The Science of Everything Podcast - Episode 72: Introduction to the Immune System Part 1

Episode Date: February 27, 2015

An overview of the human immune system, beginning with some basic anatomy of the lymphatic system, and proceeding through a discussion of the distinction between the innate and adaptive immune systems, the role of skin and mucus membranes in providing barriers to pathogen entry, the inflammatory response, an overview of the different types of leukocytes, and an initial foray into the workings of the complement system. Recommended pre-listening is Episode 10: The Cell.

You're listening to The Science of Everything podcast episode 72. Introduction to the Immune System, Part 1. And I'm your host, James Fodor. So in this episode, we're going to start looking at the immune system and immunology, and we won't get through it all today, so hopefully we'll be able to fit it into maybe two episodes and three at the most, but we'll see how we go. So in this series of shows, what we'll look at first is the basic anatomy of the immune

immune system. So we'll look at the lymphatic system and the primary and peripheral lymphoid organs. And then we'll move on to looking at all of the different types of, or major different types of cells that are active in the immune system that are called leukocytes. So we'll look at neutrophils, interphylophiles, mesophylls, lymphocytes, monocytes, and the different types of those. We'll also look at other processes involved in the immune system like mucus, membranes, inflammation, the skin as a barrier. We'll talk about the complement system, cytokines. We'll talk about antibodies and antigens and b-n-t cells

and how they form the adaptive immune system. And if we have time, we may also at the end talk a little bit about agglutination and some aspects of seriology. So that's basically testing blood samples for the presence of particular antigens. So basically the structure of this series of episodes are we trying to understand how the immune system works and how all the different bits fit together, because it's quite a complicated system. So we'll try and peel away the complexity and try and explain it in a way that hopefully makes at least a little bit of sense.

No particular prerequisite episodes for this, although it would help if you had a little bit of basic background of, say, cellular biology. So, for example, episode 10, the cell might be useful. Also, episode 25, tissues, organs and systems might also be of use. enough on that. Let's make a start on today's episode. So first of all, what is the immune system? What are we talking about? So the immune system is one of the many systems of organs and tissues that we have that make up the human body, and the immune system is that system which is responsible for essentially detecting us from pathogens. So these are things like bacteria, viruses, parasitic worms, and also cancer cells and other cells that are originally part. of us but grow out of control or causing problems. A pathogen is really just anything that can cause a disease in a host. So when we talk about germs causing infections or something like that, that's an example of a pathogen. And as I said, pathogens can be viruses, bacteria, or they can be larger organisms like worms or fungi, all sorts of things. The job of the immune system,

or its purpose, the reason for which it has evolved is to detect and detect. And ultimately destroy pathogens and any products of pathogens. This might include toxins and other things like that. So that's really what the immune system does, and it has many different and complicated ways of doing that, many different sort of interconnected parts, and we'll try and explain that through this series of episodes. Before we jump into looking at all of the different types of cells, which I guess form the real brunt or the bulk of the immune system that sort of centers around the activities of the different cells. We need to talk a little bit about anatomy, particularly we need to talk about the lymphatic system. So the lymphatic system is one of the systems of the body.

A system is made up of multiple organs and tissues which work together to perform a common set of functions. So the circulatory system is an example of a system. The nervous system is another system, and we talked about these in, I think, episode 25. The lymphatic system is another one, although it's sometimes sort of thought of as part of the circulatory system or like a sister system to the circulatory system, because they're closely related. Lymph is a fluid which circulates throughout the body, and it's quite similar to blood.

Really, the main difference between lymph and blood, which is its sort of more familiar cousin, is that lymph does not contain red blood cells or erythrocytes. So red blood cells are the cells that are responsible for basically carrying oxygen and carbon dioxide around the body and making sure cells stay oxygenated and have the excess carbon dioxide produced as a result of respiration carried away,

and then we breathe it out. That's what red blood cells are for, and they make up quite a large proportion of the blood. Red blood cells are not found in lymph. Lymph contains basically just all of the other stuff in blood, which includes the plasma, which is mostly just water and various other dissolved substances like amino acids and sugars and things like that.

It also includes things like white blood cells, which will be the focus of much of this series of episodes, so-called leukocytes. And so white blood cells are effectively the main cells that are responsible for mediating the immune responses. And so that's why lymph is very closely associated with the immune system, even though it's not really correct to say the lymphatic system is the same thing as the immune system,

because the lymphatic system is mainly just, I mean, it's sort of a pumping system, really. It pumps the fluid throughout our body and maintains fluid pressure and things like that. That's what the lymphatic system per se is for. It also includes some other tissues, but the immune system is broader than that. It incorporates the lymphatic system

inso much as the lymphatic system contains lymph, which in turn contains a lot of white blood cells and the places where the white blood cells mature and things like that. But lymphatic system should not be confused with the immune system because they don't refer to exactly the same thing.

So it's a little bit confusing in that respect. I think of the immune system as being a bit broader than the lymphatic system because it's not just the circulatory parts and the lymph nodes. It's a bit more than that. The immune system includes a bit more than that, as will hopefully become manifesto over the course of these episodes.

A few of the key components of the lymphatic system that we need to be familiar with. One is, in some sense the most important, or at least the most primary, is the bone matter, particularly contained in long bones like the femur in the leg, for example. Now, it might not be immediately clear what this has to do with lymph, you know, the fluid that circulates around the body,

because, I mean, bones themselves don't really contain lymph, or at least not so much, but the importance of bone marrow is that the bone marrow is the site where the progenitor cells of basically all of the white blood cells that mediate the immune responses descend from. So the way it works is that in the bone marrow, you start off with what I call progenitor cells. So basically these are a form of stem cells. They divide, as cells do through mitosis, and gradually the descendants sort of specify into different types, more specific types of white blood cells. So some of them become macrophages and some of them become lymphocytes and other different types we'll talk about later. So they gradually become more and more specialized as the cell sort of mature.

