We have looked at the seven major cells involved in the innate immune response: mast cells, macrophages, neutrophils, dendritic cells, basophils, eosinophils and natural killer cells. There are two useful classifications we can use when discussing these cells: granulocyte and phagocyte. Some of the cells are both. A granulocyte is a cell which contains granules of molecules which aid the immune response. Some of these molecules are involved in signalling and chemotaxis of immunocompetent cells, some are involved in directly damaging the pathogen and generally they initiate and/or mediate the immune response. Phagocytes stretch themselves around pathogens, engulf them, destroy them and may then recover antigens, which they present to cells of the adaptive immune system.
Mast cells are phagocytes and granulocytes. Their primary function is to degranulate, when stimulated to do so, and thereby instigate the inflammatory response. This may be achieved by damage to the mast cell, by activation by complement and by means of antibodies. These antibodies will be produced in response to particular pathogens and will bind to mast cells. Should the relevant pathogen then bind to two or more receptors (via the antibodies), a signalling cascade will be initiated leading to the degranulation of the mast cell. Degranulation is achieved by transporting the granule to the cell membrane, where it fuses with the membrane and so expels its contents.
Macrophages are large phagocytes. They mature from monocytes and are involved in the release of cytokines, in cleaning up debris left by neutrophils and in tissue repair. Also, of course, they phagocytose. So-called M1 macrophages are particularly aggressive hunters of pathogens, while M2 macrophages are more focused on cleaning up and repair.
Neutrophils are highly effective phagocytes and are also granulocytes and are responsible, in part, for releasing inflammatory cytokines. As well as this, they form neutrophil extracellular traps (NETs), which trap invading pathogens and destroy them by means of the proteins which make up the NETs.
Dendritic cells are "sentinels." They are prolific phagocytes and even "nibble" on perfectly healthy host cells when looking for pathogens. When they find one they phagocytose it and present antigens from it to cells of the adaptive immune system. Dendritic cells are perhaps the most effective antigen presenting cells.
Basophils are useful granulocytes. Their granules contain a number of important molecules, including histamine and heparin, as well as IL-4. Notably, basophil degranulation can be mediated by IgE antibodies.
Eosinophils are also granulocytes but, as well as inflammatory mediators, eosinophils are particularly noteworthy for releasing highly destructive chemicals. Eosinophils, then, are particularly involved with the actual killing.
Natural killer cells attack cells which have been infected by viruses, or which are otherwise "stressed" or damaged in some way. They "select" their target using stimulatory and inhibitory receptors. Inhibitory ligands - particularly MHC I - on healthy cells prevent NK cells from attacking. Thus NK cells do not harm the body they're supposed to be defending - this is self-tolerance. However, on damaged cells MHC I is often under expressed. Damaged cells are also likely to express increased levels of stimulatory ligands (or they may have expressed these when they were healthy as well, but the MHC I levels counterbalanced them). Thus, NK cells "recognise" a lack of MHC I (missing self recognition) and can then be stimulated to attack the cell by the stimulatory ligands. Put more briefly (and more accurately): NK cells attack only if the stimulatory signal is stronger than the inhibitory signal. This is the means by which NK cells select the right target and kill damaged and infected cells, without harming healthy cells. If the NK cell is activated it can release IFNγ and TNFα. The most prominent method of attack, though, is the release of granules. These contain perforin, which forms a pore in the target cell, which allows other substances in the granules to enter the cell and kill it by lysis or apoptosis. NK cells are additionally stimulated by cytokines and can be activated with the help of antibodies.
Monday, 9 June 2014
Natural killer cells
The role of natural killer cells is to attack cells of the body which have become infected by viruses, or which are damaged or dysfunctional in some other way - e.g. cancer cells. The role of natural killer cells in tumour suppression is certainly very interesting, but I will try to focus on their role in defence against pathogens.
To put it very briefly, viruses invade the cells of the body and replicate within them; they hijack the resources and structures of the cell they invade. These are supposed to be used for creating things the body needs and new copies of the cell; instead, the virus repurposes them to create copies of itself. This is how viruses work - very simply. HIV is no different and we will see more of this soon. It is the role, then, of natural killer cells to identify cells which have been infected and to shut them down and kill them. This will destroy the virus and prevent it from replicating; although it will not, of course, undo the creation of any copies of the virus which have already been made and released.
