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.
Lung macrophages
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.