But the place where this begins is in the bone marrow, particularly in the long bones, which have the marrow. not all bones have bone marrow that form white blood cells in this way. So the progenitor cells start off in the bone marrow, like, for example, in the femur, and then they migrate to other, at least some of them migrate to other parts of the body where the cells mature. So, for example, some cells begin in the bone marrow, as I mentioned, and then migrate to lymph nodes or the spleen where they mature and become lymphocytes, for example, and those are part of the adaptive immune response, which we'll get to later. So we won't worry about all of the details about what goes where,

and exactly which type of cells originate in which locations, because it's not that important for our purposes. But just bear in mind that sort of everything starts in the bone marrow, and then different types of cells specialize and migrate to different regions of the body, or different organs or tissues, where they mature and become, you know, the fully formed version of the cell, which then goes and carries out its business. So some of the places where these cells go to mature are the thymus, the spleen, and lymph nodes. So the thymus is a gland, which is located basically just right in front of your heart.

If you touch around the top of your rib cage, it sits around there. It's an organ that you may not have heard of before, because it's sort of a bit, I don't know, tend to get overlooked. But it's a specialized organ that's part of the immune system, and it's the location. where T-cells or T-lymaphysites mature. So T-cells will talk a lot more about later, but they're so-called precisely because they mature in the thymus gland. Another important location or organ relevant to the immune system is the spleen, which is sort of located up around the bottom of the rib cage,

a bit higher up than the stomach. It's also a bit larger than the thymus. it's responsible for a number of functions, but broadly speaking, we can say that it's responsible for filtering the blood system, so removing basically dead or older cells and replacing them with new ones is one way we can think about it. It's also the centre of activity for some types of leukocytes, so white blood cells, which we'll talk about in a moment,

but again, I just want to highlight the spleen as being an important aspect or location for the immune system. and the other the other ones that I wanted to mention were the lymph nodes. So, lymph nodes are a component of the lymphatic system, of course, and they're sort of like concentrations of cells, which are sort of spread throughout the body. So then there isn't, it's not like one concentrated organ, like the thymus or the spleen.

They're located all around the body in little sort of clumps. They look like kind of like little peas, at least you see them on a diagram, located near the lymph vessels, which are the basically, tubes through which lymph is pumped around the body. As I mentioned before, lymph is the fluid that's kind of like blood, but without the red blood cells part. So lymph nodes can basically be thought as a location where a lot of white blood cells sort of hang out while they're awaiting activation, or the sites from which they can grow and replicate and move around the body. That's a broad way of thinking about it. So just to recap, we've got the lymphatic system, which is a system

of tubes that pumps lymph around the body. Lymph has a lot of water in it, but also white blood cells responsible for mediating the immune response. And the lymphatic system also includes a number of other organs or tissues, including lymph nodes, the thymus and the spleen, which are basically all important sites of maturation and growth of different types of white blood cells, which then move around the body. And the ultimate origin for all types of white blood cells or as the bone marrow where the progenitor cells begin and divide up to form more specialized types of cells. So that's the basic overview of the anatomy. Now let's move on to talk more about the immune response specifically,

so what the immune system is actually doing, just bearing in mind in the back of our heads, so to speak, the different locations that I mentioned before. How does our body actually find and then destroy pathogens or invaders or infected cells? As I mentioned before, it has a number of ways of doing, this, and different functions are carried out by different types of cells. As I mentioned, leukocytes, which is basically Greek for white cell, are white blood cells, so they're cells that are found in the blood, also in the lymph, which are responsible for carrying out the

immune responses. Among the major different types of lymphocytes are five that I've mentioned here. I won't focus too much on trying to describe them in detail here, because I think it can be a bit confusing to try to do so. So what I will do is just mention their names and a few key things about them, just so you've heard the terms, and then we'll move on and talk more about how they fit together. So some of these types of cells are neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Those are the five that I want to talk about at the moment. Lymphocytes are probably the most well-known because these include the B cells and the T-cells. Remember I mentioned T cells before?

They're the cells that mature in the thymus, so they're very important. Beazephyls, eosinophils, and neutrophils are all related to each other, and I guess you can sort of gather that from the fact that they all have the same ending, the fill ending. These are some of the most common types of leukocytes that are found in the blood. And basically these are responsible for attacking and killing pathogens, bacteria, fungi, other types of parasites. And some of them are also responsible for helping with the inflammatory response.

which is to do with swelling, which we'll get to a bit later. Monocytes is the other one that I mentioned, are related to macrophages, which you may have heard of. Macrophages are a very important type of immune cell. The word means macro meaning big, and phage, basically meaning to eat. So macrophages are the big eaters. Monocytes are sort of, they're closely related to macrophages. They're similar types of cells.

They both engage in what is called phagocytosis, or phagocytosis. Phagocytosis is basically when one cell eats another, essentially, and that's one of the most important mechanisms by which the immune system actually kills pathogens, is basically just by eating them, either eating the bacteria directly or eating a cell infected by a virus or a bacteria. That doesn't work for everything, but that's a very common and very important way that the immune system keeps pathogens at bay. There are also a few other types of cells that I haven't mentioned, so there are natural killer cells. There is a type of lymphocyte. There are also mast cells, which I'll discuss later, and also related to the leukocytes are the erythrocytes, the red blood cells, which I have mentioned earlier. They're not really part of the immune system, but it's useful to remember that they are related in the sense that they all descend from the same sort of stem cell line in the bone marrow. Important to bear in mind, even though we won't really talk too much about them specifically.

