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Patrick van Nieuwenhuizen 创建




so the purpose of the immune system is to fight things it's to fight bacteria and viruses and other things that you don't want in your body so that's what it does and a question we can ask is how does the immune system know not to attack your own body and that might seem like a strange question or an obvious question but it's actually not obvious the answer to it and so in this video we're gonna go into why it's not obvious and then how the body actually does prevent its immune system from attacking itself so another way of saying this is how does the body distinguish self verse non-self and by that we mean how does it tell the difference between your own body your own proteins your own cells and foreign proteins or cells or things that shouldn't be in your body so how does it know to attack of these and not to attack these so to find out why the question itself is not obvious let's go back to b-cells and talk about b-cells so here we have a b-cell and here's its nucleus with some DNA and the most important part of the b-cell that we care most about is its b-cell receptor which later if it becomes active can be released as an antibody now this b-cell receptor is what's going to bind to foreign pieces of foreign bacteria or viruses and these antibodies are going to bind to those things and help your body get rid of them and the important thing to remember about b-cells is that these antibodies or these b-cell receptors are coded in the DNA the b-cell but that they're different for every b-cell so every b-cell has a unique set of antibodies and b-cell receptors that it makes and so we'll give them slightly different colors to make that obvious here's one with slightly different DNA and a slightly different b-cell receptor and the really critical point to remember is that these these b-cell receptors that will become antibodies are generated at random so your body kind of shuffles the DNA here and creates a unique b-cell receptor an antibody for each b-cell and it's precisely that fact which is that they're created at random which means that your body is in danger of creating b-cell receptors and antibodies that can react to your own body because while this guy might be good while he might react to let's say a bacteria out here that you want to get rid of so while that's good this guy might easily create a b-cell receptor and later an antibody that can react to something you don't want it to react to so for example let's say this is an important protein in your body maybe it's insulin you would not want a b-cell to be created which will react to insulin because then maybe it'll start creating antibodies that bind all the insulin in your blood and if you don't know what insulin does don't worry about it but by binding to insulin it'll prevent insulin from doing its function which is very important so how can you keep your body from making B cells that would react to yourself in fact there's no way to do it because as I said this process of creating different B cell receptors and antibodies is totally random so there's no way to keep your body from making B cell receptors or B cells that will react to yourself so what does that mean that means that you're gonna make them but you need to find a way to figure out which ones are reacting to you and to get rid of them so you need to figure out a way to kill the ones you don't want and by the way we're talking about a B cells here B cells but everything we're saying is equally applicable to T cells so let me draw one here T cells it's equally applicable because T cells also have a T cell receptor that's generated at random and you only want that T cell receptor to react to foreign things to non-self things and not to self things so the processes we're going to talk about are equally true maybe even in some cases more so true for T cells and B cells so let's go to the bone marrow to figure out how this process works and we're going to the bone marrow because that's where B cells come from it's where they get their unique antibody or B cell receptor they get that by by changing their DNA a tiny little bit by shuffling pieces around and so let's look at a couple of these B cells which are still young they haven't yet been allowed out of the bone marrow they haven't been vetted to see if they should be allowed out and each one has its unique receptor so let's draw a few of those receptors here and let's say that one of these guys reacts to self so one of them reacts to some protein your own body that you don't want it to and again that just happened at random because you're creating these receptors really at random so let's say that the guy that we're gonna want to get rid of this this one because he reacts to let's say it's insulin again like up there really we should have drawn insulin and yellow to show that it goes with this receptor so let's say this guy reacts to insulin so how can you figure out that this guy reacts to self and the answer is actually quite simple the answer is that you just need to keep around the various proteins that your body uses you need to keep them around in the bone marrow while these b-cells are are being vetted and so for example here you'll have a little insulin a very you know very small amount but it'll be there you'll have a little bit of you know some other protein let's say maybe hemoglobin you'll have some other protein here you'll have yet another protein over here and so all these proteins will be around and so what your body does at this stage in development is it says whatever b-cell binds to something whatever b-cell binds to something with its b-cell receptor in the bone marrow will be killed and so this b-cell right here that recognizes this insulin protein the fact that it recognizes it means that it'll bind and that will cause a little bit of a chemical change in the B cell or something and one thing will lead to another and the whole system will be programmed so that as a result this guy will die so every B cell that recognizes self if it sees that that self molecule in the bone marrow it will be killed and this works because your bone marrow will have most of the abundant proteins in your body it they'll be present there so that you can make sure that you weed out all the B cells that react to self now what happens after this step is these guys who have been vetted they can proceed onwards to maybe a lymph node somewhere where they can begin to actually be active now that they've sort of you know gone through basic training here in the bone marrow and you might ask yourself well what about here what about here when one of these B cells that doesn't react to self what about when it interacts with a