins of nontypeable Haemophilus influenzae into potent inducers of IL-6 production by both murine and human AMø (28). Given the importance of IL-6, which is outlined subsequently here, this finding may help to explain the association of viral respiratory infections with acute exacerbations of COPD (AECOPD).
Cigarette smoke induces a distinctive pattern of AMø gene expression not seen in nonsmokers or patients with asthma (29). Interestingly, although AMø of smokers strongly express matrix metalloproteinase-12, shown to be essential for emphysema in a murine model of cigarette smoke exposure (30), most of the 72 genes up-regulated in smokers relative to healthy nonsmoking control subjects were not identified in two transgenic murine models of emphysema (29). The lack of global comparisons of gene expression between human smokers and mice exposed to cigarette smoke makes it uncertain whether murine models might accelerate understanding of COPD immunopathogenesis, even if they so far fail to mimic human pathology completely.
The normal lung contains potent antigen-presenting cells in the form of DCs (31), the best described function of which is to migrate in a CC chemokine receptor (CCR) 7–dependent fashion to regional lymph nodes, where they activate naive T cells to proliferate. All four types of DC previously identified in peripheral blood (32, 33) have been identified in the lungs. These are: myeloid DC types 1 and 2, which are blood DC antigen 1+ (BDCA1+) and BDCA3+, respectively; plasmacytoid DCs, positive for both the IL-3 receptor (CD123) and BDCA2; and CD1a+ DCs (32, 34). DCs and NK cells appear to regulate one another's maturation reciprocally (35). Thus, NK cells exposed to DC-produced IL-12 enhance DC maturation and their capacity to secrete IL-12 (and, hence, to foster type 1 responses), whereas NK cells exposed to IL-4 favor DCs that are tolerogenic or inducers of type 2 responses (36). DC-activated NK cells also kill immature DCs (37), presumably to reinforce local immune response polarization to the most recently encountered pathogens.
Conflicting data exist on how cigarette smoke exposure affects DC number and immune function. In mice, smoke exposure has been reported to increase (38) or decrease lung DC numbers, to impair antiviral host defenses (39), and to increase (40) or decrease (41) lung DC expression of costimulatory molecules. One study found that smoke exposure increased numbers of Langerhans-type DCs in mice and induced changes resembling eosinophilic granulomatosis (42), a disease strongly associated with smoking. The reason for these disparate results is not immediately apparent, but standardization of smoke exposures in murine models is clearly needed to facilitate comparison between results from different laboratories. Ex vivo exposure to cigarette smoke extract skewed the priming ability of human monocyte-derived DCs from a Th1 to a Th2 phenotype (43). The effect on lung DC numbers and function of exposure to tobacco smoke or other oxidants, or of varying COPD severities and phenotypes, has not been studied systematically, and is an important, unmet research goal.
From the onset, investigators of COPD pathogenesis have debated the relative contributions of direct toxic effects of cigarette smoke (“the American hypothesis”) and the role of chronic infection (“the British hypothesis”). A novel twist, that an acquired immune response to newly created or altered epitopes is an essential component of COPD pathogenesis, has been advanced by several groups (14, 44). A possible autoimmune component to COPD is supported by the marked oligoclonality of CD4+ T cells isolated from resected emphysematous human lung tissue (45), but this finding might also reflect retention of clones specific for exogenous antigens (e.g., E1A protein) due to latent adenoviral infection (6). Additional support comes from an intriguing animal model system devised by Taraseviciene-Stewart and associates (46). Adult rats immunized with human pulmonary vein endothelial cells or pulmonary artery smooth muscle cells plus adjuvant develop significant emphysema. One elusive key point is whether autoantibodies in patients with emphysema are etiologic or are a result of tissue damage (i.e., cause vs. effect), but the entire autoimmune hypothesis does not rest on that result. That the immunologic mechanisms driving pannus formation in rheumatoid arthritis could be shared in some way with COPD is a tantalizing possibility.