Now, a very important distinction to bear in mind is the difference between the innate immune system and the adaptive immune system. They're two different wings, I suppose, of the immune system. They work a bit differently, but it's also very important to remember that they interact a lot. So they're not separate. They are just specialise, you might say, in slightly different ways of dealing with pathogens. But they interact a lot, again, as I'll discuss more as we get into some more detail. But just to explain the basic difference between the innate and the adaptive immune systems. So the innate immune system is the set of cells and refurb.

responses, proteins and so on, which has generic, non-specific responses. So it sort of reacts more or less the same to any type of pathogen or threat. I mean, it's not going to be precisely exactly the same every time, but the basic sequence of events are pretty much the same. Importantly, the innate immune system does not have any immunological memory. So the innate immune system can't remember what's happened to you in the past or what pathogens you've been exposed to in the past. It only responds to infections or pathogens identified at the present, and it responds of immediately and maximally. So it sees a threat and immediately responds sort of to the maximal possible degree. And the reason it can do that is because it pretty much has only one

set of responses. That's because it's generic, as I said before, it's non-specific. The word innate is really not very good because the adaptive immune system is also innate in the sense that it's innate in humans and lots of other animals as well. You don't have to, it's not learned. So that wording is a bit confusing. Specific and non-specific might be a better way of thinking about it. innate or the non-specific immune system, or it responds in the same way to pretty much everything, and it doesn't have any memory. So it's sort of stupid, if you like, in that sense. It's not stupid. It's very efficient and good at what it does, but it's stupid in the sense that it doesn't remember anything. Now, the adaptive immune system, or the specific immune system, is a bit smarter, if you like,

smarter in the sense that it has a memory. It has an ability to remember what pathogens it's been exposed to before, and that allows it to engage in differential specific responses to particular types of pathogens. So if it sees this particular virus or that particular bacteria infection or this particular fungal infection, it can respond specifically just to that type of organism, or more than that type of organism, that particular species, even or even more specific, that particular strain of a virus, for example, it can be very, very specific, the adaptive immune system and produce the type of antibodies and so on that are tailored just, just, precisely to deal with that particular threat.

Because it is specific in this way, and because it has a memory, there was also a lag time in its response. So it doesn't respond immediately with the most rigorous response it can give. It takes a little while, and that's essentially because of the fact that there are so many possibilities that it could, it's so flexible and specific, that it also has to sort of try out different possibilities for a while until it finds out, oh, this is exactly what I need to deal with this particular pathogen. And then it produces a lot of that. Of course, the adaptive immune system isn't conscious, so I'm speaking a bit metaphorically here,

but hopefully you get the idea. So, to key recap, difference between the innate and the adaptive immune systems. The innate immune system has no memory, and it is nonspecific, so it responds the same every time, and it responds immediately without any particular lag. Whereas the adaptive immune system has specific responses to very particular types of pathogens and different species and strains and so on. It has a lag time, so it takes a little while to get up to its full response, and it does have a memory, so it has an ability to record information about past pathogens

that it's been exposed to. Now, some of the cells that I mentioned earlier, some of the different types of leukocytes, are part of the innate immune system, and others are part of the adaptive immune system. In practice, though, the two work very closely together, so I don't like focusing too much on this innate adaptive distinction, but it's still important to bear in mind. So the basophils, nutrophils, isinophiles, and also the monocytes macrophages, all of those types of cells are part of the innate immune system,

whereas the lymphocytes, so the T cells and the B cells, and also the natural killer cells are part of the adaptive immune system. But as I said, they do work very closely together, as we'll explain in more detail shortly. So now that we've introduced a few key concepts, the idea of the different types of leukocytes, some anatomy of the lymphatic system, and the basic distinction between the...

the innate and adaptive immune systems, it's time to look at the immune system sort of in some more detail. We haven't really explained how it works yet. We've just sort of put some pieces into play. Let's now start to get into some details. And where we'll start is with something you might not have thought as being relevant to the immune system, but it actually is one of the most important components of the immune system, and that is the skin, or more generally surface barriers. Because the first line of defense against pathogens is keeping them out of the body in the first place. As they say, prevention is better than a cure, and the immune system has certainly learnt that, well, through evolution, I suppose, rather than having to try and locate and kill the pathogens inside the host, it's best just to keep them out in the first place.

And that's what one of the main functions of the skin and other sort of membrane surfaces are covering parts of the body, is just to keep out pathogens. So the skin is very well adapted to do this. The skin is quite tough and quite thick. You might not think of it as being very thick, but compared to the size of an individual cell or virus or something like that, it's very thick. The outermost layer of the skin is effectively dead tissue, which is constantly being shed. So, you know, we shed skin all the time. You just normally don't see it, which is good because whatever sort of has settled on the skin is very readily removed through shedding of the outermost layers.

The outermost layer of the skin is dry, so the cells are sort of shriveled and squashed up together, which makes it more difficult for pathogens to grow or gain access into the tissue. It's also mildly acidic, so sweat is mildly. which makes it a little bit less easy for a bacteria and other organisms to grow. Also, your skin is already colonized by a normal microflora. So there are already lots of different bacteria living over our skin, which is actually good because they compete against pathogens. So the normal types of bacteria we have living on our skin don't normally hurt us,

cause us much of any trouble. But one thing they do is keep away pathogens, which might grow on our skin if they weren't there by out-competing them, by using up the resources, basically. So the skin has many advantages to keeping out pathogens. Unfortunately, our body can't be completely covered with skin because we do need some way of getting food in and wastes out and so on. And so that's where other types of barriers are called mucus membranes come in.