In addition to this, natural killer cells are also able to release cytokines and there is emerging evidence that they are able to adjust to their environment and to "remember" pathogens which have been encountered previously and respond effectively. Thus they seem also to be a part of the adaptive immune system, as well as the innate immune system.
Precisely how natural killer cells achieve all of this is the subject of much current research. We do not yet have all the answers - although that's true of pretty much everything. In this case, though, we don't even have many of them. Nevertheless, for those who are interested, there is a very good paper by David H. Raulet called Missing self recognition and self tolerance of natural killer (NK) cells,1 which I highly recommend and which is able to shed some light on the topic.
For our purposes, though, I think I can be a little cursory, but be sure to take note of the fact that I am simplifying things and eliding a lot of detail. NK cells possess a wide range of receptors - although not all NK cells possess the same receptors. Some of these receptors - such as NKG2D - are stimulatory receptors, while others - such as KIRs (Killer-cell immunoglobulin-like receptors) - are inhibitory receptors. Now, there does seem to be substantial variation in receptors among NK cells, so all NK cells are different and there will, therefore, be some variation in how they behave.
The general principle, though, seems to be that activation of NK cells depends on the balance between stimulatory and inhibitory ligands on a cell surface, or in the environment of a cell. So, if a given cell expresses lots of inhibitory molecules, the NK cell will obviously not be activated. If there is a good balance between stimulatory and inhibitory molecules then, again, the NK cell will not be activated. Again, if there are very few inhibitory molecules (or none), but also few stimulatory molecules (or none), still the NK cell is not likely to be activated. No, one requires the presence of plenty of stimulatory molecules - without there being enough inhibitory molecules to counter-balance them - for the NK cell to be activated. Or, from the NK cell's point of view, the stimulatory signal needs to be stronger than the inhibitory signal.
This, as I have said, is a simplification, however. Some cells do not actually express inhibitory receptors at all. These cells, I gather from Raulet (2006), are hyporesponsive (i.e. less responsive than the norm). I believe these cells can be stimulated to kill, but it is likely that either a strong signal is required, or their activation is dependent on external signalling, perhaps by IL-12 and/or other cytokines.
Now, let's look at this in a bit more detail. The inhibitory receptors generally recognise MHC class I (major histocompatibility complex class I) - something else which will soon be of great importance to us. MHC class I allows the NK cells to recognise "self" cells. So, the presence of MHC class I generally inhibits NK cell activity, which is an effective way of ensuring that NK cells do not attack the body's own cells. When cells become stressed or infected by viruses, MHC class I expression can be affected. In other words, many cells which are infected by viruses (and many cancer cells, too) do not express sufficient MHC class I (if any) to prevent NK cell activation. This is referred to as missing self recognition. NK cells identify damaged and infected cells by the lack of self molecules.
However, this on its own is not enough. NK cells generally do not attack the body's own cells when they are healthy because of the presence of MHC class I. However, absence of MHC class I will not precipitate an immediate attack. Instead, the presence of stimulatory ligands is required. These include heat shock proteins, extracellular matrix fragments, altered membrane phospholipids and other general markers of stressed, infected and cancerous cells. These are expressed on the surface of the cells, but stressed cells can also release stimulatory cytokines and NK cells can be stimulated by macrophages, too.
Seemingly, some molecules present on normal, healthy cells also act as stimulatory ligands. Thus, if MHC class I is poorly expressed on these cells they will be attacked. This is useful, because it means that some unhealthy cells can be killed merely by missing self recognition and expression of additional stimulatory ligands is not necessary, since stimulatory ligands occur naturally on that cell anyway.
So, in conclusion, this balance between inhibitory and stimulatory signalling allows for self-tolerance - the body's NK cells do not attack the body's own healthy cells. Meanwhile, infected cells can be "recognised" by NK cells by virtue of the stimulatory ligands which they produce and the absence of inhibitory ligands, particularly MHC class I (missing self recognition). Notice that it's really a combination of these two factors and, in fact, it seems that the triggering of NK cell activity is dependent on the end result of the interplay of numerous signals. Indeed it may well even be dependent on the particular NK cell in question.
To pick up on that last point, one final thing to add is that, in the case of cells which do not express inhibitory receptors, it appears that hyporesponsiveness is important for self-tolerance. In other words, if these cells were not hyporesponsive, they would regularly attack healthy self cells, as they would not be able to detect the presence of MHC class I and so be prevented from attacking. Thus it is necessary that they be very loath to attack and, in this way, they only attack cells which are strongly requiring of attack.