The growing literature on apoptosis as a driving force in emphysema pathogenesis (47–49) is directly germane. In systemic lupus erythematosus, defective apoptotic cell clearance provides the self-antigens essential for autoantibody formation; whether this could be the case in COPD is unknown. Normal AMø show a markedly reduced capacity to ingest apoptotic cells relative 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 unique antiinflammatory state in Mø (54–56), defective clearance might be one factor encouraging lung inflammation.
Peripheral immune responses typically require recruitment of multiple types of hematopoietic cells from the bloodstream. This process has been demonstrated in asthma by acute bronchial challenge, and is clearly the case in pneumonia. Whether the chronic infiltration of the lung parenchyma in COPD also depends heavily on recruitment, or, once initiated, can be sustained by local proliferation, is largely unstudied. Defining the balance between these two processes is crucial to designing novel therapeutic strategies—antirecruitment strategies are worth developing only if continuous recruitment is essential for lung inflammation to persist.
Leukocyte recruitment is regulated by endothelial cell display of distinct combinations of adhesion receptors and chemokines, with the exact combinations varying between organs and hematopoietic cell types. Recruitment of lymphocytes to the prominent BALT of the nonobese diabetic mouse strain depends on lymphocyte L-selectin (CD62L), α4β1-integrin (CD29/CD49d), and lymphocyte function–associated antigen-1 (CD18/CD11a) interacting with their respective endothelial ligands (57). In murine models of acute antigen-driven lung recruitment, the endothelial selectins E-selectin (CD62E) and P-selectin (CD62P) are required by CD8 T cells, Th1 CD4 T cells and B cells, but not by monocytes, immature DCs, γδ T cells, or Th2 CD4 T cells (58–62). However, the finding that T-cell recruitment and even germinal center formation in the lungs of mice infected with Mycobacterium tuberculosis are independent of selectin ligand expression (63) implies that chronic infection might induce alternative mechanisms of lung leukocyte recruitment. Expression of selectins and other adhesion molecules on the lung vasculature in COPD is unreported, but important to define, given the imminent availability of therapeutic agents to block this adhesive pathway (64).
Cigarette smoke or other airway irritants have been postulated to induce AMø, alveolar epithelial cells, or DCs to secrete chemotactic factors for inflammatory cells. Correlations between chemokine levels in sputum, bronchoalveolar lavage (BAL) fluid, and lungs of patients with COPD and lung function or inflammatory cell numbers help to identify potential mediators of cellular influx in COPD. A modest number of reports have described chemokine and chemokine receptor expression in COPD. CC chemokine ligand (CCL) 2, a known chemoattractant for human monocytes/Mø and T cells, was increased in sputum, BAL fluid, and lungs of patients with COPD (65–67), whereas expression of its receptor, CCR2, was increased in AMø of subjects with COPD. These findings suggest that CCL2 and CCR2 may be involved in the recruitment of monocytes and immature DCs into the airways in COPD (67), roles supported by murine data (62, 68, 69). CCR5 has also been implicated in COPD immunopathogenesis. Numbers of airway CCR5+ T cells were increased in patients with COPD with mild to moderate disease severity, but not in those with severe COPD (70, 71). Likewise, CCL4, a ligand for CCR5, was increased in BAL fluid of patients with mild to moderate airflow limitation and chronic bronchitis (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 of leukocyte types. CXCL1 and CXCL8, ligands for CXCR1 and CXCR2, are elevated in induced sputum and BAL fluid from patients with COPD as compared with normal smokers and nonsmokers (65, 73, 74). CXCL8 (previously known as IL-8) is a potent PMN chemoattractant; unsurprisingly, CXCL8 concentrations in sputum and BAL fluid correlate with increased PMN accumulation (75). In rodent models of cigarette smoke exposure, a small molecule inhibitor of CXCR2 reduced PMN influx to the lungs (76, 77). Several CXCR2 inhibitors are now in clinical development for COPD (78). Numbers of CXCR3+ cells (chiefly, CD8+ T cells) in the epithelium and submucosa were increased in smokers with COPD, as compared with nonsmokers (79). Furthermore, CXCL10, a CXCR3 ligand, was expressed in bronchiolar epithelial cells and airway smooth muscle cells, suggesting that CXCR3/CXCL10 interactions may be involved in T-cell recruitment or retention in COPD. Although chemotaxis is the signature feature of chemokines and chemokine receptors, investigation should also focus on their other effects on inflammatory cells, including proliferation, differentiation, retention, and survival.
