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Inflammatory Response

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Video 1: Extravasation
So, uh, welcome to the lecture seven of our immunologic, uh, lectures. So, uh, in the last class we discussed about the immune system. And if you remember the last, uh, last day in the picture, uh, so, uh, we have this discussed about how the immediate response to a foreign invasion starts or is initiated by that it immune system and the major cells that are involved in this response. Ardagh. Neutrophils, which are the fastest acting cell of the immune system. So the neutrophils, they moved to the site of action. And then there are many other cells of the immune system, like the mosques cells, the tissue macrophages, the din writing cells, the antigen presenting cells, which then, and phagocytose, uh, pathogen or the bacteria and transfers the signal to the Adaptive system. I told him the last lecture that the init system is the first line of defense and it tries to restrict the bacteria or the pathogen that has infected our body or invested our body. And it tries to kill that on the fast site. While in doing so it can lead to, uh, complex, uh, response, which we sometimes describe as inflammatory responses. And these inflammatory responses can be local responses or they can be global responses or, uh, acute, uh, systemic responses. So. The local responses or the local inflammatory responses are primarily, uh, mediated by the neutrophils, the mast cells. And to some extent by the activated macrophages as well. And then when there is phagocytosis Interline internalization of the pathogen and see Christian of the cytokines. Then there can, that can also lead to a systemic response. So one of the major phenomenon that is very central to this, uh, inflammatory response is the migration of the leukocytes, the migration of the leukocytes to the site of action or to the tissue. Where actually the damage has occurred. So because these leukocytes they're in the bloodstream primarily, so now they have to move to the site of action. And one of the major cells that mediate this, uh, uh, inflammatory response is the neutrophils and the mosque cells. So the neutrophils has to go there. And how do they go there immediately? So what it has been seen that immediately after, uh, an infection or an, uh, tissue damage, the number of the neutrophils, they increase almost 10 folds all already. The neutrophils are, uh, the number of the neutrophils are very high in the blood and that even increases even by 10 folds. And that neutrophils, those neutrophils, they start to migrate. They start to migrate to the site of action or the damaged tissue where the pathogen has infected. Now, how does this happen? Let us, uh, for the time being live this picture here and, uh, whatever we have seen in the last class. So I will leave this picture here. Then we move on to the next page and see what actually happens during an inflammatory response. So from the last class, we have seen that the tissue macrophage. So this is the tissue macro fudge, or the antigen presenting cells, the macro fudge. Well, the antigen presenting cell has already engulfed or phagocytosed are bacteria or a pathogen and have started secreting the cytokines. So these are the cytokines that are secreted as an immediate response after internalization of the bacteria. So this is the, this is an activated macrophage. On the right side and this is the blood. So this is the blood part. And let us say, this is the tissue. So, and here we have what damage on the tissue may be due to a nail piercing or. Something like that. So, uh, then we have the bacterias here or the pathogens that has entered the body in this part. And we have the neutrophils moving to this part. So this to some extent looks still very familiar from dollar from our last class. And then also you have the. Muscles. So now the question is in response to this, how these cells or these neutrophils and the other, other cells of the immune system, of course, and primarily the neutrophils, we are talking about the neutrophils, primarily how they migrate to this site of action and immediate inflammatory response. So this migration. Off the neutrophils to the site of action is also a part of the inflammatory response. And this migration of the neutrophils is also the process is also sometimes known as extrovert because the cross, the blood vessels. And where do they cross from? So they cross from this regions on the blood vessels, which are known as the high endothelial venues or the H E V the high endothelial venoms from there, the crossing.