Now, there are a few ways in which NK cells actually go about killing abnormal cells. The primary method involves the release of granules. The NK cell will release perforin - a protein which creates a small pore in the target cell's membrane. Other molecules from the NK cell granules - generally proteins and proteases - can then enter the cell through the pore. These will then induce apoptosis in the target cell, or kill it via lysis, which we've seen before. Apoptosis, or "programmed cell death," is where a cell shuts itself down in response to certain signalling events. NK cells also release a number of cytokines themselves, most notably IFNγ and TNFα.
Finally, in addition to all the above, NK cells can perform antibody-dependent cell-mediated cytotoxicity (or ADCC). NK cells express FcγRIII (alternatively: CD16) receptors which bind to some antibodies (specifically IgG, I think). When this happens, the NK cells are activated and will induce apoptosis in the cell which has been opsonised with antibodies. This is, of course, in many ways similar to activation by stimulatory molecules and subsequent degranulation. It is important to note, however, that not only do antibodies activate NK cells, but they also seem to be able to expedite the process. Whether or not ADCC can completely bypass the usual mechanism involving other stimulatory receptors and inhibitory receptors is not clear to me. It's worth appreciating, though, another example of just how the adaptive immune system promotes and fine-tunes the innate immune system.
1Raulet, David H. 2006. "Missing self recognition and self tolerance of natural killer (NK) cells." Seminars in Immunology 18 (2006): 145-150
2http://www.nhs.uk/news/2008/05May/Pages/Antidepressantsandimmunity.aspx
To put it very briefly, viruses invade the cells of the body and replicate within them; they hijack the resources and structures of the cell they invade. These are supposed to be used for creating things the body needs and new copies of the cell; instead, the virus repurposes them to create copies of itself. This is how viruses work - very simply. HIV is no different and we will see more of this soon. It is the role, then, of natural killer cells to identify cells which have been infected and to shut them down and kill them. This will destroy the virus and prevent it from replicating; although it will not, of course, undo the creation of any copies of the virus which have already been made and released.
In addition to this, natural killer cells are also able to release cytokines and there is emerging evidence that they are able to adjust to their environment and to "remember" pathogens which have been encountered previously and respond effectively. Thus they seem also to be a part of the adaptive immune system, as well as the innate immune system.
Precisely how natural killer cells achieve all of this is the subject of much current research. We do not yet have all the answers - although that's true of pretty much everything. In this case, though, we don't even have many of them. Nevertheless, for those who are interested, there is a very good paper by David H. Raulet called Missing self recognition and self tolerance of natural killer (NK) cells,1 which I highly recommend and which is able to shed some light on the topic.
For our purposes, though, I think I can be a little cursory, but be sure to take note of the fact that I am simplifying things and eliding a lot of detail. NK cells possess a wide range of receptors - although not all NK cells possess the same receptors. Some of these receptors - such as NKG2D - are stimulatory receptors, while others - such as KIRs (Killer-cell immunoglobulin-like receptors) - are inhibitory receptors. Now, there does seem to be substantial variation in receptors among NK cells, so all NK cells are different and there will, therefore, be some variation in how they behave.
The general principle, though, seems to be that activation of NK cells depends on the balance between stimulatory and inhibitory ligands on a cell surface, or in the environment of a cell. So, if a given cell expresses lots of inhibitory molecules, the NK cell will obviously not be activated. If there is a good balance between stimulatory and inhibitory molecules then, again, the NK cell will not be activated. Again, if there are very few inhibitory molecules (or none), but also few stimulatory molecules (or none), still the NK cell is not likely to be activated. No, one requires the presence of plenty of stimulatory molecules - without there being enough inhibitory molecules to counter-balance them - for the NK cell to be activated. Or, from the NK cell's point of view, the stimulatory signal needs to be stronger than the inhibitory signal.
This, as I have said, is a simplification, however. Some cells do not actually express inhibitory receptors at all. These cells, I gather from Raulet (2006), are hyporesponsive (i.e. less responsive than the norm). I believe these cells can be stimulated to kill, but it is likely that either a strong signal is required, or their activation is dependent on external signalling, perhaps by IL-12 and/or other cytokines.
