The mucosa of the respiratory system lines the nasal passages, nasopharynx, trachea, and bronchial tree. Alveoli, the epithelium lined sac-like termini of the bronchial airways, also may be considered part of the respiratory mucosa. Inhalation of air exposes the respiratory mucosa to a wide variety of foreign substances, including airborne infectious organisms, plant pollen, dust particles, and various other environmental antigens. The microbial flora of the airways is less dense and less diverse than that in the gut, and the deep airways and alveoli have fewer organisms than the upper airways. Nonetheless, similar mechanisms have evolved in the respiratory mucosal immune system to achieve a balance between immune activation to protect against pathogens and immune regulation to avoid unnecessary or excessive responses that might impair physiologic functions. Failure of the immune system to control bronchopulmonary infections and excessive immune or inflammatory responses to infections are major causes of morbidity and mortality worldwide.
Innate Immunity in the Respiratory System
The pseudostratified, ciliated columnar epithelium that lines most of the respiratory mucosa, including the nasal passages, nasopharynx, and bronchial tree, performs physical and chemical barrier functions similar to those of gut epithelium, by virtue of tight junctions between cells and secretion of mucus, defensins, and cathelicidins. The mucus in the airways traps foreign substances, including microbes, and the cilia move the mucus and trapped microbes out of the lungs. The importance of mucus and cilia in innate immune protection in the lung is illustrated by the greatly increased frequency of serious bronchopulmonary infections in people with decreased cilia function, such as heavy smokers, or abnormal mucus production, such as patients with cystic fibrosis.
Tuft cells, similar to those found in the gut, are found in the upper respiratory tree, including the trachea and bronchi, where they perform sentinel innate immune functions. The chemosensory receptors on tuft cells can recognize microbial molecules, which signal the cells to secrete IL-25, leukotrienes, and acetyl choline. These mediators act on ciliated bronchial epithelial cells and nerve fibers, promoting mucus secretion and ciliary action to clear airway infections.
Innate responses in alveoli serve antimicrobial functions but are tightly controlled to prevent inflammation, which would impair gas exchange. The alveoli are susceptible to infection spreading from bronchioles (bronchopneumonia), and alveolar lining cells can be directly infected by viruses. Surfactant proteins A (SP-A) and D (SP-D), which are secreted into the alveolar spaces, are members of the collectin family and bind to carbohydrate PAMPs on the surface of many pathogens. These surfactants are involved in viral neutralization and clearance of microbes from the alveoli, but they also suppress inflammatory and allergic responses in the lung. For example, SP-A inhibits TLR2 and TLR4 signaling and the production of inflammatory cytokines in alveolar macrophages, and SP-A also binds to TLR4 and inhibits lipopolysaccharide binding. SP-A and SP-D reduce the phagocytic activity of alveolar macrophages.
Alveolar macrophages represent most of the free cells within the alveolar spaces. These tissue-resident macrophages are mostly derived from the yolk sac and fetal liver, and are functionally distinct from those in many other tissues in that they maintain an antiinflammatory phenotype. They express IL-10, nitric oxide, and TGF-β and are poorly phagocytic compared with resident macrophages in other tissues, such as the spleen and liver. Alveolar macrophages inhibit T-cell responses as well as the antigen presentation function of airway DCs, effects that are attributed to the IL-10 and TGF-β they secrete.
ILCs are present in bronchial mucosal tissue and contribute to pulmonary inflammatory responses to helminths and environ mental allergens. Damage to bronchial epithelium by microbes results in the release of alarmin cytokines such as IL-33, IL-25, and TSLP, which activate ILC2s and Th2 cells. Pulmonary ILC2s also can be activated by neuropeptides derived from autonomic nerves and also from bronchial neuroendocrine cells. ILC2s and Th2 responses, so called type 2 immunity, are associated with allergic asthma, and drugs targeting development or effector cytokines of these cell types are used to treat this disorder.
Adaptive Immunity in the Respiratory System
Protective humoral immunity in the airways is dominated by secretory IgA, as in other mucosal tissues, although the amount of IgA secreted is less than in the gastrointestinal tract. Secretory IgA plays an important role in the upper airway. The anatomic sites of naive B-cell activation, differentiation, and IgA class switching include tonsils and adenoids in the nasopharynx and lymph nodes in the mediastinum and adjacent to bronchi in the lungs. There are relatively few aggregated or isolated lymphoid follicles in the lamina propria in the lower airways com pared with the gut and likely less initiation of humoral immune responses in these locations. The homing of IgA-secreting plasmablasts back into the airway tissue in proximity to respiratory mucosal epithelium depends on the chemokine CCL28 secreted by respiratory epithelium and its receptor CCR10 on the plasmablasts. IgA is transported into the airway lumen by the same poly-Ig receptor mechanism of transcellular transport as in the gut. IgE responses to airway antigens occur frequently and are involved in allergic diseases of the respiratory system, including hay fever and asthma. Antigen binding to IgE triggers inflammation when the IgE is attached to mast cells, which are abundant in the submucosa of the airways.
T-cell responses in the lung are initiated by DC sampling of airway antigens and presentation of these antigens to naive T cells in peribronchial and mediastinal lymph nodes. A network of DCs is present in the mucosa of the airways, and a subset of these bronchial DCs extend dendrites between the bronchial epithelial cells into the airway lumen. These DCs sample air way antigens, migrate to draining lymph nodes, and present the processed antigens to naive T cells. Other DCs are found in the lamina propria beneath the epithelial cells, where they capture antigens that cross the epithelium. Airway DCs may drive differentiation of naive CD4+ T cells toward different phenotypes, depending on the nature of the antigen and the disease context. For example, Th1 cells are often generated in viral and mycobacterial infections, while Th2 cells are frequent in allergic responses to inhaled allergens in asthma.
