Lung Defence Mechanisms and Immunology
Inhalation of air also allows ingress of dust, irritant particles and pathogens. The huge surface area of the lungs provides multiple opportunities for damage, and the warm humid environment provides ideal conditions for bacterial and other infestations. The respiratory tract, however, has a range of powerful defence mechanisms. Dysfunction of these mechanisms underlies many respiratory diseases, for example asthma (Chapter 24) and f brosis (Chapters 30 & 33).
Physical and physiological defences
The nostrils and nasopharynx provide a physical barrier to particles greater than 10 μm, in the form of hairs and mucus to which particles adhere (Fig. 18a). Mucociliary transport (see below) subsequently transfers these to the pharynx, where they are ingested. Only particles less than 5 μm generally get further than the trachea. The nasopharynx also provides important humidifying and warming functions for in haled air, preventing drying of epithelium. Irritant particles in the nose and trachea, whether inhaled or transported from distal regions by mucociliary transport, stimulate irritant receptors (Chapter 12), provoking sneezing and coughing which eject foreign matter.
Mucus and airway secretions
The respiratory epithelium is covered with a 5-10 μm layer of gelatinous mucus (gel phase) f oating on a slightly thinner f uid layer (sol phase) (Fig. 18b). Mucus is produced by goblet cells in the epithelium and submucosal glands (Fig. 18b). The major constituents are carbohydrate-rich glycoproteins called mucins which give mucus its gel-like nature. The f uidity and ionic composition of the sol phase are controlled by epithelial cells. The cilia on epithelial cells beat synchronously, and as they do so their tips catch in the gel phase and cause it to move towards the mouth, transporting particles and cellular debris with it (mucociliary transport or clearance). It takes approximately 40 minutes for mucus from large bronchi to reach the pharynx but several days from the respiratory bronchioles. Many factors can disrupt this mechanism, including an increase in mucus viscosity or thickness, making it harder to move (e.g. inflammatio and asthma), changes in the sol phase that inhibit cilia movement or prevent attachment to the gel phase, and defects in cilia activity (cilia dyskinesia). Mucociliary transport is reduced by smoking, pollutants, anaesthetics and infection, and in cystic ﬁbrosis dysfunctional f uid transport results in viscous mucus (Chapters 34). The rare congenital immotile cilia syndrome is due to a defective 'motor' protein in the cilia themselves. Reduced mucociliary transport causes recurrent respiratory infections that progressively damage the lungs causing for example bronchiectasis, where the bronchial walls are thickened, permanently dilated and inflame (Chapter 34 and 45).
Mucus contains several factors produced by epithelial and other cells or that are derived from plasma. Antiproteases such as α1-antitrypsin inhibit the action of proteases, trypsin and elastase released from bacteria and neutrophils which degrade proteins and left unchecked would damage the airways; α1-antitrypsin deﬁciency therefore predisposes to disruption of elastin and development of emphysema (Chapter 26). Surfactant protein A, apart from its actions on surface tension, enhances phagocytosis by cells such as macrophages (see below) by coating or opsonizing (literally 'making ready to eat') bacteria and other particles. Lysozyme is secreted by granulocytes in large quantities in the airways and has antifungal and bactericidal properties; together with the antimicrobial proteins lactoferrin, peroxidases and neutrophil-derived defensins, it provides non-specifi immunity to the respiratory tract.
Secretory immunoglobulin A (IgA) is the principal immunoglobulin in airway secretions and with IgM and IgG agglutinates and opsonizes antigenic particles; it also restricts adherence of microbes to the mucosa. Secretory IgA consists of a dimer of two IgA molecules produced by plasma cells (activated B lymphocytes, see below) and a glycoprotein secretory component. The latter is produced on the basolateral surface of epithelial cells, where it binds the IgA dimer (see Fig. 18b). The secretory IgA complex is then transferred to the luminal surface of the epithelial cell and released into the bronchial flui (see Fig. 18b). It can account for as much as 10% of the total protein in bronchoalveolar lavage f uid. Agglutinated and opsonized antigenic particles can be subsequently ingested and removed by phagocytes such as macrophages and neutrophils.
Macrophages are mobile mononuclear phagocytes that are found throughout the respiratory tract. They act as sentinels in the airways, providing innate protection against inhaled microorganisms and other particles by phagocytosis (ingesting them) and production of potent antimicrobial agents including reactive oxygen species. Phagocytosed organic material is usually digested, whereas inorganic material is sequestered inside the cell. As alveolar epithelium does not have cilia, alveolar macrophages are key to removing material and are the major cell present in the alveoli. Other functions include clearance of surfactant proteins and suppression of unnecessary immune responses by production of anti inﬂammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor β (TGFβ). However, in more severe infections, they can initiate inflammator responses and by release of chemoattractants such as leukotriene B4 promote neutrophil infiltratio from the plasma. They can also act as antigen-presenting cells (see below).
Basics of immunity
T and B lymphocytes migrate to lymph nodes, tonsils and adenoids and diffuse patches of bronchus-associated lymphoid tissue (BALT) within the lamina propria. Here, they interact and are programmed. Antigen is presented to CD4 T lymphocytes (T helper or TH cells) by antigenpresenting cells. The most important are dendritic cells, highly specialized mononuclear phagocytes (Fig. 18c). Macrophages, B lymphocytes and some epithelial cells can also act as antigen-presenting cells.
On presentation of antigen, TH cells release cytokines such as IL-2, IL-4, IL-13 and interferon-γ (IFN-γ ). IL-2 activates CD8+ T lym- phocytes (cytotoxic or TC cells), which kill infected cells. IL-4, IL-13
and IFN-γ activate B lymphocytes in the presence of antigen binding to surface immunoglobulins (IgM) (Fig. 18c). Activated B lymphocytes proliferate and differentiate into plasma cells that re-enter the blood-stream. These secrete large amounts of antigen-specifi antibody (immunoglobins, e.g. IgG and IgA). Binding of antibody to antigen may neutralize some toxic molecules, but more commonly activates secondary mechanisms, either directly by opsonization, allowing recognition and phagocytosis by macrophages and neutrophils, or by activation of complement. When activated, complement can kill pathogens by lysis (bursting the cell membrane), opsonize the antibody-antigen complex and recruit inflammator cells. Note that allergy, for example in asthma (Chapter 24), is specificall associated with IgE, which is otherwise at low levels. For more detailed information see Immunology at a Glance.