To date, no chemotactic factors have been shown to be unique to COPD, as opposed to lung inflammation due to other causes, or indeed, to inflammation in other organs. However, several instances of tissue-specific lymphocyte homing have been demonstrated, and the molecular basis for two, the gut and the skin, is increasingly becoming understood. The ability to home to the small intestine depends on high levels of α4β7-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 α4β7-integrin and CCR9, and to home to the gut in vivo, even though DCs from Peyer's patches, peripheral lymph nodes, or spleen all induced equivalent activation markers and effector activity (80). This induction of gut tropism 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 inducing CCR10-mediated responsiveness to the skin-specific chemokine CCL27 (82). Whether analogous lung-specific lymphocyte tropism exists, and if so, whether lung-draining DCs can similarly induce it, are currently unknown.
The presence of well-developed lymphoid follicles containing germinal centers in GOLD-3 to GOLD-4 COPD argues for at least a component of local proliferation. Lymphoid follicles are also a feature of severe chronic inflammation in several organ-specific autoimmune diseases, including rheumatoid arthritis, Sjögren's syndrome, and Hashimoto thyroiditis. Development of such structures, termed lymphoneogenesis, typically depends on lymphotoxin-α and the chemokine, CXCL13, the same factors that are crucial for formation of secondary lymphoid structures during ontogeny (83–85). Neither of these factors has been examined in COPD. However, this paradigm may not apply completely to the lungs, based on the results of experimental influenza infection in gene-targeted mice devoid of lymphotoxin-α (86). These mice, which lack spleen, lymph nodes, and Peyer's patches, show very abnormal primary response to antigen and allografts, but do develop intrapulmonary antigen-specific T- and B-cell responses to respiratory viruses (with delayed kinetics). Organized peribronchovascular lymphoid aggregates also develop in double-transgenic mice expressing both IL-6 and the IL-6 receptor (87). However, because these mice also develop hepatosplenomegaly, systemic lymphadenopathy, and glomerulonephritis, it is unclear to what degree this model system is relevant to advanced COPD. In addition to being the most important inducer of acute-phase protein synthesis, IL-6 also mediates T-cell activation, growth, differentiation, and survival. IL-6 expression is elevated in BAL fluid in COPD, appears to correlate with disease severity (74), and increases during exacerbations (88). In vivo evidence supports a role for IL-6 in amplifying leukocyte recruitment to sites of inflammation (89).
In COPD, CD4 and CD8 T cells accumulate in the alveolar walls, with CD8+ cells predominating. The stimulus for this accumulation is largely unknown, but one plausible contributor is the immune response to respiratory viral infections, common in patients with COPD. After viral infections, both CD4 and CD8 memory T cells persist at stable frequencies in peripheral organs without any obvious reexposure in mice (90–96), and for 4–18 years in peripheral blood in humans (97–99). Effector memory T cells can be harbored in the lung tissue and airways; murine models of both influenza and Sendai virus infections show that memory CD4 and CD8 T cells can be recovered from the lung for 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 initially quite high, and comprises two population (100). A proliferating minority population probably accounts for the long-term stabilization of airway T-cell numbers. The majority population does not proliferate, leading to a decline in absolute numbers over the next 6 months (a substantial percentage of the life of a mouse), with a half-life of approximately 40 days (91). The net loss of airway memory T cells correlates with reduced efficacy of the immune response to respiratory viral challenges, despite stable numbers of memory T cells in the spleen (101). This finding suggests that lung effector memory T cells help mediate immune responses to recall viral infections, possibly through their production of cytokines, including IFN-γ, which may limit viral replication and dissemination (102, 103).
Lung effector memory CD8+ T cells express high levels of receptors typically associated with acute activation, which distinguishes them from memory T cells in secondary lymphoid organs (95, 100, 104, 105). For this reason, they have been called “persistently activated T cells.” The presence of these persistently activated T cells in the lungs offers a potential but unproven explanation for the large numbers of lymphocytes seen in the airways of patients with COPD (106). Evidence supports the existence of specific antiviral resident lung CD8+ T cells in humans (107). However, it is unresolved whether effector memory T cells are simply retained for long periods within lung parenchyma, as originally suggested, or depend on prolonged local antigen stimulation, as implied by some recent experimental data (108–110).
