COPD immunopathology

Gaetano Caramori, Paolo Casolari, Adam Barczyk, Andrew L Durham, Antonino Di Stefano, Ian Adcock, Gaetano Caramori, Paolo Casolari, Adam Barczyk, Andrew L Durham, Antonino Di Stefano, Ian Adcock

Abstract

The immunopathology of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune responses to the chronic inhalation of cigarette smoking. In the last quarter of the century, the analysis of specimens obtained from the lower airways of COPD patients compared with those from a control group of age-matched smokers with normal lung function has provided novel insights on the potential pathogenetic role of the different cells of the innate and acquired immune responses and their pro/anti-inflammatory mediators and intracellular signalling pathways, contributing to a better knowledge of the immunopathology of COPD both during its stable phase and during its exacerbations. This also has provided a scientific rationale for new drugs discovery and targeting to the lower airways. This review summarises and discusses the immunopathology of COPD patients, of different severity, compared with control smokers with normal lung function.

Figures

Fig. 1
Fig. 1
In the Western world, COPD is mainly related to cigarette smoking. The cigarette smoke activates macrophages, dendritic cells and airway epithelial cells in response to toxic particles in the smoke. Once activated, these cells release mediators that recruit and activate CD8+ T-lymphocytes (CD8+ Tc cells) and neutrophils. The inflammatory process also mediates small airway fibrosis. The activation of these and other cell types and the activation of inflammatory and remodelling processes lead to small airway fibrosis, obstructive bronchiolitis, pulmonary emphysema and mucus hypersecretion
Fig. 2
Fig. 2
Representative immunohistochemical staining for CD68 (DAB; brown) of alveolar macrophages (a, b) and for neutrophil elastase (alkaline phosphatase, red) (c, d) in paraffin sections of the small airways of stable moderate COPD patients (b, d) and of control smokers with normal lung function (a, c). Pictures total magnification = ×200; bar = 50 μm
Fig. 3
Fig. 3
Representative immunohistochemical staining showing the expression and localisation of CD4+ T cells (a–c), CD8+ T cells (d–f) and CD68+ macrophages (g–i) in the airways. The differences in expression between smokers with normal lung function (CS; a, d and g), mild/moderate COPD subjects (COPD; b, e and h) and in severe COPD patients (S-COPD) are also shown. Arrows indicate the positively stained cells
Fig. 4
Fig. 4
Interleukin 12 (IL-12) acts on IL-12R localised on Th0 to drive Th1 polarisation in conjunction with activation of the IL-18R and the T cell receptor (TCR). IL-12 and IL-27 can also act on their receptors on Th1 cells to elicit the expression of interferon (IFN)-γ via STAT activation. The activation status of Th1 cells is also regulated by the CCL5/CCR5 and CXCL9, CXCL10 and CXCL11/CXCR3 axis
Fig. 5
Fig. 5
Autoimmunity develops in COPD when environmental triggers transform the production of benign autoantibodies to pathogenic antibodies in susceptible subjects. Small airways remodelling and emphysema develops with the deposition of immune complexes within the alveoli
Fig. 6
Fig. 6
The increased risk of lung cancer seen in COPD patients may result from abnormal DNA damage/repair processes in response to oxidative stress. Cigarette smoke-induced oxidative stress causes DNA strand breaks and a reduction in the expression of key repair protens such as Ku86 and sirtuin 1 (SIRT1). The resultant failure to repair the damaged DNA foci leads to accelerated lung ageing and cancer
Fig. 7
Fig. 7
Key chemokines such as CCL2, CCL3, CCL4, CCL5, CCL6, CCL7 and CCL27 and CXCL6, CXCL7, CXCL8, CXCL9, CXCL20 and CXCL11 in COPD mediate their effects through targeting specific chemokine receptors including CCR2, CCR5, CXCR1, CXCR2 and CXCR3 localised on alveolar macrophages, Th1 cells, neutrophils and airway epithelial cells
Fig. 8
Fig. 8
The presence of viruses, bacteria and air pollutants can drive COPD exacerbations by causing an acute-on-chronic inflammatory state within the airways. This results in systemic inflammation causing cardiovascular complications, airway bronchoconstriction oedema, mucus and lung hyperinflation which together are associated with the signs and symptoms of an exacerbation. This acute-on-chronic inflammation is also associated with reduced responsiveness to inhaled and systemic glucocorticoids

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