Video 2: Migration of Neutrophils
Now this process of migration of the neutrophils, which as I described is a part of the Inflammatory response. This occurs in steps, and this is also mediated by certain mediators, which are known as the cams or the cell addition, molecules, the camp, the cell addition molecules. You feel looking at this picture here, here. This part. So this is just a magnified, uh, diagram of what we are seeing here, a single neutrophil. Okay. And then, um, endothelial cell, which is, uh, magnified in this region. So there, we can see, there are at least four different classes off there, at least four different classes of this cams or de cell addition molecules. And these are the mucins, which are usually expressed on the surface of the neutrophils. So these are the mucins the selectins. So the selectins. Which are usually expressed on the surface of the endothelial cell. Then you have the integrins N a fourth class of the cam, which are known as the, I cam. Which are also known as the immunoglobulin superfamily cell addition molecules, or the I G super family cams or the cell addition molecules. And that's why they are known as the icons. So now what happens in this part? So this migration of the neutrophils. This occurs by four different steps. If you see here, the step one, the step two, the step three and step four. So the step, the four different steps are step one is known as rolling. Then it is activation. Then addition, and then finally trans endothelial migration. No, you should try to correlate this four steps. One, two, three, and four in this region here. So step one is rolling. Step two is activation. Step three is addition and the fourth is the trans endothelial migration. That means it migrates through this. Hi, endothelial venial and crosses the blood vessel and enters into the tissue and goes to the site of action. So now we try to understand the four different steps and how this four different steps actually occur the first step. So the first step is initiated by the binding of. The mucins to the selectins. So the museums are a class of the camps or the cell adhesion molecules that can specifically bind to the selectins, which are being expressed on the surface of the endothelial cells. So the museum binds to the selecting and as this binding occurs, so the cells which were kind of flowing in the bloodstream, they are now. Attached to the endothelial cell, the first step of attachment, and they start to rule on the, on the surface. They start to roll. The second step is very important. That is the activation. No activation involves dark effector molecules or the chemo kinds. So. We will, uh, describe, or we will discuss about the cytokines and chemokine in our later classes in details for the time being, we are just, uh, try to understand how this chemokine is. As the name suggests they are actually chemo attractants. So they attract. Something. So the chemo kinds usually work by binding to specific receptors expressed by specific cell types. For example, neutrophils, they express a class of chemokine receptors. The, uh, T lymphocytes express, a class of chemokine receptors, the billing for sites, they also express a class of the chemokine receptors. So most of the cells of the immune system, they on their surface have the chemokine receptors being expressed. So if you look into the picture here, this, this here is a chemical and receptor, for example, which is expressed on the surface of our neutrophils. And this green circle here, this describes a chemokine. So now a chemokine it's being secreted by the endothelial cell and by virtue of that, so the chemokine to chemokine receptor is something like, um, uh, iron to magnetic attraction. So it's just iron magnetic attraction. So now when there is a chemokine present in the surrounding and a cell, which has on its surface, which is expressing.

Uh, a chemokine receptor, then it will be quickly attracted towards that schema towards that chemokine. So that is the principle of chemo attraction. So this cell will now get attracted towards the endothelial cells and there are some downstream signaling here inside. There are some downstream signaling. We are not describing those signals for the timing. So what happens is now, if we look into the next step, that is the activation step. So this, this step here describes the first step or the rolling step. So it is only binding of the select into the museum. Does the cell has just anchored. So it's just anchoring of the cell on the endothelial surface on the endothelial cells and by the select, by the selecting museum, uh, interaction. And then there is release of the chemo kines, and this leads to the chemokine binding to the chemokine receptors and the cell. So. Immediately. It is more attracted towards the endothelial cell. The chemokine binds to the chemokine receptor and here the mucin, which is already bound to the selectin molecule. Like this, and then you have another class of a dog. There is another class of this cell adhesion molecules, which integrates now there's integrins they are present in a given confirmation. If you see in a confirmation, uh, something like this and across confirmation, it looks something like this