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Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Correspondence and requests for reprints should be addressed to Steven R. Duncan, M.D., NW 628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213. E-mail: duncsr{at}upmc.edu
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, and one of the few major diseases in which mortality continues to rise (1). There is a growing body of evidence that implies that adaptive immune responses could play a role in the pathogenesis of COPD (2–4). As with other immune-mediated diseases, activated effector lymphocytes can result in direct cytopathic effects, elaborate diverse proinflammatory mediators, and recruit and activate other "downstream" effector cells (5–8). Armed effector T cells have been specifically implicated in a variety of tissue injuries, including epithelial necrosis and fibroproliferation (8). Histologic and morphometric analyses confirm an increase in cellular inflammation and further suggest a correlation between this response and advancing disease, as defined by GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria (9, 10). Subepithelial lymphoid aggregates (BALT) have an increased prevalence in advanced COPD (10). These reports are highly suggestive that an immune stimulus and corresponding response appear relevant to the pathogenesis of COPD. We characterized phenotypic alterations in T lymphocytes of subjects with COPD and demonstrated that they are indeed activated and elaborate proinflammatory cytokines capable of promoting tissue injuries.
Some of the results of these studies have been previously reported in the form of an abstract (11).
METHODS
Current and former smokers with no history of asthma and at least a 10-pack-year history of smoking were recruited through the Emphysema–COPD Research Registry at the University of Pittsburgh Medical Center. All subjects were rigorously characterized, including a complete history and physical, spirometry, diffusion capacity, plethysmography, sputum, and symptom scores, and chest computed tomography scan. Peripheral blood was obtained from each subject after informed consent. Peripheral blood mononuclear cells were isolated by density gradient centrifugation (Histopaque 1.077; Sigma-Aldrich Biotechnology, St. Louis, MO), and stained for selected cell surface markers and intracellular cytokines (after stimulation with PMA and ionomycin in the presence of Golgistop) with monoclonal antibodies. Flow cytometry was used to determine expression of cell surface markers and cytokine elaboration. Expressions were quantified after gating on live lymphocyte populations (> 10,000 events). Blood samples obtained from age-matched nonsmokers (n = 20) were used as controls.
RESULTS
A total of 65 subjects have been recruited to date. The average age is 64 yr and 58% are male. Subjects had an average smoking history of 54 pack-years and 23% were currently smoking. Subjects were well distributed across GOLD stages, with 17 subjects with GOLD 0–1, 19 with GOLD 2, 14 with GOLD 3, and 15 with GOLD stage 4 disease.
CD4+ T cells from patients with COPD demonstrated significant down-regulation of CD28, a costimulatory molecule, as compared with control subjects. Similar findings have been reported in immune diseases characterized by chronic or repeated antigen exposure, including autoimmune disorders and lung transplant rejection (12, 13). A significantly greater number of CD4 lymphocytes from patients with COPD produced transforming growth factor (TGF)-ß1 as compared with those from control subjects (24 vs. 2%; p < 0.0001). When subjects were stratified by GOLD staging, TGF-ß1 elaboration positively correlated with disease severity. There was also an apparent trend for greater interleukin (IL)-2 production by CD4 T cells from patients with advanced COPD (GOLD stages 3 and 4), compared with those with less extensive disease (p = 0.06).
CD8+ T cells from subjects with COPD showed a higher degree of activation as assessed by expression of major histocompatibility class (MHC) II, and the magnitude of this abnormality was correlated with disease severity (as defined by GOLD criteria). A significantly greater number of COPD CD8+ T cells in patients with advanced GOLD stages also produced IFN-
(p < 0.05). In addition, IL-8 and TGF-ß1 elaborations were also correlated with disease extent (Figure 1).
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COPD is a complex disease with evidence of local tissue destruction as well as systemic effects. Although smoking is the primary risk factor for disease, there is evidence to support a role for adaptive immune responses in the pathogenesis and progression of COPD (2–4). In an initial effort to characterize the adaptive immune response in patients with COPD, we examined peripheral blood T-lymphocyte populations to identify alterations in degree of activation and proinflammatory cytokine elaboration as compared with control subjects.
CD4+ T cells from subjects with COPD demonstrated significant down-regulation of CD28, a costimulatory molecule. Similar findings have been described in several chronic immune disorders, including autoimmune diseases (12) and chronic lung allograft rejection (13). This particular finding may have special relevance in light of recent implications that emphysema may have an autoimmune etiology (14). In addition, CD4+ lymphocytes from patients with severe COPD produced greater amounts of TGF-ß1, which is known to have an effect on extracellular matrix deposition by myofibroblasts (15) and could play a role in airway remodeling. In addition, TGF-ß1 has been shown to down-regulate ß2-adrenergic receptors (4) and could thus play a role in abrogating the bronchodilator response of ß2-agonists.
CD8+ lymphocyte populations of patients with COPD demonstrate a higher degree of activation compared with control subjects, as assessed by MHC class II expression, and this abnormality positively correlated with disease severity. Elaborations of several other proinflammatory cytokines by CD8+ T cells were also correlated with disease stage, including IFN-, IL-8, and TGF-ß1. IFN- can mediate apoptosis of type I pneumocytes via CXCR3 chemokines, whereas IL-8 is a potent neutrophil chemoattractant with considerable potential importance in COPD (4). Several other reports have shown CD8+ T cells are increased in histologic sections of emphysema, as well as in bronchoalveolar lavage from patients with COPD (2–4, 10). Our findings suggest an armed effector CD8+ lymphocyte phenotype correlates with disease severity, with considerable potential to mediate tissue injury by production of proinflammatory cytokines.
In summary, T-lymphocyte subpopulations in subjects with COPD demonstrate a markedly abnormal effector phenotype, and elaborate inflammatory cytokines implicated in the pathogenesis of COPD. These findings correlate with disease severity, implicating a role for adaptive immunity in the progression of this disease.
FOOTNOTES
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form March 17, 2006; accepted in final form May 6, 2006)
REFERENCES
This article has been cited by other articles:
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  C. A. Feghali-Bostwick, A. S. Gadgil, L. E. Otterbein, J. M. Pilewski, M. W. Stoner, E. Csizmadia, Y. Zhang, F. C. Sciurba, and S. R. Duncan Autoantibodies in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., January 15, 2008; 177(2): 156 - 163. [Abstract] [Full Text] [PDF]
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K. F. Rabe, B. Beghe, F. Luppi, and L. M. Fabbri Update in Chronic Obstructive Pulmonary Disease 2006 Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1222 - 1232. [Full Text] [PDF]
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