Video 1: An Overview of B-Cells
So, uh, welcome to the immunology lectures. So today we will, uh, try to understand the, we will continue with, uh, adaptive immunity that we started, uh, in the last lecture. So in the last lecture we started with the cell mediated part of the adoptive immunity. So as I described that the adaptive immunity or the eruptive immune system can be classified or has two branches. So the cell-mediated part, which is primarily mediated by the T-cells activation of the T-cells. And then there is the humeral part of the humoral response. Which is the antibody immediate response, and that is mainly carried out by the B cells. So if we look into the picture from the last class or the last lecture, uh, we described the cell-mediated immunity. Uh, there is a T-cell mediated immunity, and, uh, we left where in the, uh, primarily in this, uh, lymph node. We discussed how these T-cells, they get activated in the pet aquatics and then differentiates into different types of T-cells among which are very important class. He's the T helper cells combats a CD for plasty cells, which, uh, differentiates into the T helper cells. And then these T helper cells, they help in. The activation and the differentiation of the B-cells, which will now be producing that antibodies. So let us see how this B-cell actually gets activated and then it starts producing antibodies and it does many other functions. Like it also forms a memory, uh, the memory B cells. So let us see what happens in the human or branch of immunity. We try to get into. Overview of the humeral branch of immunity, how it works and how things are connected. So there's a whole, the whole system of this immune, the whole immune system is kind of connected. It's like a connection. So between the eruptive and the eNett system, and again, within the nexus, within the adaptive system, there is connection between the humoral and cell-mediated parts. So it's all connected. We cannot think of individual compartments in, in, in immunology. So we have to get our overall gross picture of whatever is happening. So to get across picture starting. Yeah, from where we left in the last class that is in the lymph node, the events that are occurring in the lymph node. So we discussed the events in the para in the pear aquatics where, uh, the T-cell activation occurs. Primarily. Now we move on to the lymph node. Again, we look into the lymph node, the cortex part. Now in the cortex part, we described in our last class where I told in the last lecture, uh, that we have specialized centers, which are known as the germinal centers. And these germinal centers are the sites of B-cell activation and differentiation. Well, what happens in these germinal center and how the B-cell match your Bissell, how it starts to get activated and then produces different types of immunoglobulins and develops into a plasma cell or a memory cell memory. B-cell what happens there. Let us see into those events very quickly. So as, uh, we know all that, uh, these B cells, they match your in the bone marrow, and then they come to this, uh, lymph node and where they encountered with the antigens, but only an encounter with the antigens will not lead to the activation of the B cell. There are other events that are required. So again, some co-stimulatory effects or events would occur that will lead to the activation of the B-cell and many other, uh, events leading to finally differentiation of these B cells into the different, uh, producing different classes of antibodies or even globally. Now what happens in these germinal centers. So now these matches will be cells. Uh, they come to this, uh, lymph node and, uh, as I told that there are three distinct sections of the lymph node that is the medulla, the cortex and the cortex. So this middler is primarily the site of the B and the T-cells. So it hosts both the B-cells as well as the T-cells. We can find the T-cells only in the, mostly in the pet aquatics and the B-cells in the cortex region. Now this business, the main feature of these B-cells is that the B-cells are also antigen presenting cells. So they can also bind to antigen. They can also express MHC molecules on the surface, and that is required. For their activation. So no antigens, which are being presented by the antigen presenting cells or the antigens that are reaching this lymph node that has reached this lymph node. They will, uh, confront with those PCLs and these B cells, which are match your B cells. They on their surface are already producing, are already, uh, expressing on the surface dark. IGMs. So now they can find these antigens, but this binding is not sufficient for activation of the B-cells. There are some other events which are required and, uh, co-stimulatory events that are required for activation of these B cells. Now what happens in this germinal center? Let us, uh, magnify and have a closer look of the germinal center. So, Let us say, this is the germinal center. This gentleman at the center can again have two zones. We call them the dark zone and the light zone. So this is the dark zone. And though Lighter