Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

Abstract

Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease.

Figure 1. Immune pathways leading to allergic lung disease.

(i) Initial allergen exposure leads to uptake by lung conventional DCs and their migration to regional lymph nodes using CCL19/21-CCR7 interactions. In the nodes, DCs regulate MHC class II–dependent generation of CD4⁺ Th2 cells and consequent B cell (and, in turn, plasma cell) production of allergen-specific IgE. (ii) Chronic allergen exposure causes IgE cross-linking and FcεRI signaling, leading to activation of mast cells (and likely basophils and other cell types), with consequent recruitment of Th2 effector cells to the airway. Th2 cell production of IL-4 and/or IL-13 leads to alternatively activated macrophagedifferentiation, while IL-5 generation leads to eosinophil accumulation and further IL-13 production in the airway. (iii) Additional T cell subsets that regulate the allergic response include Th17, Th9, and Tregs that may influence the Th2 response and may act independently of this response as well. (iv) IL-13 (as well as other cytokines) drive mucous cell metaplasia (MCM) and airway hyperreactivity (AHR) that are characteristic of allergic asthma. Modified with permission from the American Journal of Respiratory Cell and Molecular Biology (140).

Figure 2. Immune pathways leading to postviral lung disease.

(i) Early viral illness is characterized by the induction of IFN-α/β/λ and ISG expression to control viral replication and promote cell death and subsequent phagocytosis by CCL5-protected macrophages. (ii) Late viral illness includes lung DC migration to regional lymph nodes for MHC class I–dependent generation of CD8⁺ T cells and MHC class II–dependent generation of CD4⁺ Th2 cells and consequent B cell (and, in turn, plasma cell) production of antiviral antibodies (including IgE). (iii) Acute postviral disease is marked by IFN-α/β– and CD49⁺ polymorphonuclear (PMN) cell–dependent upregulation of FcεRI expression on resident lung DCs. In turn, FcεRI activation by viral antigen and antiviral IgE leads to the production of CCL28 and the recruitment of CCR10-expressing IL-13–producing Th2 cells to the lung. (iv) For chronic postviral disease, virus-activated APCs orchestrate CD1d-dependent glycolipid antigen presentation and consequent activation of iNKT cells. These iNKT cells then interact directly with lung macrophages via IL-13–IL-13R and invariant Vα14 TCR–CD1d interactions. These signals lead to increased expression of IL-13R and production of IL-13 that drives a positive feedback loop to amplify IL-13 production and activation of M2 macrophages, marked by chitinase 1 and arachidonate 15-LOX expression. In this immune axis, the airway epithelial cells may also release cytokines (e.g., IL-25, TSLP, and IL-33) that contribute to immune cell activation and chronic inflammatory disease in the form of asthma and COPD. Modified with permission from the American Journal of Respiratory Cell and Molecular Biology (140).