in a cross confirmation. No. When there is a chemokine binding to the chemokine receptor, there are downstream signaling, leading to reorganization of the integrates. That means there is a change in the confirmation of the integrates. So the integrates, which were initially looking like this, they become like this. So they arrange. In a different way now there's integrated or this integrates, um, they become competent to bind due to this confirmational change. They become competent to bind to another class of cell addition molecule, which are known as de I cams. So now. This integrations and this process is known as the activation. So when there is the chemokine binding to the chemokine receptor, that leads to reorganization of the integrins and this reorganization allows the card step to occur. So this is the second step. This is the second step. And then there is activation. And then there is addition. So this allows the third step to occur, where this I can do integrate interaction is completed. So there's I come to integrate interaction is completed and. No, the cells, they add here more formally to these endothelial cells. So this is the step three. And then due to the opening of this high endothelial venues, the are opened up and then there is. Trans endothelial migration. That means now these cells can quickly move on and move out of the bloodstream and go to the tissue. Now, as soon as it goes to the tissue, Now the question is it goes, it goes out of the bloodstream. That is fine. Now, how does it reach the site of action? It has to reach the site of action also. So it has to go to the site of action. So now there are farther, farther chemoattractants there are more other chemoattractants in this, in this tissue, in this region, there are other chemoattractants and there are also presence of chemokine lines. Of course chemokine and other than chemokine kinds, there are other chemoattractants as well that also attracts this, uh, neutrophils or the other cells of the immune system to go to this site of action among this among them are the chemokine lines, the some Clift compliment products. We will discuss compliments in details. And then we will, at that time, we will discuss more in details about, uh, what the compliment mediated, the compliment Clif products and compliment mediated, inflammatory responses. Uh, so there are compliment cliff products like . And C5 , which can also act as chemo attractants, which can also lead to whisky and bind to the mask cells. So there's compliment clip products like C3 EA . They can go and bind to the sub because of the muscles and they can also lead to the de granulation of the cells leading to release off. Histamine. And this histamine is actually, what is it doing? It is increasing the vascular permeability. And by that it is allowing more of this transcend luteal migrations. So this endothelial migration is more facilitated. So the more cells, it leads to vessel dilation. This increases, vascular permeability allows more neutrophils and more cells to go to the tissue. And there are other chemoattractants in this area. There are other chemoattractants in this area, which actually helps the cells to migrate to the site of action.

Video 3: Process of Inflammation:
Apart from the histamines, apart from the histamines, this, uh, model granular sites, like the mussels, for example. The mosque cells, as well as activated macrophages, they produces other types of small molecules or effector molecules other than histamine, like the prostoglandins, the leukotrienes. Which are also mediators of inflammation. So there are several mediators of inflammation. So the process of inflammation primarily starts with migration of the leukocytes. The primarily the, the, the neutrophils, the neutrophils have major role in inflammation because. They are the fastest acting cells, which have the immune system, which goes to the site of action. And the movement of the neutrophils from the blood to the site of action is primarily assisted by this kind of sale addition molecules, a specialized cell addition, molecules, and certain chemo attractions like the chemo kinds, for example. And, uh, uh, of course chemokine is our class of cytokines. We will discuss them later on. And then you have this activated macrophages and the tissue muscles, which produces certain small molecules, like histamine, the prostoglandins and the leukotrienes, which also are mediators off. Oh, inflammatory response. So these are all responsible for local inflammatory responses and that can lead to, so whenever you have, for example, uh, an insect bite, let us say an insect biting or a nail, uh, going in or a small pin, a sharp object going in, uh, damaging your tissue. Then you can have a redness or swelling. In that area. So these are local responses and this can occur from this kind of mediators of inflammation, like histamine, prostaglandins, leukotrienes, because they are all, most of them increases vascular permeability and they also assist in movement of the neutrophils to the site of action. So this, uh, prostaglandins and leukotrienes, they are also secreted from though. Both from this activity and macrophages, they can come from activated macrophages as well