During a recall viral challenge, the T-cell receptor repertoire may gain additional clones via a new primary T-cell response that develops in tandem with the existing memory response (111–113). However, repeated T-cell receptor stimulation, as in chronic infections, can actually decrease CD4 effector expansion and cytokine production, and impair migration. In mice lethally challenged with influenza virus, repeatedly stimulated Th1 effectors were unable to provide protective immune responses (114). Emulating the real world, in which people are exposed to multiple viruses, murine models have shown that antigen-specific memory T cells have a role in the response to unrelated viruses, 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 the previously encountered viruses (117, 118). These murine data are generally interpreted to imply that there is a limit to the size of the total memory T-cell pool, but one human study contradicts this view (119).
Experimentally, memory T-cell populations generated in response to one virus can actually alter the course of disease in response to an unrelated virus (120). Heterologous immunity can skew Th1/Th2 responses and immunodominance, possibly leading to a less effective or even potentially harmful T-cell response (121, 122). Direct support for the relevance of these concepts in humans is currently modest, but does come from the experience in dengue, and from recent analysis of Epstein-Barr infections (123). Thus, the repertoire of viruses to which individual patients have been exposed might result in an inappropriately severe or weak immune response, and have an impact on the development or the course of COPD, a point to which we will return.
The bulk of existing data indicate that lung lymphocytes in COPD are type 1 cytokine-producing CD8 T cells (i.e., Tc1 cells) (49, 71, 79, 124) that may be identical to the persistently activated murine 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-13 and IL-9 (125–127). Two recent studies suggest that Tc2 cytokines could also be crucial in COPD (128, 129). Perhaps, as in asthma, both cytokine phenotypes contribute.
However, recent developments in cytokine biology imply that COPD might be better explained by the T helper 17 (Th17) phenotype. IL-17A, the prototype of a new cytokine family, is a 20–30 kD glycosylated homodimeric cytokine produced exclusively by T cells (130). IL-17 induces bronchial epithelial cells and fibroblasts to release IL-6 (131); IL-6 and IL-17 are central to mucus production by airway epithelial goblet cells and submucosal glands, respectively. In fact, when primary human tracheobronchial epithelial cells were stimulated using an extensive panel of cytokines, the MUC5AC and MUC5B genes were only induced by two cytokines: IL-6 and IL-17 (132). Additionally, IL-17 potently induces epithelial cells to secrete PMN attractants—notably, CXCL8 (133, 134). Finally, IL-17 family members increase the sensitivity of Mø to pathogen-associated molecular pattern (PAMPs), and may even directly induce tumor necrosis factor-α, although it is uncertain whether human AMø express the IL-17 receptor.
IL-17A can be produced by CD4 and CD8 T cells of both type 1 and type 2 cytokine profiles. In mice, IL-17 can also be induced by IL-15 in CD4 T cells, but not in CD8 T cells. IL-17 has been implicated in rheumatoid arthritis and several models of autoimmunity. Transgenic overexpression in the alveoli of IL-17 induces lung inflammation (135). IL-17 has been shown to be increased in the lungs in asthma, but there are little data on IL-17A production in COPD (131, 136). IL-17A is itself induced by a product of the innate immune system, IL-23 (137–139), implying the possibility of positive-feedback loops. This and other recently identified cytokine-mediated interactions between the innate and adaptive immune responses could explain variability in the cardinal symptoms of AECOPD, as described in the final section.
In many patients with COPD, the initially silent process of lung inflammation in early GOLD stages becomes punctuated by AECOPD, which accelerate the declines in lung function and functional status. Most, but certainly not all, AECOPD have been linked to specific infections, which can be bacterial, viral, both, or neither (reviewed elsewhere in this issue). The cardinal symptoms of AECOPD—increased dyspnea, cough, and mucus production—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 cytokines are induced by a variety of infectious agents, AECOPD severity or duration might relate directly to the pathogenicity of specific organism(s) infecting the lower respiratory tract.
