The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research

Abstract

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").

Figures

Figure 1.

Correlation between the onset of pathologic processes in chronic obstructive pulmonary disease (COPD) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity stage. The natural history of the decline in FEV1 in the working men followed by Fletcher and colleagues (4) is shown with the GOLD categories superimposed as dotted horizontal lines. Note that only a minority of the smoking population (estimated to be approximately 20% of the total) experienced the rapid decline in lung function that leads to severe (GOLD-3) and very severe (GOLD-4) COPD. Data from Reference confirmed that the populations of macrophage, neutrophil, and lymphocyte subtypes infiltrate the peripheral lung tissue of symptomatic smokers with normal lung function (GOLD-0). In addition, they confirmed that this infiltration increased in both extent (number of airways involved) and severity (accumulated volume of cell type) as COPD progressed through 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) increases from moderate (GOLD-2) to very severe (GOLD-4) COPD, and that the formation of lymphoid follicles, which provides histologic evidence for an adaptive immune response, increased sharply in severe (GOLD-3) and very severe (GOLD-4) COPD. A multivariate analysis of these data indicated that 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 by permission from Reference .

Figure 2.

(A) The migration of a population of predominantly acute inflammatory cells (white arrows) migrating through the airway epithelium of an animal in response to an acute exposure to tobacco smoke inhalation. (B) The lamina propria and adventitia of the airways are supplied by separate sets of bronchial vessels (black arrows) that interconnect (black arrowhead) with each other. (C) A collection of bronchus-associated lymphocytes (BALT) with a germinal center (GC) which is supplied by bronchial vessels from the adventitial set of bronchial vessels. (D) A drawing of a lymph node for comparison to (C). The black arrowheads indicate the limits of the specialized epithelium overlying BALT. Note that the BALT structure has neither the capsule nor the afferent lymphatics that supply the lymph node. Reprinted by permission from Reference .

Figure 3.

The Goldilocks hypothesis of acute exacerbations of COPD pathogenesis. In some cases, the innate and adaptive immune response successfully eliminates the infection, and the response is mild and transient (middle panel, “just right”). Lung inflammation can be excessive and/or prolonged when the adaptive pulmonary immune response is inappropriate in either of two ways: adaptive immunity could fail when needed to control certain infections (left panel, “too little”), or it could excessively amplify or prolong lung inflammation through its regulatory effects on innate immunity (depicted here by the T cell products IFN-γ and IL-17A) (right panel, “too much”). AMø = alveolar macrophage; DC = dendritic cells; iDC = immature DC.