Phagocytes

The phagocytes are a large group of cells, which actually includes mast cells. Mast cells are a little exceptional, though, so I thought it best to treat them first. Alongside mast cells, we have the three cells I listed in Innate immunity - macrophages, neutrophils and dendritic cells. These are the most notable professional phagocytes - although there are others. Alongside the professional phagocytes, we have a number of non-professional phagocytes. The difference between the two groups is really how well the cells of those groups phagocytose. Professional phagocytes possess receptors which greatly improve their ability to phagocytose, whereas non-professional phagocytes tend to primarily fulfil other roles.

So, I've given you a list of different types of phagocytes and you know from Innate immunity broadly what they do - they ingest pathogens and destroy them. Here, I will go into more detail about what phagocytes are, what they do, and how they do it. Although I will be writing about phagocytes in general, I will have cause to look at specific examples. Then I will treat each of the professional phagocytes I have named individually.

As you know, phagocytes are attracted to sites of infection by chemotactic factors - for example, C5a is a chemotactic factor of neutrophils, among other cells. It is also possible for phagocytes to be drawn to pathogens by the pathogens themselves and it is even possible for phagocytes simply to collide with a pathogen by chance.

Now, upon arriving at the site of an infection, phagocytes phagocytose. Phagocytosis is instigated by the binding of a ligand on the surface of a pathogen to a receptor on the phagocyte. In some cases, this may be the binding of a PAMP to a PRR on the phagocyte. In many cases, opsonins assist in the process, or may be necessary for it to take place at all. Opsonins - such as C3b and various antibodies - work by binding to the receptors on the phagocyte instead of the pathogen's own molecules. In plenty of cases it is only the opsonins which bind to the phagocyte's receptors. The utility of opsonisation is very obvious. Phagocytes are naturally equipped with receptors which bind well to opsonins and this allows the body to respond effectively to all manner of pathogens. The opsonins effectively "draw the attention" of phagocytes, they make the process more efficient, since they tend to coat the surface of pathogens, and - in many cases - they promote phagocytosis which couldn't have happened otherwise. Here we see another example of how antibodies can induce the correct response to specific pathogens. Opsonins also allow phagocytes to overcome the natural repulsive forces they experience from pathogens, which are due to the fact that the cell membranes of both pathogens and phagocytes are negatively charged.

When the receptors of the phagocyte bind to ligands on the pathogen, the phagocyte will begin to project its cell membrane outwards, towards and around the pathogen. This process is mediated by a signalling cascade initiated by the receptors and is achieved in a manner similar to neutrophil chemotaxis (see Chemotaxis). Ultimately, under the direction of the signalling cascade, the actin cytoskeleton is reorganised and in this manner the phagocyte engulfs the pathogen and encapsulates it in a vesicle called a phagosome.

Figure 1.50: A simplified diagram showing the first three steps of this process. (Image courtesy Graham Colm (via Wikipedia))

The phagosome is then transported within the cell and fuses with a granule or with a lysosome. A lysosome is simply an organelle (a structure within cells - a bit like an organ of a cell) containing substances which can break down many biomolecules. When the phagosome fuses with a lysosome or a granule, the resulting structure is called a phagolysosome.

The phagolysosome is a place which is extremely hostile to most pathogens and its purpose is their destruction. A few pathogens have evolved mechanisms to survive within the phagolysosome, but it is - broadly speaking - very effective. There are a number of ways in which pathogens may be killed within a phagocyte. Some of these are oxygen-dependent while the rest - as you'd expect - are oxygen-independent.

The first oxygen-dependent method begins with the production of O−
2 - or superoxide. Superoxide is very harmful to bacteria and it can also be converted to hydrogen peroxide - another substance which is damaging to pathogens. The superoxide can then react with the hydrogen peroxide and this produces hydroxyl radicals (^•HO), which are highly reactive and, again, destructive to pathogens.

The second of these methods occurs in neutrophils. In this case, when the phagosome fuses with granules, an enzyme called myeloperoxidase produces hypochlorite (ClO⁻) from hydrogen peroxide and chlorine, which - of course - is used to destroy the pathogen.

These are the most effective mechanisms and the chemicals involved are very damaging - which is why they are contained within lysosomes and released into the phagolysosome (or produced in the phagolysosome itself). If this were not the case, the chemicals involved would be every bit as harmful to the phagocyte as to the pathogen. The oxygen-independent methods are less effective but still quite interesting. One such way uses charged proteins to inflict damage on the cell membranes of bacteria. Another uses lysozymes, which are antibacterial enzymes that I mentioned right at the very beginning. Lysozymes damage the cell wall of bacteria and destroy them that way. A very clever method employed by neutrophils uses lactoferrins. These are antimicrobials which work by essentially trapping iron - which is necessary for microbes to thrive. Finally, proteases and other enzymes may be used to hydrolyse¹ peptide bonds between bacterial proteins. In other words, these enzymes digest the proteins of bacteria. I believe this is usually done at the end to "clean up" the remains.

Given below is a very simple - but very useful and informative - diagram showing a broad outline of the process:

Figure 1.51: A simplified diagram of phagocytosis. (Image courtesy Graham Colm (via Wikipedia))

In addition to all of this, phagocytes may be stimulated to release nitric oxide, which actually harms and destroys pathogens outside of the phagocyte. However, this does have the disadvantage of causing damage to the body's own cells as well.

Though phagocytosis is really the distinguishing feature of phagocytes, it is far from the only thing they do. As we saw when we discussed cell signalling using the example of macrophages, phagocytes release inflammatory cytokines to draw other phagocytes - and other leukocytes generally - to the site of infection. One cytokine which we have seen before - TNFα - is particularly important as it is also involved in the killing of cancer cells and cells which have been infiltrated by viruses.

Another very important function of phagocytes - particularly macrophages and dendritic cells - is antigen presentation. It really would not be wise to discuss that right now - we will learn all about this when we consider adaptive immunity. Right now, you only need to appreciate that, when the pathogen has been killed, in some cells it is possible for antigens to be recovered from the general debris and these can be "presented" to cells of the adaptive immune system. This serves to sensitise the immune system to that particular pathogen and to instigate a response to it at that time. It also contributes to the process whereby that pathogen can be recognised in future.

¹i.e. cleave chemical bonds by hydrolysis