So a membrane is basically just some sort of surface or when we talk about tissues. It's basically an outer layer which protects some inner layer. And a mucus is, well, you have an idea of what mucus is, I imagine. Mucous membranes are membranes that excrete mucus as a way of generally sort of protecting the underlying tissue and keeping out pathogens or other substances that aren't wanted. So there are lots of examples of mucus membranes which help to protect the body from unwanted intruded. So, for example, well, the skin is effectively a form of membrane and we sweat and we extrude the outer layer of skin over time, as I mentioned before. these help to defendants from pathogens, as I mentioned. The gastrointestinal tract, so basically the digestive system is another example of a mucus membrane.

Peristols, that the process of essentially pushing globules of food or progressively digested food through the system and then out through the anus, that that's a way of keeping pathogens out of the body, essentially. They're not allowed to stick around just for as long as they like. They're pushed through and out the other end, essentially. This is a form of sort of flushing out toxins or other pathogens that might have got in. There are also lots of other substances like gastric acid, for example. We have very strong, very corrosive acids in our stomach, which are useful for digesting food, but they're also useful for killing bacteria, which we might eat.

Respiratory airways. So, for example, we have mucus in our trachea and mouth and nose and places like that, essentially, which is helpful when we need to cough or sneeze or choke up things. Hopefully we don't need to, but if we, for example, breathe something into our lungs, having the mucus there is very helpful because it helps us to push out. extrude, get rid of the invasive substances. It would be much harder. I mean, basically, the mucus acts as a lubricant. Things stick to it, and you can help to slide them along to get them out. It might not sound very nice, but, I mean, it works. That's effectively what the mucus is for.

Keeps things out and helps to get things out when they get places we don't want them. Even tears from the teard ducks in the eyes, which you may not have thought of as being related to the immune system, are helpful because they continually clean the eyes. They make it more difficult for or pathogens or other unwanted particles to get into the eyes, and then they could move around the body, because we're constantly flushing them out through the tearducks. So lots of systems like this, mucus membranes used to excrete some substance, which helps to keep cleaning out and pushing away the substances we don't want.

Many mucus membranes also contain chemicals or enzymes which help to break down bacteria. So one common one is called lysosine, which helps to break down. I think it's bacterial walls or membranes, I forget which, but a number of these different mucus secretions, so in tears, in saliva and so on, contained chemicals which help for this as well. Alas, the skin and mucus membranes aren't always enough, and despite our best efforts of these this outer layer of defences, the pathogens still sometimes make it through. So what happens then if the first line of defences is breached?

Well, a common reaction, one that you hope is occurring, or will occur, is called inflammation or the inflammatory response. Now, inflammation is a protective response, which occurs when the, well, it occurs when the skin is broken, but also just generally when there's some sort of cause of injury or stress damage to cells that will often trigger the immune response or the inflammatory response. The classic signs of inflammation you would, of inflammation you would be familiar with, heat, redness, swelling, loss of function and pain. Inflammation is a generic response, so it's part of the innate immune system. You remember I talked about innate versus adaptive. So inflammation doesn't, you know, it's not different depending on what type of, whether it's a bacterial infection or, you know, a viral infection or what type of damage has been caused. There might be minor differences, but basically it's the same response. So it's innate, it's the same, it's part of the innate immune system. But it's a very useful response, even though it's not pleasant, and we generally want to, you know, get rid of the swelling or make the pain and the redness go away. But it's very important that we have that, because if we didn't, the immune system would be much less effective. So what's the point of the inflammatory response? Why do we need all this heat,

this redness and heat and swelling and so on. Well, basically the purpose of it is to get more leukocytes to the site of the damage or the lesion or the infection. Because remember, the leukocytes contained in the lymph-slash-blood, both of them, are the workhorses of the immune system. These are the cells that are going to kill the pathogens. So we need to get them to the site of the infection

or the site of the damage. And we want to get them there as fast and as large a numbers as possible because much of the immune system is a numbers game, you know, just one cell is not going to do very much. You need a lot of cells all attacking the pathogen to be able to rid yourself of the infection. That's why it's a numbers game the other way as well. The more viral particles or bacterial cells that you ingest or are exposed to, then the more likely it is that you'll develop the disease

because it's harder for your immune system to deal with. You know, one cell is probably not going to be too much of an issue, but if you ingest a thousand cells, a million cells, a billion cells, then it's harder and harder to respond. But inflammation helps that as much as it, can by trying to get as many cells in there as possible. And the way it does that is essentially by releasing chemicals which causes the blood vessels to dilate, which is the cause of the swelling, and the heat and the redness. Basically, your blood vessels are leaking and blood is accumulating

in the tissues surrounding the injury or the infection, and that's causing the redness and the swelling. So that's deliberate. Why would we want the blood vessels to dilate like that, to start leaking? Well, it's because the various leukocytes that are contained in the vessels then can come out of the blood vessels, where they normally hang out, well, the blood vessels and the lymph vessels as well, and enter the tissues, or more importantly, the intercellular fluid that surrounds the different cells in tissues, so muscle tissue or wherever it be exactly. So this is a way of, so leaking blood cells is a way of getting those leukocytes to the side of infection or damage as soon as possible. And leukocytes include things like, for example, neutrophils, which are, which are a cell that I mentioned before. They're part of the innate immune system. They are phytocytic cells, so they eat, basically, pathogens.