inside the dark sun. This B-cells this match your B-cells expressing on this surface, that immunoglobulins already by GM, they interact with the antigen. Now this leads to cross-linking of this immunoglobulins, and there is some signaling that occurs leading to the expression of class two MHC molecules on their surface. Now they start expressing MHC on their surface. Plus two emphases on the surface. And as soon as they can express the class two MHC molecules on their surface, they can interact with the helper. T-cells the P H or the T helper cells. So the T helper cells interact with the T-cell receptor. And of course, with the CD four, they interact. With the B-cell, which expresses that MHC, the MHC class two on their surface and this CD four interaction. This is a T helper cell, and this is a visa. Let us look into this interaction more carefully because this interaction is very vital. This interaction is it. It is not just an MHC to the T-cell receptor interaction. There are Southern other, other co-stimulatory interactions that are also required. One of them is so let us see what exactly happens. So let us say, this is a Bissell expressing. You mean a globally bound to the antigen leading to the expression of the image C plus two, and then you have a helper T cell, the T H. So now this da cell expresses that DCR or the cell. Receptor the CD four core receptor. And of course we have seen in our last lecture that they also express this CD 28. And that can again, interact with the B seven, which is expressed on the. Match your B-cells. So this B seven to CD 28 interaction is also vital. And then there is another interaction between that we call the CD. 40 L that is expressed on the surface of the T helper cells or the TA cells, the CD 40 L L for the ligand. So it is the L is the ligand, the CD 40 ligand and the CD 40, which is expressed on the surface of these B-cells. So you have at least four. Types of interactions, which needs to be completed before our diesel can be activated.
Video 2: Activation and Differentiation of B-Cells
So then once these interactions are complete, once these interactions are complete, then there is activation of the B-cells. So what are the interactions? Let us just revise them. So you have received this, uh, IgM binding to the indeed gen MHC class two expressed on the surface of the B-cell leading to its interaction with the T cell via the T cell receptor and the CD four core receptor along with CD 28 to be seven interaction and CD 42 CD 40 ligand interaction. So now this is our T helper cell, and this is a B cell. So a B cell to . The interaction is kind of established here. Now this, once this interaction is completed, then this B cell, which is in still in the dark zone, starts proliferating. And what we get are basically thus central blasts. We call them the central blasts. They're still expressing that on their surface, the immunoglobulin molecules on the surface. So these are those central blast. What occurs immediately after this interactions immediately after this interaction, there are many other events occurring in the bees and many signaling going on in the Bissell among which one of the very vital events is the somatic hypermutation. You will read about this somatic hypermutation, uh, you will study about the somatic hypermutation, uh, maybe more in details, but, but what happens is there's, there are mutations, uh, in the, uh, variable region of the heavy or the light chains and this, that leads to a change in the affinity of this. Immunoglobulin molecules towards the antigen. So the antibodies they develop into either higher affinity or low affinity antibodies. So those who having higher affinity for the antigen and some, a class of antibodies, having less affinity for the antigen. So naturally as we can understand from the logic that only those. Antibodies, which has been, uh, which has developed a higher affinity for the antigen by the somatic hypermutation they will sustain and those which have lower or lesser affinity for the antigen, they will be destroyed. So now these central blasts. They start to call you for it. And in between they have this somatic hypermutation and they start developing this type of antibodies. There are mutations in the variable, uh, variable regions. And by that they start to become either high affinity or low affinity. They express higher affinity or low affinity antibodies. Now these central blasts also express something else. They start to express on this surface specialized receptors that can bind to the chemokine lines. I have described the chemokine lines in a one of my previous lectures that the chemokine start the chemo attractants. So they attract the cells from one site to another site. So it's kind of a magnet to irony interaction. So the chemokine. Are secreted from the light zone. So now these cells, which started to express the chemokine ones, chemokine receptors binds to these chemokine lines and they migrate to the lights on. So that, that is the stimulus, which leads to the migration of this. Cells from the dark zone to the light zone. And now these are known as the