as the tissue muscles. And how do they come from? So they are basically products. The precursor of this prostaglandins and leukotrienes are.africa. Donek acid. the attic hedonic acid, which originates from the membrane phospholipids. So this, we will discuss more in details when we will be discussing about hypersensitivity reactions, uh, for the time being. We just know that, uh, these prostaglandins and leukotrienes, they come from the academic acid and they are produced by the mosque cells as well as from activated macrophages and as well as there is histamine, uh, from the mast cells. So they all, all of them try to the main, their, their main function is to activate. Uh, to increase the vascular permeability and to bring more and more of the neutrophils to the site of action. And now if you look into it, this activated macrophage on this side, this activated macrophage, as we described in our last class, secretes cytokines, and what does this cytokines do? So this cytokines can lead to some. Global responses like increase the body temperature increases temperature leading to fever. So you can have high body temperature activates the T and the B lymphocytes activates liver to produce. More of the proteins, like the compliment proteins and they can also, uh, lead to a production of increases the production of the neutrophils. so there are certain, uh, leading to some systemic inflammatory responses as well. Uh, this, uh, from this, uh, from the, in response of the cytokines that are being produced from this activated macrophages, So, if we look into this overall picture, what is happening in case of an inflammatory response, we will see, uh, it is the innate immune system, which is, uh, acting in response to a tissue damage or a pathogenic invasion. And, uh, there is, uh, very quickly I try to summarize. Uh, so, um, there is, uh, this, uh, movement of the neutrophils, the neutrophils, which are present in the blood. They tried to move immediately to the site of action because the neutrophils are okay. The fastest acting cells. So there are four steps in the neutrophil movement. One is the rolling. The second is the activation. The third is the addition. So add hearing to the, uh, to the endothelial cells and the fourth is a trans endothelial migration. So now these four steps proceeds by the action of certain, uh, cell adhesion molecules, like the mucins, the selectins, the ICAPS and the integrates. So the initially there is a musing to selecting binding. Which we describe as the ruling, then there is activation activation is primarily because of, uh, this, uh, secretion of the chemokine. The, the major chemokine that is involved here is interleukin eight isolate, which is, uh, responsible for this, uh, um, uh, second step. Yeah, activation step. So when there is this chemokine binding to this chemokine receptor here. That lead activates and leads to rearrangement or confirmational change of the integrations leading to, or facilitating it's binding to the immunoglobulin superfamily of the receptors. Now of the, uh, cell adhesion molecules, which are present on the endothelial cell leading to the third step or the addition, and then there is the fourth step or the trans endothelial migration. And by that they migrate to the tissue. There's a neutrophils, they migrate to the tissue and then inside the tissue. There are other chemoattractants. There are many other chemokine others, small molecules that are present in the tissue, which attracts these neutrophils more towards the site of action or the damaged tissue and brings them closer to the pathogen. And then they will start engulfing the pathogen. And then there are the tissue macrophages. Which also initiates, uh, another parallel response. There is a parallel response being initiated by the tissue macrophages. Uh, we're what we see on this right side, in this part. So now the tissue macrophages, uh, they can bind to the pathogen by recognizing the PMPs as we had described in the last class. And then, uh, this, um, the whole set of action that starts on. And then there is the cytokines which have been produced and the cytokines, the immediate, a lot of systemic, uh, responses at the same time, the mosque cells, they are activated by the compliment cleavage products mainly and, uh, leading to release of histamine, uh, leading to the release of the histamine and also. Uh, other molecules like prostaglandins leukotrienes, which all tries to increase the vascular permeability and allow more neutrophils to be produced more neutrophils, to migrate from the blood to the tissue and coming to the site of action and enhance the inflammatory response. So, uh, we have tried to summarize in, uh, from the last class and this class, what we can summarize is how. That eNett system tries to respond immediately when there is, uh, Invasion of foreign bacteria or a foreign, uh, pathogen invading our body. And what, uh, what is the immediate response coming from the inner system and the local inflammatory responses, uh, that are, uh, initiated, uh, immediately. So, uh, that's all for this class and we will continue, uh, describing, uh, all these, uh, more in details slowly, slowly. Now our next lectures. Thank you for today.