And they're sort of one of the early responders, if you like, to this process of inflammation. There's a special process by which the leukocytes sort of bump along the capillary walls, or blood vessel walls, and then sort of adhere to it and sort of push their way through and get into the intercellular tissue and then head towards the stimulus that's a trillions. them, which basically comes from the side of infection, and it starts eating up the bacteria or whatever it be. But we didn't go into the details of that, but it's quite interesting how it works. They literally sort of bounce and sort of roll along and then adhere and then squeeze through the walls or the gaps between cells, actually. Another type of cell that I mentioned earlier, mast cells are important in mediating the inflammatory response.

So mast cells released a chemical called histamine, which you may have heard of. It is, basically, histamine increases the permeability of the capillaries to white blood. cells, so allowing the leukocytes, for example, to squeeze through and other white blood cells to get to the side of infection, as I said before. You may have heard of medications that are antihistamines, while an antihistamine is going to counteract the action of histidine, which would therefore reduce the permeability of capillaries. So basically, antihistamines are anti-inflammatories. They're going to reduce swelling or prevent swelling. Now, this is often a good thing because often the inflammatory response does more harm than good. Well, I don't know about often,

but at least it can, and we want to reduce swelling because, for example, people can't breathe, because they're having an allergic reaction to something. In that case, the inflammatory response isn't helping. It's doing harm. So the immune system isn't perfect in that way. There are a number of cases where the immune system hurts us more than it helps us. But that's the subject of another time. That's enough on the inflammatory response. Let's now move on to talk about the phagocytotic cells, which, as I said before, are cells that eat other cells. cells, or particularly pathogenic cells. So I've used this very vague term, eat.

Obviously, cells don't have mouths and chew up their food and digest them through their intestines or anything like that. So what do I mean when I say that a cell eats another cell? Let me explain the process in brief, and hopefully we'll get a bit of an idea by what this means. So, first of all, it's important to remember that phagocytotic cells are generally bigger than the cells that they eat. I mean, it wouldn't really be possible, I don't know, maybe there's exceptions, but it wouldn't really be possible for a small cell to eat a bigger cell, because it has to sort of engage engulf it. So, luckily, most of the things that, well, many of the pathogens that were affected with will be a bacterial, and bacterial cells are much smaller than eukaryotic cells, so that's

all right. Also, macrophages are particularly large, so they can engulf even some eukaryotic cells, so cells infected with viruses, for example. Much bigger things like, for example, parasitic worm infections are not going to be able to be dealt with by this same method, but luckily we have other cells to deal with those, which we'll get to later. But phagocytosis is certainly a very useful method because it can deal with a lot of types of infections, viral, and bacterial, and even some eukaryotic. So, how does this process work, though? So, first of all, what happens is that the phagocytic cells, say, call it a macrophage,

that's one example of a phagocytic cell, somehow it detects the pathogen. So let's say that it's a bacterial cell. So it detects it in some way, usually through the release of certain chemicals called cytokines, but it may have just happened on it randomly or followed the sort of chemical trail. We'll talk a bit more about that, but it detects it somehow and sort of moves towards it. Then basically what happens is that the cell membrane will sort of open up in a sort of a pocket, like a little mouth almost will form, an indentation in the membrane. And literally the membrane will just close around the bacteria cell,

and mouth bits of the membrane, if you like, will pinch together. And then you'll have this little hole, in a sense, inside the macrophage, which is called a phagosome or a phagocytotic vesicle. Literally, the cell membrane is sort of pocketed out and surrounded and engulfed the bacterial cell. But the bacterial cell is still there. It hasn't really done anything to it yet. It's just engulfed it in the phagosome. What happens then?

Well, what usually happens is that another vesicle, remember a vesicle is basically just a sort of a storage sack, if you like, inside the cell membrane. Another vesicle called a lysosome comes along. A lysosome is a vessel that contains a lot of enzymes or chemicals that help digest things. break them down. So they're digestive enzymes. Lysosome comes along, fuses with the phagosome, and releases all of these enzymes and chemicals, which then do their work and digest the micro, break it up, and punch holes in its membrane and digest proteins,

and break down carbohydrates, and all of that sort of stuff. Breaks it down to smaller molecules, kills it. And then once that process is completed, there will remain a sort of a vesicle containing residual components of indigestible materials. They're just bits and pieces remaining from the bacteria, which couldn't be absorbed or ingested by the cell, then that little vesicle will move through,

it's called a residual body, it moves through the cytoplasm, and basically merges with the cell membrane, the macrophage membrane, and then ejects out all of the waste products, and they're ejected into the intercellular environment. So it's conceptually a fairly simple process. The macrophage, or whatever cell it is,

opens up its cytoplasm, swallows the microbe or cell or whatever particle it is, injects a bunch of enzymes into it, into the resulting vesicle, that digests, kills the microbe or whatever's in there, and then it ejects the waste cells out the other end. That's the basic idea of the process of FACocytosis. So you can see it really is quite analogous to how humans or other animals eat, just on a cellular level.