Now, let's look at this in a bit more detail. The inhibitory receptors generally recognise MHC class I (major histocompatibility complex class I) - something else which will soon be of great importance to us. MHC class I allows the NK cells to recognise "self" cells. So, the presence of MHC class I generally inhibits NK cell activity, which is an effective way of ensuring that NK cells do not attack the body's own cells. When cells become stressed or infected by viruses, MHC class I expression can be affected. In other words, many cells which are infected by viruses (and many cancer cells, too) do not express sufficient MHC class I (if any) to prevent NK cell activation. This is referred to as missing self recognition. NK cells identify damaged and infected cells by the lack of self molecules.
However, this on its own is not enough. NK cells generally do not attack the body's own cells when they are healthy because of the presence of MHC class I. However, absence of MHC class I will not precipitate an immediate attack. Instead, the presence of stimulatory ligands is required. These include heat shock proteins, extracellular matrix fragments, altered membrane phospholipids and other general markers of stressed, infected and cancerous cells. These are expressed on the surface of the cells, but stressed cells can also release stimulatory cytokines and NK cells can be stimulated by macrophages, too.
Seemingly, some molecules present on normal, healthy cells also act as stimulatory ligands. Thus, if MHC class I is poorly expressed on these cells they will be attacked. This is useful, because it means that some unhealthy cells can be killed merely by missing self recognition and expression of additional stimulatory ligands is not necessary, since stimulatory ligands occur naturally on that cell anyway.
So, in conclusion, this balance between inhibitory and stimulatory signalling allows for self-tolerance - the body's NK cells do not attack the body's own healthy cells. Meanwhile, infected cells can be "recognised" by NK cells by virtue of the stimulatory ligands which they produce and the absence of inhibitory ligands, particularly MHC class I (missing self recognition). Notice that it's really a combination of these two factors and, in fact, it seems that the triggering of NK cell activity is dependent on the end result of the interplay of numerous signals. Indeed it may well even be dependent on the particular NK cell in question.
To pick up on that last point, one final thing to add is that, in the case of cells which do not express inhibitory receptors, it appears that hyporesponsiveness is important for self-tolerance. In other words, if these cells were not hyporesponsive, they would regularly attack healthy self cells, as they would not be able to detect the presence of MHC class I and so be prevented from attacking. Thus it is necessary that they be very loath to attack and, in this way, they only attack cells which are strongly requiring of attack.
Now, there are a few ways in which NK cells actually go about killing abnormal cells. The primary method involves the release of granules. The NK cell will release perforin - a protein which creates a small pore in the target cell's membrane. Other molecules from the NK cell granules - generally proteins and proteases - can then enter the cell through the pore. These will then induce apoptosis in the target cell, or kill it via lysis, which we've seen before. Apoptosis, or "programmed cell death," is where a cell shuts itself down in response to certain signalling events. NK cells also release a number of cytokines themselves, most notably IFNγ and TNFα.
Finally, in addition to all the above, NK cells can perform antibody-dependent cell-mediated cytotoxicity (or ADCC). NK cells express FcγRIII (alternatively: CD16) receptors which bind to some antibodies (specifically IgG, I think). When this happens, the NK cells are activated and will induce apoptosis in the cell which has been opsonised with antibodies. This is, of course, in many ways similar to activation by stimulatory molecules and subsequent degranulation. It is important to note, however, that not only do antibodies activate NK cells, but they also seem to be able to expedite the process. Whether or not ADCC can completely bypass the usual mechanism involving other stimulatory receptors and inhibitory receptors is not clear to me. It's worth appreciating, though, another example of just how the adaptive immune system promotes and fine-tunes the innate immune system.
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| (a) An image of two natural killer cells attacking a cancer cell. (Image courtesy the NHS2) |
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| (b) A schematic representation of a natural killer cell. (Image courtesy "A. Rad" (via Wikipedia)) Figure 1.57: The natural killer cell |
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1Raulet, David H. 2006. "Missing self recognition and self tolerance of natural killer (NK) cells." Seminars in Immunology 18 (2006): 145-150
2http://www.nhs.uk/news/2008/05May/Pages/Antidepressantsandimmunity.aspx
Eosinophils
Eosinophils are also produced in the bone marrow, from where they migrate to areas such as the medulla oblongata, the spleen and the lymph nodes. Some of them will remain in the circulation, where they can live for 8-12 hours, while in tissue they can survive for 8-12 days. During an infection, eosinophils are attracted to the site of infection by chemotactic factors such as CCL11, CCL24, CCL5 and leukotriene B4.
