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Phagocytosis


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.

Digestive enzymes

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).