Article Update

Tuesday, April 20, 2021


The respiratory system is in intimate contact with the environment through the inhalation of large volumes of air every day (  ̴10,000 L). Protecting the respiratory system from pathogens and toxins while avoiding unnecessary inflammation when harmless proteins are inhaled is a challenge. Physical barriers such as the filtration of air by the nose and upper airways and the mucociliary apparatus, which moves inhaled particles, organisms, and cells toward the pharynx, where they can be swallowed, provide the first line of defense. Ingestion of organisms and particulate material by macrophages resident within the lung is another important line of defense. Ingestion of silica particles or asbestos fibers by macrophages may fail to clear these particles and may lead to persistence of inflammation and ultimately lung tissue damage.
        The airway epithelial cells have the capacity to ingest bacteria and have a variety of receptors, such as Toll like receptors, on their surface that may lead to activation of the epithelium on exposure to bacterial or viral products (e.g., DNA, RNA, lipopolysaccharide). Activated epithelium secretes chemoattractant molecules that will attract neutrophils, eosinophils, and lymphocytes, depending on the particular need. Cytokines secreted by the epithelium may also promote inflammation. Defensins are proteins that are secreted by epithelial cells that may bind to microbial cell membranes and create pores that assist in killing organisms. Epithelial cells also produce surfactant proteins that may assist in the elimination of pathogenic organisms.
Adaptive immune responses to pathogenic organisms and foreign proteins involve lymphocyte populations. Intraepithelial lymphocytes are usually CD8  T cells, which are well placed to exert cytotoxic effects on infected epithelial cells. Indeed, the epithelial cells are the primary target for a variety of respiratory viruses such as rhinovirus and adenovirus. After infection, cells may present antigen on their surface that leads to activation of CD8 + T cells and cell killing through release of perforin and granzyme or by Fas-Fas ligand interactions. However, the common cold rhinovirus infects epithelial cells without inducing killing of these cells and triggers inflammation. Other viruses that target the airway epithelium such as respiratory syncytial virus (RSV) may cause severe inflammation of the small airways in infants. Both rhinovirus and RSV are associated with asthma attacks.
Under the epithelium, there is a network of dendritic cells. These large cells have projections that protrude between epithelial cells into the airway lumen and may sample foreign antigenic substances. After ingestion of foreign protein, these cells migrate to regional lymph nodes, where they present an antigenic fragment of the protein to CD4+ T cells with a T-cell receptor with a high affinity for the antigenic peptide. The subsequent T-cell reaction may lead to the clonal expansion of the cells and their differentiation into one of several subsets of CD4+ cells. These cells recirculate and may home to the site of origin of the dendritic cell, where they may now produce cytokines that play a key role in directing the type of inflammation. Whereas Th1 type cells are associated with delayed-type hypersensitivity reactions, Th2 cells may lead to typical eosinophil-rich allergic inflammation, immunoglobulin E synthesis (IgE), mucous cell differentiation, and airway hyperresponsiveness. These are all characteristic features of allergic asthma. Coating of mast cells in the airways, which are recruited after exposure to aeroallergens, with IgE renders these cells susceptible to activation by allergens. Release of histamine, growth factors, and cytokines occurs, and the synthesis de novo of leukotrienes and prostaglandins contributes to bronchoconstriction and inflammation. Bronchoconstriction is often biphasic; an early response occurs within minutes and resolves within 1 or 2 hours, and a secondary wave of airway narrowing called the late response occurs after several hours. This latter reaction is also T-cell dependent.
Several other T-cell subsets are of importance in controlling inflammation and host defense. Regulatory T cells may prevent, limit, or participate in terminating inflammation. Other newly described T-cell subsets such as Th17 cells are associated with inflammation that has a strong neutrophilic component, and these cells may be implicated in more severe forms of asthma. T cells bearing an alternative TCR, the ᵞᵟTCR, are important in host defense against certain infectious agents, including Mycobacterium tuberculosis and Pneumocystis jiroveci. Natural killer (NK) cells and invariant NKT (iNKT) cells participate in immunologic responses. NK cells are required for protection against several viral infections, rtussis, and Mycobacterium tuberculosis.

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