At the site of infection, eosinophils must be activated by cytokines released by T cells, e.g. interleukin-3 (IL-3) and interleukin-5 (IL-5). When activated, eosinophils degranulate; eosinophils are very destructive - their activation has a lot less to do with mediating inflammation and a lot more to do with the actual business of killing pathogens. Eosinophil granules contain cationic granule proteins such as ECP (eosinophil cationic protein) and MBP (major basic protein), which are highly cytotoxic. These can be very destructive - including to host tissue. MBP is able to stimulate the degranulation of mast cells and basophils and ECP is able to create pores in the cell membranes of pathogens, allowing cytotoxic molecules to enter the cell. As well as these, eosinophils release harmful oxygen species - such as superoxide and peroxide - eicosanoids, numerous cytokines - such as TNFα and IL-8 - and various enzymes and growth factors. In addition to this, they release RNases - which are able to combat viral infection - are important mediators of inflammation and may be involved in antigen presentation.
At the site of infection, eosinophils must be activated by cytokines released by T cells, e.g. interleukin-3 (IL-3) and interleukin-5 (IL-5). When activated, eosinophils degranulate; eosinophils are very destructive - their activation has a lot less to do with mediating inflammation and a lot more to do with the actual business of killing pathogens. Eosinophil granules contain cationic granule proteins such as ECP (eosinophil cationic protein) and MBP (major basic protein), which are highly cytotoxic. These can be very destructive - including to host tissue. MBP is able to stimulate the degranulation of mast cells and basophils and ECP is able to create pores in the cell membranes of pathogens, allowing cytotoxic molecules to enter the cell. As well as these, eosinophils release harmful oxygen species - such as superoxide and peroxide - eicosanoids, numerous cytokines - such as TNFα and IL-8 - and various enzymes and growth factors. In addition to this, they release RNases - which are able to combat viral infection - are important mediators of inflammation and may be involved in antigen presentation.
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| (a) An image of an eosinophil granulocyte. (Image courtesy "Bobjgalindo" (via Wikipedia)) |
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| (b) A schematic representation of an eosinophil. (Image courtesy "A. Rad" (via Wikipedia)) Figure 1.56: The eosinophil |
Basophils
Basophils are quite few and far between, making up only around 0.01-0.3% of all circulating leukocytes; nevertheless, they pack quite a punch. Now, as I say, basophils are circulating white blood cells, they do not have a home like mast cells - their fellow granulocytes - do. Instead, like neutrophils and immature dendritic cells, they circulate in the blood stream awaiting an invasion by a pathogen. When pathogens are detected by immunocompetent cells, basophils can be recruited from the bloodstream as part of the inflammatory response.
As granulocytes, the primary function of basophils is to degranulate when stimulated to do so. As with mast cells, these granules contain histamine and heparin, as well as cytokines and a number of other things. One of the most notable things released by basophils is interleukin 4 (IL-4), a very important cytokine.
Basophils exhibit a number of receptors, including our friend FcεRI. As with mast cells, basophils bind with IgE antibodies, which are involved in the degranulation process. Again, it is important to appreciate that basophil degranulation will be triggered by specific pathogens - i.e. the ones which bind to IgE antibodies. In this way the right response to a given pathogen is produced.
As granulocytes, the primary function of basophils is to degranulate when stimulated to do so. As with mast cells, these granules contain histamine and heparin, as well as cytokines and a number of other things. One of the most notable things released by basophils is interleukin 4 (IL-4), a very important cytokine.
Basophils exhibit a number of receptors, including our friend FcεRI. As with mast cells, basophils bind with IgE antibodies, which are involved in the degranulation process. Again, it is important to appreciate that basophil degranulation will be triggered by specific pathogens - i.e. the ones which bind to IgE antibodies. In this way the right response to a given pathogen is produced.
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| (a) An image of a basophil granulocyte. (Image courtesy Department of Histology, Jagiellonian University Medical College (via Wikipedia)) |
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| (b) A schematic representation of a basophil. (Image courtesy "A. Rad" (via Wikipedia)) Figure 1.55: The basophil |
Dendritic cells
Dendritic cells also likely originate as monocytes, which then mature into dendritic cells in response to a particular signal, or series of signals. I myself am not sure precisely how dendritic cells arise, but when they have done so, they are very useful. Wikipedia perfectly describes them as "sentinels." Immature dendritic cells use PRRs - e.g. TLRs, which we've seen before - to seek out any pathogens. Some will even phagocytise small amounts of host cells in their search for anything which should not be in the body. This is rather delightfully referred to as "nibbling."