bacteria that you actually want it to fight is the same thing gonna happen is it going to die just because it recognizes the the molecule that it's made to to bind to and the answer is obviously not you don't want this guy to die because you need him because you want to fight this bacterium and so the reason why he doesn't die is because well we're just we're in a different environment there are different rules or different other cells around and this B cell has matured and become different so the rules are different and he's not going to die so this weeding out of B cells that react to self proteins is sort of the first of two mechanisms that I'd like to talk about that the body uses to not react to self and actually the same exact thing happens for T cells except it doesn't happen in the bone marrow it happens in the thymus because that's where T cells mature so in the thymus we have really the identical process where T cells differentiate and each one has a unique receptor and the ones that reacts to self in the thymus too strongly are killed but it's not a foolproof method or else we wouldn't need step two every once in a while a b-cell will get out there a visa will escape which reacts to self and it's just because every process has its mistakes and maybe you don't have every single protein here in the bone marrow and enough abundance to find the B cells that react to a protein of your own body so let's say this is a b-cell that escapes the bone marrow even though it reacts to self what's gonna happen now well it's gonna find that protein that it was sort of made at random to react with so it's gonna find that protein that your body makes and that your body needs and it's going to bind to it what's it gonna do now well if you remember it's now going to take that protein ingest it break it up into little pieces and then present it on an MHC 2 molecule MHC 2 molecule and if you recall it'll just present a small piece of that protein on the MHC 2 molecule I think it'll present a different piece of protein on a a different MHC 2 molecule over here something like that and the reason it does this is because it needs a t-cell to come along so here's a t-cell and needs a t-cell to come along that will recognize that same piece that it's put there on its surface and it needs that in order to activate so it's going to sit there and wait for this t-cell to come along who has the perfect receptor and so here's that t-cell and they're going to interact and they're gonna have some some kind of intracellular kiss that's going to finally allow this b-cell to activate so usually without the t-cell coming and recognizing the antigen that the b-cell reacts to the b-cell cannot activate it needs this t-cell to recognize it and so this is exactly the second mechanism of defense that I'd like to to bring to your attention which is that even if a b-cell escapes that reacts to self almost always it's also going to need a t-cell that reacts to self to come and activate it and so you need both the b-cell to escape the the weeding out in the bone marrow and the t-cell to escape the weeding out in the thymus for you to get an active b-cell that's now going to start putting out antibodies that react to self and by the way this the cellular kiss here is usually going on in the lymph node now looking at this whole process you might have a few complaints and I encourage you to think about how it might go wrong well one way you might think it could go wrong is what if bacteria got into the bone marrow and certainly that's very very possible because when you get infections the you know the thing that's infecting you can move around your body so this bacterium gets into your bone marrow does that mean that now this B cell is going to it's going to bind to it and therefore is going to be killed because at this stage whenever the B cells bind to something they're killed and the answer is yes this is exactly what happens but the reason why it's not too much of a problem is that even if you have this bacterium here in the bone marrow for you know for a week or two or maybe a month after that once this bacterium goes away or is killed then it won't be there anymore and you can start producing these B cells that react to that bacterium again and hopefully you already had a bunch of these B cells that could react to this this bacterium that you had made previously and that we're already out in the lymph nodes and so those guys will be there to to fight the infection while maybe the infection might be in your bone marrow preventing you from making more of those B cells to kill it so you already have some of those B cells out there in the lymph nodes and they can proliferate out there and sort of leave the battle from there now even though your body has these mechanisms to keep your immune system from reacting to yourself it still happens sometimes the process still goes wrong sometimes and the results is auto immune disease it's called autoimmune because you're immune to yourself and so your immune system basically starts attacking your own body and some pretty terrible diseases can result and so to kind of bring it to life for you I'd like to tell you about one example of this so this is a muscle fiber and the way your muscle fibers are activated because you don't want to be flexing all of your muscles all the time the way that they're activated is that they have a little receptor which I'll draw here and this receptor is ready to receive little molecules from a neuron part of a nerve receives little molecules from this neuron that activate this receptor and therefore activate the muscle fiber and so if you want to you know if you want to tighten this muscle fiber you just need to send a signal down the neuron and it'll release these little molecules which will activate the muscle fiber but in one example of immune disease you get antibodies against this receptor here on the muscle and so they bind to it and that either stops it from functioning makes it possible for it to react to the the neurons signals or causes that receptor to be destroyed and those are two mechanisms that have been seen and so in this autoimmune disease what do you think will happen well what happens is that your body can no longer activate muscle fibers as easily the disease is called myasthenia gravis and the etymology of that is that my sort of means muscle and asthenia means means a weakness so muscle weakness and gravis just means it's serious because it gets serious over time if you can't activate the muscle fibers in your body you slowly become paralyzed so you know you don't need to remember this exact mechanism that's not really important but I just wanted to give an example of one kind of autoimmune disease and how it works