Okay, so that's what FACocytosis is, and that's one of the big ways that our immune system deals with pathogens. It eats them. monocytes, macrophages, neutrophils, and dendritic cells are all different types of leukocytes, so white blood cells, which exist in slightly different locations and they have slightly different origins and they work in slightly different ways, but they all carry out the basic similar task of phagocytosis, eating cells. And again, this could be bacterial cells or it could be your own cells that have been infected by viruses or it could be various, you know, if you have affected by some protist or other organism like that. So any of these sorts of infectious agents can be eaten through, many of them at least, can be eaten through phagocytosis. Now, you may have noticed that I missed out or didn't really explain one key component of

this whole process of phacocytosis, which is how does the macrophage or the other cell know where the pathogen is and how to get to it, and how can they recognize a pathogenic cell from all of the other cells that exist in our body? Because it wouldn't be very good if these phagocytes just went rampant throughout the body eating everything that they came across, we would die. And indeed, this is what an autoimmune disorder is when an immune system starts attacking our own cells, and that's not very good. The immune system needs some way, or multiple ways, really, of identifying pathogens and selectively choosing them, selecting them out for phagocytosis, or killing in other ways,

and avoiding attacking our own cells, our own body cells, in this same way. Very loosely speaking, this is what much of the rest of the immune system, the parts that I haven't talked about yet, or only just mentioned, is responsible for, it's responsible for helping phagocytes to locate, identify, find the cells that they need to target. Now, that's a gross oversimplification because the rest of the immune system does a bunch of other things as well, but that's a really, really central purpose of the rest of the immune system. And so I want to put that as a focus of them what we're about to discuss, particularly the B cells and the T cells, because they really do help with this process.

However, I did say that there are a few other things that the immune system does as well. So I want to briefly mention a couple of the other types of cells that do things apart from phagocytosis. So you've got the phagocytosis, your macrophages, your monocytes, your neutrophils and dendronic cells, all types of phagocytotic cells, all eating bacteria or viral infested cells or whatever. But there's a few other types of cells that I mentioned as well, which have important functions. One, natural killer cells, these are part of the adaptive immune system. These are not phagocytotic cells, so what do they do? Well, they don't directly attack invading microbes,

rather what they do is they destroy compromised host cells, like tumor cells, for example, or cells infected by viruses. Basically, what natural killer cells do is they have special proteins or molecules on their cell membranes, which look at any cell they come in contact with, and see if it has a special marker, which, again, just other proteins that stick out from the cell membrane. And this cell surface marker is called the MHC1 complex, which stands for major histocompatibility complex, but we didn't worry about that.

Basically, every cell in your body, pretty much every cell, should have this MHC1 complex on its surface, on the surface of its cell membrane. Because this is, this complex, it's just a bunch of proteins that stick out of the membrane. This complex acts as a flag in a sense, which says, don't shoot. I am friendly. I am self. I am part of the body. So every cell should have this, because all of the cells should carry your genetic material, your genetic material will coat for these types of cells, and the proteins and all of the exact specificity will be different for different people.

That's why you can't just take one person's organ and transplant into another person, because they'll have different self-markers. So what natural killer cells do is go around looking at these. And when I say looking, obviously they don't have eyes, but what they do is they essentially bind their proteins on the natural killer cell surface to the proteins on the surface of the whatever cell it's looking at. And if they match up, if there's the right type of binding, then it's all good. Essentially, they've recognized the MHC1 complex.

They've recognized the appropriate signal, and they know that it's a self-cell, and they leave it alone. But if the cells don't possess these MHC1 markers, then sort of the red lights go off. The natural killer cells go into attack mode. They start releasing toxins which punch holes in the membrane, and also other chemicals which can trigger apoptosis, which is basically cell suicide, a series of reactions which leads to the cell killing itself. So they're called natural killer cells, because they're in some sense quite aggressive. They go around everywhere looking for this MHC1 complex. If it's not there, bam. They just shoot out all of these toxins which punch holes in the membrane and get the cell to kill itself

and very, very vicious, non-forgiving. And that's why they're very useful for attacking tumor cells and viral infected cells, because both of these types of cells tend to lose their MHC1 complexes. Remember, tumor cells are just our own cells which have grown out of hand, growing without limits, and virus-infected cells are also our own cells which have become infected by a virus. So they started off as our own cells. They should have started off with the complex, but often when they become cancerous or become infected by virus, they lose it. Not always, though, which is how some cancers and viruses can evisers. the immune system. They can basically put up false signals that they pretend to be cell cells,

but they aren't really. But anyway, often, at least often enough for it to be useful, these MHC-1 complexes are lost in cancer and viral-infected cells or in other conditions. And as a result, these cells can't put up the flag that says I'm self, and so they get smashed to bits essentially by the natural killer cells. So a very important part of the immune system, the natural killer cells. But not phandisiotic, so they don't eat cells. I think of them as they shoot at them in a sort of literal sense. They don't have guns, but they do shoot chemicals at them and punch holes in their cell membrane.

So it's kind of like that. So that's a natural killer cells. What are the other type of non-facocycocytocytes? So the two other types that I want to talk about are basophils and eocinophils. These two are part of the innate or the non-adaptive immune system. And they have slightly different functions, but basically they both help with the inflammatory response. So if you recall earlier, I talked about the inflammatory response about the leaking blood cells and getting the leukocytes to the site of infection or tissue damage as quickly as possible.

Well, basophils and xenophils help with this. They contain chemicals which they release in response to various other chemicals, which then leads to a reaction which eventually leads to the inflammatory response. The details aren't of importance to us here, nor do I really understand them. And indeed, I don't know if anyone fully understands all of them, because they're very complicated. But suffice it to say that these. cells are important for mediating that, along with mast cells, which I mentioned earlier. Eocinophils also fulfill, are responsible for combating multicellular parasites.

So that's things like parasitic worms or other large organisms that we might get infected with. They're specialized for dealing with those, because remember, you can't phagocytize those because they're too big, and likewise natural killer cells aren't well adapted to deal with them. So that's what the eosinophils are for. That's not the main type of thing people tend to be affected with, but it's still useful to have that as part of the arsenal. Okay, so we just went through the phagocytotic cells, which cells and some of the non-facocytocytes,

natural killers, basophils, and eocinophils. Now, I'm going to move on to what I promised to talk about, which is how exactly do the phagocytotic cells in particular, but also other types of cells, but particularly the phagocytotic cells. How do they figure out what cells to eat and what cells not to eat? Now, we got a hint before when we talked about the natural killer cells, because remember the natural killer cells basically look for this special flag, a marker, the MHC1 major histocompatibility complex, the bunch of proteins on the surface of the membrane of the cell that says, I am self, don't hurt me.

