And onto the germinal centers for the specifics of affinity maturation. So, here is a table you're going to find at the end of your outline and the parts that we're going to look at are what happens when the activated B cell enters the follicle or begins to basically promote the arrangement of a secondary follicle and turns it into a primary follicle with the germinal center, and we're going to look at the activities that go on there and what happens as the cell, then finally achieves its destiny as a plasma cell. So, first of all, here's a reminder. The cells come in from the surface, will, again, organize a follicle and we have a secondary follicle here that has a light zone in the middle and a dark zone in the periphery. So, what the first thing that's going to happen of course is that they come in from the outside. So, here they are in the dark zone and interestingly enough at this point, they're going to stop making surface receptors, they're going to basically, then those will get recycled. So, you'll have cells that don't have anything on their outer surfaces and at this point they begin to rapidly divide, undergo this clonal expansion except that, in this case, this is where, in this process, they will mutate the regions that code for the loop. So, here's one for the light chain showing you the three regions. So, as these cells divide they're going to accumulate mutations in these regions. Now, mutations are things that happen at random, so it means that when you start out this process, you have exactly one kind of gene and then when you finish it what you're going to have is a spectrum of genes that have changes to the region that codes for the most important part of the recognition process. That is of course going to happen in both the light and the heavy chain. So, when they are done with this, or at least this process, they're going to stop dividing and then go back to making the receptors. So, here's a sample of our new receptor and our new receptor is actually more than one kind of receptor because if we look back at how we changed the instructions to make this, we can see that we have targeted the variable regions of both the heavy and light chain and we've targeted mutations to the regions that code for the loops. The cells have divided and in the course of dividing, they have randomly received mutations and so the original cell has divided into population of cells each with slightly different recognition regions. Now, these are random mutations and anytime you have a random mutation, the chances are you're going to make a receptor that doesn't bind as well as it used to, or maybe you're going to make some that bind and bound as well as they used to. However, once in a great while, you will make a receptor that binds better than the original receptor. So, the next problem is how do we identify which cells have those better receptors? So, it's back to the anatomical picture of this follicle. These cells are then going to move from the dark zone into the light zone, and what awaits them there is the follicular dendritic cells. In this case, these follicular dendritic cells have little packets on the surface the name for them is exosome. Probably you don't really need yet one more vocabulary word but the point is these little yellow dots represent packages of antibody-antigen complexes. These are going to serve as growth signals. So, again, it's like we're keeping score here so here are our cute little B-cells with their different versions. You can see none of them looks exactly the same, and these ones seem to be very good at binding to these packets. The ones that are not so good are not going to be competing very well and they're not going to get growth signals. So, in this case, the B cells with the rare B cells that have rearranged their genes, mutated their genes to produce an effective receptor, will get signals to grow and divide. The ones that haven't will actually not get any signals and they will actually undergo apoptosis and get cleaned up by macrophages that are sitting there for exactly that purpose. So, again, what we've done is we have a scarce resource here at the antigen-antibody complexes and those that compete best for these things will live. The other thing of course is that in addition to this, we also have T-cells around giving them that CD 40 ligand to the CD-40 receptor signal that keeps them dividing and activated. Again, that doesn't work very well either if the B cells cannot display antigen back to the T-cells and so, another reason for making this work well is that the B-cells that are good at getting the antigen are of the same B-cells that are good at getting the T-cells to give them the go-signals. Okay, so, let's go again take another look at this. So, here is the ultimate purpose of all this. If a maturing B-cell is supposed to go and make antibodies, here they are, and it's supposed to make them better. So, if it begins dividing, it's going to, again, receive these signals. So, just as a quick review, we have here an accelerated form of natural selection. This revised plasma cell is the result of an evolutionary event that takes place in the dark zone. So, in that dark zone, we have random mutation and excess production, reproduction, and then we have them migrating back in for a competition for a scarce resource. So, that those that are better at capturing that scarce resource will be the ones that survive to produce the antibodies. Now, there's a whole bunch of different words for describing these things and they're on your table and I try not to use them unless I put them in context so you can figure out what I'm talking about. So, again, what is the point of all of this? The point of all of this is to produce a better version of the CDR. We start out with something that can bind to the antigen and that's really how we're going to get our initial antibody-antigen complexes to make this whole thing work. So, your initial antibodies have the CDR that is in a sense good enough for a first pass but in this process, we're going to use a form of accelerated natural selection to produce a version of this antibody that has even better binding properties. So, the purpose of all this is to improve the binding that we get at the CDR. So, if we look at this, the function of this follicular dendritic cell is to provide the signals but to provide a scare source of signals so that not all of the B cells will do a good job of capturing the antibody-antigen and therefore, not all of the B cells will be able to stimulate the T-cells in the matter we've seen previously. Therefore, only some of the B cells will continue on to the next stage. So, just a reminder about the signal, the follicular dendritic cells play an important role in the selection in that they provide the signals that judge the effectiveness of the new CDR or antigen recognition site. The scarcity of this then makes a difference in the ability of different B-cells to present antigen to the Th cells and thus get the return signals that they need in order to keep dividing. The Th cells then will also take this population of improved B cells and improve them further by letting them know how to class switch into a better or more effective category of antibody. So, the class switching is in the next segment.