Should an immature dendritic cell successfully phagocytose a pathogen, it will mature and set about its primary function of antigen presentation - which dendritic cells do better than any other cells. Additionally, the chemokine receptor CCR7 - among other things - is upregulated, which helps guide the cell to the spleen or a lymph node. Here the dendritic cell will sensitise cells of the adaptive immune system to that particular antigen (and, therefore, the particular pathogen it has phagocytised) and a powerful response to it is occasioned.
As before, I will now give you a picture, so you can see what they look like:
Should an immature dendritic cell successfully phagocytose a pathogen, it will mature and set about its primary function of antigen presentation - which dendritic cells do better than any other cells. Additionally, the chemokine receptor CCR7 - among other things - is upregulated, which helps guide the cell to the spleen or a lymph node. Here the dendritic cell will sensitise cells of the adaptive immune system to that particular antigen (and, therefore, the particular pathogen it has phagocytised) and a powerful response to it is occasioned.
As before, I will now give you a picture, so you can see what they look like:
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| (a) This is a very detailed image of a dendritic cell, taken from a journal article by Judith Behnsen et al. It is actually a screenshot of a video and the screenshot was uploaded to Wikipedia |
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| (b) A schematic representation of a dendritic cell. (Image courtesy "A. Rad" (via Wikipedia)) Figure 1.54: The dendritic cell |
Neutrophils
The neutrophils are the most plentiful of all white blood cells. They live fairly short lives, lasting for around 5.4 days, and during this time they "roam" the body, searching out pathogens. As I mentioned above, they tend to be the first respondents and will flood a site of infection, navigating by means of chemotaxis.
Once there, being phagocytes, one of the things they do is phagocytise any pathogens that they come across. They are also capable of releasing inflammatory cytokines and recruiting other immunocompetent cells. As I have stated before, neutrophils are granulocytes, as well as phagocytes, and - like mast cells - can be stimulated to release their granules, which are very effective at killing pathogens.
The other extremely interesting thing that they do is form neutrophil extracellular traps (NETs). These are actually reminiscent of nets - they're fibres of DNA. The fibres are composed of chromatin as well as serine and other proteins from neutrophil granules. These proteins then destroy invading pathogens. Brilliantly, it seems that the NETs may actually serve as nets - trapping pathogens. They also prevent the antimicrobial proteins from doing serious damage to the body, as they are kept attached to the neutrophil.
Neutrophils look like this:
Once there, being phagocytes, one of the things they do is phagocytise any pathogens that they come across. They are also capable of releasing inflammatory cytokines and recruiting other immunocompetent cells. As I have stated before, neutrophils are granulocytes, as well as phagocytes, and - like mast cells - can be stimulated to release their granules, which are very effective at killing pathogens.
The other extremely interesting thing that they do is form neutrophil extracellular traps (NETs). These are actually reminiscent of nets - they're fibres of DNA. The fibres are composed of chromatin as well as serine and other proteins from neutrophil granules. These proteins then destroy invading pathogens. Brilliantly, it seems that the NETs may actually serve as nets - trapping pathogens. They also prevent the antimicrobial proteins from doing serious damage to the body, as they are kept attached to the neutrophil.
Neutrophils look like this:
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| (a) Some actual neutrophils (giemsa stained). (Image courtesy Dr Graham Beards (via Wikipedia)) |
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| (b) A schematic representation of a neutrophil. (Image courtesy "A. Rad" (via Wikipedia)) Figure 1.53: The neutrophil |
Macrophages
For the most part, the body's macrophages are to be found in vulnerable locations and in places which are likely sites of infection. Here they can live for many months - and occasionally longer - ready to respond to any pathogen they come across. A small number act as "scavengers," being carried along by the blood, where they may encounter pathogens or damaged cells. Such macrophages have a half-life of only about a day.
Macrophages begin life as monocytes, which will mature, under certain influences, into macrophages or dendritic cells. Monocytes are produced by bone marrow and are released from there into the bloodstream. The majority of them migrate to the spleen - a kind of monocyte base - or vulnerable areas such as the lungs. Once in these areas they generally mature into macrophages, with each location engendering peculiar macrophages. This allows the body to maintain a regular turnover of macrophages in these areas.
There are actually two types of macrophages - M1 and M2. M2 is the phenotype of the majority of resident macrophages which remain in tissue. Here, they can respond to any pathogens which they may encounter - as well as damaged cells - and can initiate the immune response.
