Phagocytosis
Numerous
cells are able to ingest foreign materials, but the ability to increase this activity in response to
opsonization by antibody and/or complement, so as to acquire antigen
specificity, is restricted to cells of the myeloid series, principally polymorphs,
monocytes and macrophages; these are sometimes termed
‘professional’ phagocytes.
Apart from some variations in their
content of lysosomal enzymes, all these cells use essentially similar
mechanisms to phagocytose foreign objects, consisting of a sequence of attachment
(top), endocytosis or ingestion (centre) and digestion (bottom).
In the figure this process is shown for a typical bacterium (small black rods).
In general, bacteria with capsules (shown as a white outline) are not phagocytosed
unless opsonized, whereas many non-capsulated ones do not require this. There are certain differences
between phagocytic cells; e.g.
polymorphs are very short-lived (hours or days) and often die in the process of
phagocytosis, while macrophages, which lack some of the more destructive
enzymes, usually survive to phagocytose again. Also, macrophages can actively secrete
some of their enzymes, e.g. lysozyme. There are surprisingly large species
differences in the pro- portions of the various lysosomal enzymes.
Several of the steps in
phagocytosis shown in the figure may be specifically defective for genetic
reasons (see Fig. 33), as well as being actively inhibited by particular
microorganisms (see Figs 27–32). In either case the result is a failure to
eliminate microorganisms or foreign material properly, leading to chronic
infection and/or chronic inflammation.
Chemotaxis The process by which cells are attracted towards bacteria, etc., often
by following a gradient of molecules released by the microbe (see Fig. 7).
Pinocytosis ‘Cell drinking’; the ingestion of soluble
materials, including water, conventionally applied also to particles under 1 µm
in diameter.
Hydrophobicity Hydrophobic groups tend to attach to the hydrophobic
surface of cells; this may explain the ‘recognition’ of damaged cells,
denatured proteins, etc. (see Fig. 29).
Pattern-recognition receptors Phagocytic cells have surface and phagosomal
receptors that recognize complementary molecular structures on the surface of
common pathogens (for details see Fig. 5). Binding between pathogens and these
receptors activates intracellular killing and digestion, as well as the release
of many inflammatory chemokines and cytokines (see Figs 23 and 24).
C3 receptor Phagocytic cells (and some lymphocytes) can
bind C3b, produced from C3 by activation by bacteria, etc., either directly or
via antibody (for details of the receptors see Fig. 6).
Fc receptor Phagocytic cells (and some lymphocytes,
platelets, etc.) can bind the Fc portion of antibody, especially of the IgG
class. Binding of several IgG molecules to Fc receptors on macrophages or
polymorphs triggers receptor activation, and activates phagocytosis and
microbial killing.
Opsonization This refers to the promotion or enhancement of attachment
via the C3 or Fc receptor. Discovered by Almroth Wright and made famous by G.B.
Shaw in The Doctor’s Dilemma, opsonization is probably the single most
important process by which antibody helps to overcome infections, particularly
bacterial.
Phagosome A vacuole formed by the internalization of
surface membrane along with an attached particle. The phagosome often fuses
with the lysosome, thus exposing the internalized microorganism to the
destructive power of the lysosomal enzymes or cathepsins. However, some
pathogens (e.g. some species of Salmonella) have evolved ways to avoid
phagolysosome fusion, and thus survive within the phagocyte unharmed.
Microtubules Short rigid structures composed of the protein
tubulin which arrange themselves into channels for vacuoles, etc. to travel
within the cell.
Microfilaments Contractile protein (actin) filaments
responsible for membrane activities such as pinocytosis and phagosome
formation. There are also intermediate filaments composed of the protein
vimentin.
ER Endoplasmic reticulum: a membranous system of
sacs and tubules with which ribosomes are associated in the synthesis of many
proteins for secretion.
Golgi The region where products of the ER are
packaged into vesicles (see also Fig. 19).
Lysosome A membrane-bound package of hydrolytic enzymes
usually active at acid pH (e.g. acid phosphatase, DNAase). Lysosomes are found
in almost all cells, and are vehicles for secretion as well as digestion. They
are prominent in macrophages and polymorphs, which also have separate vesicles
containing lysozyme and other enzymes; together with lysosomes these constitute
the granules whose staining patterns characterize the various
types of polymorph
(neutrophil, basophil,
eosinophil). Genetic defects in specific lysosomal enzymes can result in serious or even fatal lysosomal
storage diseases, such as Tay–Sachs,
or Gaucher’s disease.
Phagolysosome A vacuole formed by the fusion of a phagosome
and lysosome(s), in which microorganisms are killed and digested. The pH is
tightly controlled, and varies between different phagocytes, presumably so as
to maximize the activity of different types of lysosomal enzymes.
Autophagy Literally, ‘eating oneself’, this refers to a
process whereby cells can sequester cytoplasm or organelles into newly formed
mem- brane vesicles, to form autophagosomes, which then fuse with lysosomes
and degrade the contents. It is stimulated by cell stress or starvation, but
also by activation of many innate immune receptors (see Fig. 5). Autophagy is
an important mechanisms for cells to turn over old or damaged proteins and
organelles, and may function as an additional source of energy when cells are
stressed or damaged. Autophagy is also important in resistance to some
microorganisms, including tuberculosis, although the mechanisms remain unclear
(see Fig. 18).
Lactoferrin A protein that inhibits bacteria by depriving
them of iron, which it binds with an extremely high affinity.
Cationic proteins Examples are ‘phagocytin’, ‘leukin’;
microbicidal agents found in some polymorph granules. Eosinophils are
particularly rich in cationic proteins, which can be secreted when the cell
‘degranulates’, making them highly cytotoxic cells.
Ascorbate Ascorbate interacts with copper ions and
hydrogen peroxide, and can be bactericidal.
Oxygen and the oxygen burst Intracellular killing of many bacteria requires
the uptake of oxygen by the phagocytic cell, i.e. it is ‘aerobic’. Through a
series of enzyme reactions including NADPH oxidase and superoxide dismutase
(SOD), this oxygen is progressively reduced to superoxide (O2- ), hydrogen peroxide (H2O2), hydroxyl ions
(OH- ) and singlet oxygen (1O2). These reactive
oxygen species (ROS) are rapidly removed by cellular enzymes such as catalase
and glutathione peroxidase. ROS are highly toxic to many microorganisms but
excessive ROS production may contribute to damage to host tissues, e.g. blood
vessels in arteriosclerosis.
NO Nitric oxide produced from arginine is another
reactive oxygen-containing compound that is highly toxic to microorganisms
when produced in large amounts by activated mouse macrophages; its importance
in humans remains less well established. In contrast, much lower levels of
nitric oxide are produced constitutively by endothelial cells, and have a key
role in the regulation of blood vessel tone.
Myeloperoxidase An important enzyme of PMNs that converts
hydrogen peroxide and halide (e.g. chloride) ions into the microbicide
hypochlorous acid (bleach). Reaction of antigens with hypochlorous acid may
also enhance their recognition by T lymphocytes.
Lysozyme (muramidase) This lyses many saprophytes (e.g. Micrococcus
lysodeicticus) and some pathogenic bacteria damaged by anti-body and/or
complement. It is a major secretory product of macrophages, present in the
blood at levels of micrograms per millilitre.
Digestive enzymes The enzymes by which lysosomes are usually
identified, such as acid phosphatase, lipase, elastase, β-glucuronidase and the
cathepsins, some of which are thought to be important in antigen processing via the MHC class II
pathway (see Fig. 18).