An unproven alternative we find attractive is that AECOPD symptom intensity relates to the success of the adaptive immune response in controlling the innate response. We call this the “Goldilocks hypothesis” (Figure 3). Pathogens to which the patient has optimal immunity are cleared rapidly with a minimum of inflammation (i.e., the pulmonary immune response is “just right”). By contrast, we hypothesize that severe, slowly resolving, or relapsing AECOPD result from excessive innate immune responses due to two types of inappropriate adaptive pulmonary immune responses.
One type of inappropriate adaptive response does not clear the pathogen (“too little”), because it insufficiently activates lung macrophages, or fails in essential direct cytotoxic roles of CD8+ T cells or NK cells. Such a response could be a direct consequence of immunosuppressive viral products in AECOPD resulting either directly from viruses, or from mixed viral–bacterial infection. Insufficient responses might also result if repetitive viral infections have punched “holes” in the diversity of T memory or if chronic colonization had induced T regulatory cells that excessively dampen antibacterial responses. In these cases, persistent stimulation of lung pathogen recognition receptors by PAMPs induces excessive lung inflammation. In a second type of inappropriate adaptive response (“too much”), vigorous recruitment of circulating lymphocytes and immature DCs leads to excessive or relapsing inflammation. Such a response might result when a pathogen expresses antigens recognized by a disproportionate fraction of resident lung T cells or memory T cells elsewhere in the body, or from synergy between viral and bacterial PAMPs (28). Autoimmune cross-reaction between pathogen and host epitopes might also fuel lung inflammation in some AECOPD. It is important to stress that we do not postulate that all AECOPD are directly infectious, as airway irritants such as ozone might also induce an innate response to PAMPs of airway colonizers.
This hypothesis, which we are currently testing in a series of observational human trials, has important implications for AECOPD pathogenesis. For one thing, this model allows a role for genetic differences in the immune response to contribute powerfully to AECOPD pathogenesis (e.g., via polymorphisms regulating inflammatory cytokine production, and the effect of major histocompatibility complex alleles on T-cell repertoire). However, based on the tenets of the heterologous response cited previously here, this model also predicts a substantial degree of stochastic variation in response intensity driven by the unique history of respiratory infections of each patient with COPD.
The first generation of the 21st century is at once a sobering and exciting time for researchers of COPD immunopathogenesis. Even as COPD prevalence and morbidity continue to increase throughout the world, insights from basic immunobiology and genetics provide myriad opportunities for possible intervention. We are beginning to define the unique “traffic signals” essential for recruitment of inflammatory cells to the lungs, and simultaneously to appreciate the degree to which repeated infection can populate the lung with long-lasting sentries. Viral infections have been shown to have complex and potentially long-lasting effects, in part by synergizing with other stimuli of innate response activation. The intriguing possibility of an autoimmune component to lung destruction, especially in emphysema, requires, and deserves, considerably greater investigation.
The authors thank Drs. Fernando J. Martinez, Antonello Punturieri, Ian Sabroe, Galen B. Toews, Moira K. B. Whyte, and all the members of the Ann Arbor Veteran's Affairs Research Enhancement Award Program for helpful suggestions and discussion, and Joyce O'Brien and Rebecca Weeks for secretarial support.
Note added in proof: Since submission of this manuscript, Lee and colleagues have published direct evidence of antielastin autoimmunity in patients with emphysema (140).
Supported by National Heart Lung and Blood Institute, United States Public Health Service grants RO1 HL082480, T32 HL07749, and RO1 HL063117; Merit Review funding; a Research Enhancement Award Program grant from the Biomedical and Laboratory Research and Development Service, Department of Veterans Affairs; and by Canadian Institutes of Health Research grant 7246.
Conflict of Interest Statement: J.L.C. has been reimbursed by Sepracor for attending a conference and received $3,000 in speaker's fees, and is an investigator in 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 interest in the subject of this manuscript. J.C.H., during the calendar year 2006, served as 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 in which Merck and GlaxoSmithKline have served as industrial partners. He has received less than Can $20,000 as compensation for this work.