In the initial stages of inflammation, however, a lot of the "work" is done by neutrophils. After around 48 hours the initial "wave" of neutrophils will have aged and the neutrophils will have begun to die. The macrophages can then engulf them and clean up the general mess. This work is usually done by the resident macrophages. Macrophages will not tend be drawn to the site of infection in large numbers for some time. Usually, 24-28 hours is required before monocyte levels start to build up.
Macrophages are also heavily involved in tissue repair. M2 "repair" macrophages are capable of producing molecules which aid in tissue repair, but their primary role is to rid the area of any damaged tissue. They also release cytokines which attract other cells which can help to the area and they produce factors which aid in angiogenesis. More generally, M2 macrophages additionally produce anti-inflammatories which regulate the immune response and keep it from harming the body.
Now, when pathogens or damaged cells are detected, the monocytes (and any macrophages which are in the bloodstream) are attracted to the area by inflammatory cytokines. They leave the blood flow and enter the interstitial fluid, where they then move by chemotaxis towards the infected area. Once there, the monocytes are stimulated to become macrophages (or dendritic cells) through numerous processes. In the case of substantial infection, large numbers of monocytes will travel to the site of infection, where they will mature into macrophages.
M1 "killer" macrophages are particularly oriented to hunting down pathogens and cellular debris and phagocytising them. It is possible for T cells - which will become very important to us soon - to cause M1 macrophages to become particularly aggressive. Indeed, macrophages have an incredible appetite and have been known to eat iron filings, for instance.
In general, macrophages are also effective antigen presenting cells and, as we have seen in some detail, are responsible for releasing many inflammatory cytokines and for mediating the immune response as a whole.
For those of you who are interested, the macrophage itself looks like this:
Macrophages begin life as monocytes, which will mature, under certain influences, into macrophages or dendritic cells. Monocytes are produced by bone marrow and are released from there into the bloodstream. The majority of them migrate to the spleen - a kind of monocyte base - or vulnerable areas such as the lungs. Once in these areas they generally mature into macrophages, with each location engendering peculiar macrophages. This allows the body to maintain a regular turnover of macrophages in these areas.
There are actually two types of macrophages - M1 and M2. M2 is the phenotype of the majority of resident macrophages which remain in tissue. Here, they can respond to any pathogens which they may encounter - as well as damaged cells - and can initiate the immune response.
In the initial stages of inflammation, however, a lot of the "work" is done by neutrophils. After around 48 hours the initial "wave" of neutrophils will have aged and the neutrophils will have begun to die. The macrophages can then engulf them and clean up the general mess. This work is usually done by the resident macrophages. Macrophages will not tend be drawn to the site of infection in large numbers for some time. Usually, 24-28 hours is required before monocyte levels start to build up.
Macrophages are also heavily involved in tissue repair. M2 "repair" macrophages are capable of producing molecules which aid in tissue repair, but their primary role is to rid the area of any damaged tissue. They also release cytokines which attract other cells which can help to the area and they produce factors which aid in angiogenesis. More generally, M2 macrophages additionally produce anti-inflammatories which regulate the immune response and keep it from harming the body.
Now, when pathogens or damaged cells are detected, the monocytes (and any macrophages which are in the bloodstream) are attracted to the area by inflammatory cytokines. They leave the blood flow and enter the interstitial fluid, where they then move by chemotaxis towards the infected area. Once there, the monocytes are stimulated to become macrophages (or dendritic cells) through numerous processes. In the case of substantial infection, large numbers of monocytes will travel to the site of infection, where they will mature into macrophages.
M1 "killer" macrophages are particularly oriented to hunting down pathogens and cellular debris and phagocytising them. It is possible for T cells - which will become very important to us soon - to cause M1 macrophages to become particularly aggressive. Indeed, macrophages have an incredible appetite and have been known to eat iron filings, for instance.
In general, macrophages are also effective antigen presenting cells and, as we have seen in some detail, are responsible for releasing many inflammatory cytokines and for mediating the immune response as a whole.
For those of you who are interested, the macrophage itself looks like this:
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| (a) A macrophage of a mouse involved in phagocytising two pathogens. (Image courtesy "magnaram" (via Wikipedia)) |
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| (b) A schematic representation of a macrophage. (Image courtesy "A. Rad" (via Wikipedia)) Figure 1.52: The macrophage |
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