Well, that is more or less, or a similar idea to what happens in the rest of the immune system, so how phagocytes recognize the cells that they should attack. Because basically, like our own cells have flags that say, don't attack me, I'm friendly. most, or basically all pathogenic cells, particularly bacteria, have proteins on the surface of their cell membrane slash cell walls, which say, I am the enemy. So they wear uniforms in some sense. And that's how our immune system can identify them. Remember, I mean, immune cells don't have eyes, so they can't just look and see what uniform the cells are wearing. What they have to do is they have to have mechanisms of recognizing particular proteins that are on the surface of the cell wall or the cell membrane.

then triggering a process that leads to those cells being eaten, and just those cells being eaten and not the cell next door, which is a self-cell that we want to keep. So how exactly does that happen? Well, that's what I'm going to be talking about for much of the rest of the series here. There are three sort of key ideas that I want to discuss that all relate to how the immune system performs this function,

how it recognises the good from the bad. One is the complement system, another is cytokines, and the third are antibodies. And these are all closely related to each other. Like they're different, but they all interact. And so it's a bit hard to talk about one without talking about the others. But I'll sort of go through them all and then go through them again together to try and put things in perspective and hopefully bring things together a bit.

And the B cells and T cells, again, parts of the adaptive immune system that I mentioned earlier, they're coming up as well because they are very important for producing antibodies and cytokines and interacting with complement. But we'll get to those. First of all, let's talk about complement, cytokines, and antibodies, each in turn. Okay, so, how does the complement system help out the phancocytotic cells into figuring out which cells to attack? Well, first of all, we have to answer what is the complement system. The complement system is basically just a whole bunch of different types of proteins

that are found throughout the blood and the lymph. Mostly they're made by the liver, and they circulate around the body, usually in inactive form when they're not doing anything in particular. So it's just a bunch of proteins. That's why it's called a complementary. They're complementary. They help our proteins. They don't, well, they can kill cells directly, but that's not, they don't usually sort of do that. Mostly they help macrophages, or, sorry, they help phagocytotic cells. So the leukocytes and the macrophages and the monocytes do their job. How do they do that?

When they're just protein, what are they going to do? Well, in order to do something, in order to activate a response, they have to become activated. There are three ways that they can become activated. They're so-called the classical alternate and lectin pathways, but I mean, don't worry about those too much. We'll get to those. But they become activated in some way, which will get to how that works. But what do they do once they're activated? Well, this is the key point here.

One of the main things that they do is engage in something called obsonization. So one type of sort of set of proteins, because there's many different proteins that make up the complement system. One type of these proteins engages in obsonization once it's been appropriately activated. What does that mean? Basically, these proteins bind to the cell wall or membrane of a microbe and market for destruction by macrophages. So basically, they're putting up flags. These proteins are binding to the pathogen,

and the macrophage is able to, or other phagocytotic cell, is able to recognize these proteins and see, ah, yes, this is one of the cells I need to kill, and so it goes and targets that and eats stuff. The way this works in detail is essentially that when these proteins, when the complement proteins bind to the surface of the pathogen cell, they help to increase the affinity of phagocytotic cells for binding to it. So phagocytotic cells can bind to and then eat up microbial cells,

pathogenic cells, without the complement system helping. This is the so-called opson and independent pathway. So they can go it alone, do it by themselves, but they're not as efficient, they're not as effective as doing that. I mean, they're going to miss a lot of bacterial cells doing it this way, because they don't see the flags, essentially. Obsonization helps them be much more efficient. They find the cells that they need much more quickly, much more easily,

and are much more systematic in getting all of them. So it dramatically increases the binding affinity between the phacocytotic cells and the microbes, which then allows phagocytosis to occur much more readily and quickly and efficiently. So that's really important. Once you activate complement cells, you activate opsonization process, which then really helps out the phagocytes in dealing with them. But how do you activate the complement system?

It doesn't just activate itself. Ah, well, we'll get to that. Don't worry, all will be revealed. But first, I need to finish explaining what the complement system does, and then we'll get to explaining how it gets activated. This is complicated, but unfortunately, the immune system evolved to be complicated. So hopefully, eventually all the pieces will fit together, and it will make some sense.

But we just have to slog through for the moment. So if things are a bit fuzzy, don't worry too much. All will hopefully be clear. So right now we're trying to explain how the complement system helps macrophages and other phagocytotic cells to eat up the bad guys, and particularly how it helps them figure out who are the bad guys. Well, one way we've said is opsonization, by which the complement cells bind to the surface of the bad guys, and increases the binding infinity between the macrophages and the pathogens and therefore enables phagocytosis. But what else does the complement system do? Well, the complement system can also directly kill microbes, basically by forming structures which punch holes in the cell wall or the cell membrane.

They form channels by connecting a bunch of the proteins connect up together and literally form walls which sort of punch a hole through the membrane. And that's a problem, because when the membrane is breached, then you have a direct transfer of fluid between the cytoplasm inside the cell and the extracellular fluid, which effectively kills the cell. The cell needs to be surrounded and protected for it to exist as a separate entity, and if that's breached, the cell's not going to be able to survive. That's called cell lysis, so just rupturing the cell.

So that's another thing that the complement system can do. So they can call out, basically, they can help out their buddies, the macrophages, or they can just do with themselves, cell lysis. Of course, they do both. Different types of proteins are responsible for doing these different tasks, so the proteins responsible for obsonization are called C3B, and the one's responsible for the cell lysis. or C5 through C9, but we don't care about those.