central sites. So now these are the central sites, which comes to the light zone. Now in the light zone, we get some specialized cells which helps in the B-cell activation and selection of this. Correct visas. So there are in every step in the immune system in every step you see whether it be the T-cell maturation or the T-cell maturation, the T-cell activation in every step. We have certain, uh, specialized cells and molecules, which are helping in a process of selection. So selecting the correct molecule, selecting the correct cell. So like, for example, the timing epithelial cells, which were helping in selection of the CD four and the CD eight cells CD four and CD eight plus cells. So similarly there are specialized cells which are waiting in this light zone and these are the follicular dendritic cells and that T follicular helper cells. So now this follicular helper cells and the follicular dendritic cells, they are present in doll. So the follicular dendritic cells have this kind of a branched structure and these cells, they are waiting inside dark lights on and up. They have the, this antibodies bound on this. No, what happens is an affinity selection. So. Now these central sites, which were the central blast previously after the somatic hypermutation and expression of the cytokine chemokine receptors on their surface, they have migrated to the light zone. They're now known as the central sites. Now these central sites, they start interacting with this antigens. So they start to compete for these antigens. So there basically is a competition. So now they, this, these central sites, there are many of these central sites and some of them are having high affinity. Some of them are having low affinity, so they will now start to compete the higher affinities, the higher affinity, the central sites, which are expressing high affinity antibodies on the surface. They will start competing with the central sites, which has low affinity antibodies. So now there will be an affinity selection, affinity based selection. And so depending on their affinity for their antibodies, so high affinity selection Ockers and only those B cells, which has antibodies expressing antibodies, having higher affinity. For dentition will be selected. And so these are the high affinity selection and those with low affinity, that means those which could not compete with the higher affinity cells to bind to the antigens. They will be excluded. And they will finally die by apoptosis. So now they are excluded. As I told in all this, all over the immune system, we get this kind of selection processes where the better or the best is being selected and those which are not good, they are rejected. And those cells, they die by some process of apoptosis or programmed cell death. So those were just selected for this higher affinity antibodies. There will now undergo a phenomenon of class switching. So now they will start class switching. And finally they will either produce the memory B cells or they'll plasma B cells. So these are, they will start producing the antibodies. They have. These plasma B-cells are the cells, which are finally effector cells. So they will produce the antibodies. Now, these antibodies will now go to the site of action. That is the site of infection on the site of inflammation and loose Everett. They do their respective jobs.
Video 3: Summary of the Actions in Germinal Center
So now overall, what we have seen what happens inside the germinal center. So this is the germinal center. So what happens inside the gentlemen on the center, at least three major events are occurring. So you have somatic hyper mutations. So at least. Three different events are occurring. One is the somatic hypermutation. Okay. So let us start from this region. So here, the first thing is the interaction of the BA the B cells or the billing for sites with the T helper cells leading to activation. So we call this the activation of the B-cells. So now there are at least three different, four different classes of interactions, including the co-stimulatory interactions. So you have the class two MHC interacting with the T-cells, the T-cell receptor, the CD four plus cells. So CD four, uh, core receptor and the T-cell receptor with the class . And along with that, you have the B seven two CD 28 interaction. You have CD 42 CD 40 ligand interaction. When these interactions are completed, the B-cell is activated. So there are some signaling inside the cell. And leading to proliferation of the cells of the central blasts. And in the meantime, there is somatic hypermutation. So this is the second stage. The cart stage is then they start to migrate. So it's migration of these cells to the light zone from the dark zone. This cell starts to migrate to the light zone. Where you have the follicular dendritic cells. So we call them follicular dendritic cells. So you have the follicular dendritic cells. This follicular dendritic cells then helps in affinity selection. So only the high affinity. Antibody producing cells will be selected. So the B cells are selected for the high affinity antibodies and those after