We searched Medline for the past 10 years with the search terms “COPD” or “emphysema” in combination with one of the following terms: “immunity”, “macrophages”, “neutrophils”, “mast cells”, “natural killer cells”, “T-cells (Th1, Th2, Th17, or Treg)”, “B-cells” or “(auto)antibodies”. We largely selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications. The date of the last search was April 26, 2011. We also searched the reference
SeriesNew insights into the immunology of chronic obstructive pulmonary disease
Introduction
Chronic obstructive pulmonary disease (COPD) affects more than 200 million people worldwide and is the fourth leading cause of death.1 Although the major environmental risk factor for COPD is tobacco smoking, only 20% of smokers develop COPD.2 Indoor air pollution from burning biomass fuels is associated with an increased risk of COPD in developing countries.3
Immune dysregulation arises in the peripheral blood of patients with COPD, and might contribute to the pathogenesis of the extrapulmonary effects of the disorder.4, 5 Although overspill of inflammation in the lung into the circulation is suggested to cause systemic inflammation in a subset of patients with COPD,4 other pathogenic mechanisms such as smoking, ageing, abdominal obesity, and physical inactivity are probably involved.6 We focus on the role of local immune responses in the airways and lungs in the pathogenesis and progression of COPD due to cigarette smoking (figure 1). Table 1 shows characteristics of the innate and adaptive immune system.
Several mechanistic concepts have been implicated in the pathogenesis of COPD. First, the hallmark of COPD is development of exaggerated chronic inflammation in the lung in response to inhalation of cigarette smoke compared with smokers without lung disease.7 Host factors including genetic susceptibility, epigenetic changes, and oxidative stress (webappendix p 2) contribute by amplifying inflammation induced by cigarette smoke. Second, patients with deficiency of α1-antitrypsin, the main inhibitor of neutrophil elastase, develop emphysema early in life,8 due to an imbalance between proteinases and antiproteinases leading to a net increase in proteolytic activity. Third, an imbalance between oxidants and antioxidants in the lungs of patients with COPD, resulting in excessive oxidative stress, not only amplifies airway inflammation in smokers, but also induces cell death of structural cells in the lung (mainly alveolar epithelial and endothelial cells).9 Disruption of the balance between cell death and replenishment of structural cells in the lung contribute to the destruction of alveolar septa, leading to emphysema. Additionally, age-related changes and cellular senescence further impair tissue repair in response to repetitive cigarette smoke-induced injury of the lungs.10 Autoimmunity has been proposed as a late pathogenic event in the progressive course of the disease.11 The diverse mechanisms do not operate separately in the pathogenesis of COPD, but are strongly interrelated. Oxidative stress, for example, contributes to the imbalance between proteinase and antiproteinase by inactivating antiproteinases, whereas an excess of apoptotic cells leads to secondary necrosis and can exaggerate continuing pulmonary inflammation.12, 13
Section snippets
Innate immune responses in COPD
To prevent invasion of pathogenic microbes into the lower respiratory tract, the airways and lungs have innate defence mechanisms encompassing the epithelial barrier, mucociliary clearance, humoral factors (eg, antimicrobial peptides, complement proteins, and surfactant proteins) and cells that participate in innate immunity: macrophages, dendritic cells, monocytes, neutrophils, natural killer cells, and mast cells.
The first step towards the induction of innate immune responses is recognition
Dendritic cells and innate and adaptive immunity
Dendritic cells are specialised antigen-presenting cells that link innate and adaptive immune responses (figure 1 and webappendix p 3).33 By the integration of many signals of the microenvironment dendritic cells promote CD4+ T helper (Th) cell differentiation and CD8+ cytotoxicity (figure 3). Smoking of cigarettes has been associated with an expansion in the population of Langerhans-like dendritic cells in the epithelial surface of the lower respiratory tract. After acute smoke exposure,
Adaptive immune responses in COPD
In both the airway and alveolar compartment, the CD8+ cytotoxic T cell is the predominant T cell in patients with COPD.11, 23 The number of pulmonary CD8+ T cells in COPD increases substantially with higher stages of airflow limitation and emphysema.23 The expression of the chemokine receptor CXCR3, preferentially expressed on type 1 T lymphocytes, and its ligand interferon-induced protein 10 (also known as CXCL10) (table 3) is increased in peripheral airways of smokers with COPD, suggesting
Infection in COPD
Infections of the respiratory tract contribute to the pathogenesis and course of COPD in at least two different ways.57 First, viral and bacterial infections are the most important cause of acute exacerbations of COPD. As airflow obstruction progresses in COPD, the frequency of exacerbations greatly increases.58 Second, colonisation and chronic infection of the lower airways by respiratory pathogens can amplify and perpetuate chronic inflammation in stable COPD. The frequency of chronic
Is COPD an autoimmune disease?
On the basis of the presence of B-cell lymphoid follicles in patients with advanced COPD and the detection of diverse autoantibodies in serum of a subgroup of patients with COPD,44, 73, 74 COPD has been regarded as an autoimmune disease.11 Lee and colleagues44 showed the presence of antielastin antibody and Th1 responses in patients with COPD, which correlated with severity of emphysema. However, several other research groups could not detect increased antielastin antibody titres in patients
Why does pulmonary inflammation persist despite smoking cessation?
Airway inflammation in patients with COPD persists after smoking cessation.76 Although autoimmunity might contribute to the perpetuation of pulmonary inflammation in a subgroup of patients with advanced COPD and emphysema, several other mechanisms are likely to be involved in persistence of the inflammatory response despite smoking cessation. These mechanisms are not mutually exclusive and encompass self-perpetuating innate immune responses, airway wall remodelling, impaired macrophage
Therapeutic implications
Smoking cessation attenuates the accelerated decrease in lung function in patients with COPD.87, 88 A pooled analysis of three bronchial biopsy studies showed that, in established COPD, the numbers of inflammatory cells in the bronchial mucosa are much the same as in former smokers and in persistent smokers.76 However, analysis of bronchoalveolar lavage fluid of COPD patients suggests that smoking cessation partly changes the macrophage polarisation from a proinflammatory M1 towards an
Search strategy and selection criteria
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