Just remember that it's different types of proteins doing the different specific task, but they are all related because they're all part of the complement system. But that's not all the complement system does. The complement system also is engaged in something called chemotaxis, which is how it attracts macrophages and neutrophils, basically phacocytotic cells, to the area of infection or to the region where pathogenic organisms are located. Now, chemotaxis is basically a process by which Chemicals are released, which then diffuse throughout the tissue or the bloodstream or whatever it is.

Generally the tissue, because the bloodstream will carry around pretty fast. But the point is that the concentration of the chemical will vary. The chemical will be most concentrated at the location where it was released, which of course will be at the location where the infection has occurred or where the pathogenic organisms are located. The less concentrated the chemical becomes the further way you're moving. So basically what macrophages and the other phagocytocytes cells can do is they can be sensitive, they are sensitive to these special types of chemicals, and they move along concentration gradients.

So this is basically like someone telling you if you're getting warmer or getting cooler, when you're trying to find something and you don't know where it is. They don't need to tell you where it is. All they need to tell you is if you're getting warmer and cooler, and if you're sensitive enough to that, eventually you'll find it. And this is effectively how a chemotaxis works. all the macrophages and other phagocytocytes cells have to do

is follow the chemical gradients and eventually they'll get there and that's how the complement cells are able to effectively tell the phagocytic cells where to go just by following this chemical gradient of chemicals that are released by the complement system

at the site of the infection. And some of these chemicals that are responsible for signaling between cells are called cytokines so basically signal proteins and they can be responsible for all sorts to things. So, for example, when a cytokine binds to the surface of the membrane of a cell, it can lead to changes in gene expression. So maybe it produces the right protein, which the cell

needs to excrete in order to produce this chemotaxis gradient, for example. So these methods are also mediated by cytokines, which is the second of the three types of things that I'm talking about, complement cytokines and antibody. So I might mention cytokines again, so just bear them in mind as to what that means, signaling molecules, basically. But coming back to the complement system. There's yet another thing that the complement system does, and that is that it helps out with the inflammatory response. Remember the inflammatory response? Leaking blood vessels, getting elucocytes to the place of infection. Complement system also helps out mediating that. Again, the type of protein is responsible for that. It activates the mast cells, which in turn

released the histamine, which is necessary to increase the permeability of the blood vessels. So remember the mast cells are involved in this, also the basophils and the eucinophils are involved in this, which I mentioned before. Compliment system also involved all interacting with each other and sending out messenger chemicals and so on between each other to cooperate. Very, very useful

the complement system. It does a lot. It's involved in obsonization, which is helps out the macrophages finding the things that they need to bind to and eat up. It helps out with chemotaxis, which is attracting the macrophages and the noosophils to the sites of infection. It helps with cell lysos directly by it.

That's the punching the holes in the membrane, killing cells directly. And it also helps with activating mast cells and thereby mediating the inflammatory response. So these little proteins that are floating around the bloodstream are very, very useful in the complement system. They don't necessarily do a lot of the killing directly. They do some of it, but they really are very helpful for the other aspects of the immune system. But there's one thing that I haven't explained yet, and that is how is the complement system activated? How do the proteins get to be there and get to be there in large enough

numbers and get to be in the active form so that they actually start doing stuff? Because again, if they're just punching the cell, holes in the membrane of any cell around, or binding and obsonizing with any cell willy-nilly, then that's going to lead to a lot of autoimmune responses, which you don't want. That would be bad. You only want to be specific to the things that you want to kill.

I mentioned before, I mentioned very briefly that there are three ways that it can be activated, the classical, the alternative pathway, and the lectin pathway. I'll mention the lectin one first, because that is related to things we've already discussed. when macrophages basically engage in phagocytosis, when they eat up something, they release particular chemicals which activate the complement system.

So this is through the lectin pathway. So basically, when one macrophage eats up a cell, it spits out a chemical which then activates the complement system, which in turn leads to the activation of more macrophages. So macrophages help the complement system, complement system helps macrophages. so it goes in a cycle. These are called feedback loops, and that's how you can go from a system where maybe just one macrophage,

by chance, happens to come along across a pathogen, because, you know, the body's a big place, and the macrophages are all over the place, pathogens might be fairly diffused as well. But by luck, one macrophage happens to hit the pathogen and recognize it needs it up. It can spit out then some lectin, which then leads to this chemical cascade,

which leads to the complement system being activated, the complement proteins in the region then start opsonizing with the or the process of obsonization with the other pathogens that are in the region which and also at the same time we get the process of chemotaxis, remember where the chemical gradients start processing, then you have macrophages

coming from other regions of the body following the chemical scent if you like and once they've got to the site of the infection then they find these nice sort of obsonized microbes which is you know obsonization meaning the surface of them has been covered by all these flags saying eat me and it eats them up and then it releases more

this chemical, which it attracts even more macrophages, and so the process goes on until you've sort of overcome the infection. So that's an example of how these different components, the complements and the macrophages work together in a sort of synergistic way. Okay, so I think I'll leave that there for this episode. Next episode will go into talking more about the adaptive immune system, particularly how antibodies are produced and B cells and T cells and how that interacts with the innate immune system, and I'll go over everything that we've already discussed as well and sort of try to put things together and summarize. So fear not if things are still a bit hazy at this point.

If you enjoyed the show, then I'd be grateful if you'd jump onto iTunes and give the show a favourable review. You can also send me an email. My address is FOD12 at gmail.com. That's FODS-1-2 at gmail.com. Thanks for listening, and I'll talk to you next time.