this affinity selection by this follicular dendritic cells and the TFH cells, then you have the fourth and the final event that is the class switching. So this is number three. So, if you look into this whole, even from starting from here is a one is activation this team, uh, T helper, cell mediated activation in the dark zone. Then you have the somatic hypermutation that is also occurring in the dark zone. Then the B-cell starts to proliferate and strong starts to express on their surface, the chemokine receptors. Then they're attracted towards the light zone. They moved to the light zone. There is migration inside the light zone. You have this follicular dendritic cells waiting for the B-cells to come or the central sites to come. So now they are the central sites and this central sites then which express the higher affinity, uh, antibodies. They are selected by the follicular dendritic cells. Now those which are selected for the high affinity antibodies. They will now undergo class switching, and then they will produce either the memory B cells, which primarily have IDG expressing IgG and then have the plasma cells, which are producing different types of immunoglobulins. And they will secret. The antibodies and these antibodies will now be secreted and they will go to the site of action. So now we gain, if you recall, from our, uh, one of our initial classes, then we again go back to that. Tissue portion where there was a tissue invasion and there were pathogens getting in and different types of cells. So if we, again, go back to this tissue, so now these antibodies. Which have been produced from the plasma cell, they will go to the site of action or the site of inflammation, and they usually mediates three different functions. What are the functions these antibodies do so they can either do neutralization, which means they can directly interact with the antigens on the surface of the pathogen. So they can neutralize the pathogen directly. They can also perform opsonization. So that means assist the antigen presenting cells in, in golfing. For example, the macrophages they can assist the antigen presenting cell or the macrophages, for example, to engulf or phagocytose the pathogen, or they can do a third thing that is compliment. So they can also lead to complement activation and that can lead to so. Binding to the surface of the pathogen and leading to the compliment activation and killed the cells by formation of what is called a membrane attack complex, where we call a membrane at a complex leading to hole on the surface of the pathogen and leading to memory Neta complex and killing the cells. So there's antibodies. So we, if we look uh, into the entire picture again, very quickly, so in the lymph node, Uh, we have these three regions, the medulla, the pedal cortex, and the cortex. The cortex portion primarily has this germinal center. The germinal center. If we look into the germinal center is the center for the ma for the, uh, activation and differentiation of the B cells, the B cells, the primarily interacts with the T helper cells, the T eight cells. We. Discussed about how the TA cells are produced or activation of the T-cells in our last lecture. So now these T helper cells by virtue of these interactions and some costs, stimulatory interactions, it leads to activation of the B cells. So this is the first step, the activation of the B-cells, which operates in the dark zone assisted by the T helper cell. Then it leads to somatic hypermutation in the B-cell. Leading to, uh, then, uh, leading to the proliferation of the Bissell. So you have different central blasts. This B cells then will enter into the light zone, migrates into the light zone, where it is selected for the high affinity antibodies, the B cells that are producing the high affinity antibodies. And then. There's high affinity. Uh, the B-cells producing high affinity antibodies will be selected. Those B cells, which produce low affinity antibodies will be rejected. High affinity antibody producing B cells when then undergo class switching. And finally it will produce either the memory B cells or the plasma B cells plasma B cells are ultimately thus secretory cells are the secret stock and the bodies. And these antibodies can then perform several functions at the site of action, or they go to the site of inflammation or the site of action, and they perform several functions like neutralization, opsonization, or compliment activation neutralization, directly neutralizing the pathogen binding to the pathogen ostracization. They assist. The macrophages or the antigen presenting cells to engulf the pathogen and also they can activate the complement system so they can activate the complement system leading to a cascade of events. We will study about the compliment system, more in details in our upcoming lectures. So, uh, that is all. Uh, for today with the adoptive, uh, immune system, the, primarily with the humoral immunity, uh, we will, uh, uh, continue with our, uh, discussion next class. So thank you very much. And that's all for today.
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