Advanced Pathophysiology

Immunology—Immune System: Overview

All right, engin-nerds, so the goal of this video is to cover an entire adaptive and innate overview. And again, I get a prize if I do this under 20 minutes. So we're definitely going to try to make this kind of quick. Good overview here.

So again, starting with innate immune system, right, with the innate, there was some type of damage, right, because of this bacterial cell. It caused the release of endotoxins caused what? A massive release of inflammatory cytokines, right? Such as all of these ones that we've already talked about here. What is the overall result of these guys? One thing that they're going to do is is they're going to act on smooth muscle cells and cause vasodilation, which increases the blood flow and causes heat and redness. They're also going to act on the endothelial cells, cause contraction, right, which is going to cause a lot of fluid to leak out increasing permeability. And a lot of fluid leaking out can compress on the pain receptors and bradykinins can activate pain receptors, inducing pain. And that fluid exited that leaks out can cause swelling. So that covers swelling, pain, heat, and redness, which are the four cardinal signs of inflammation, right?

And if there's a really, really bad form of inflammation, like you burn your hand, third degree burn around your hand, it actually can cause a lot of inflammation around this joint to where you can't move it, right? So that's joint immobility.

What else can happen? These histamines and all these other chemicals, they can also cause the production of certain types of cell adhesion molecules. And we've already talked about these in great detail. There's no need to go over them again. These things could be like P-selectins, E-selectins, ICAMs and VCAMs. And what is their whole purpose? To enhance the margination response. In other words, cling to the edge of the capillary bed and rolling on the surface, right? Then as it rolls it can move through the actual endothelial cells by diapedesis, which is that amoeboid motion. And then what? It can actually migrate to the site of injury, where all these bacteria molecules are due to these inflammatory chemicals and it's going to move towards that area by positive chemotaxis, right? So that's the overall result there.

What else can happen though? A lot of these inflammatory cytokines that's also being released like Interleukin-1, Tumor Necrotic Factor alpha, Interleukin-6, what can they do? Let's follow it up here. Look what they can do. They can cause fever within the hypothalamus, right? They can cause the liver to produce C-reactive peptide, which is a good indicator of active inflammation. And they can trigger the bone marrow to make more leukocytes via leukocytosis. That's the entire inflammatory response for the vascular and some of the cellular effects, right? So it's not that bad right?

Now, what else can happen? Well, once these phagocytes get out here into this area and they start fighting with this bacteria, what can be the result? Phagocytosis. They eat the bacteria, right? So they take the bacteria and through the pseudopods, which is called phagocytosis, and remember they form the phagosome combined with the lysosomes, form the phagolysosome, break them down through the lysosomal actions, but neutrophils sometimes depend upon how intense the bacteria or foreign microbe may be, it might have to do free radical reactions called oxidative burst or release its chromatin out into the extracellular space to tag bacterial molecules for the structure from, for example, Cathepsin G.

What else can happen? The macrophages they can phagocytose those actual bacteria, and actually what? Expose those antigens on the cell membrane with MHC-II molecules, major histocompatibility complex type two. But remember all nucleated cells, all nucleated cells in your entire body express what's called MHC-I molecules. So that's important and we'll talk about that when we get to adaptive. All right, so that's one mechanism there.

What else can happen? Remember you also have complement proteins. Your liver is a constantly making these complement proteins and they're circulating within our plasma in the inactive form. And whenever they're in the inactive form what can happen? Whenever they actually act, they become activated due to certain types of chemotaxis or due to the increased permeability or due to the FC portion of antibodies, so on and so forth. What happens? You activate these proteins and they undergo specific cascades like the classical pathway, which is antibody-mediated, right? So it has to be antibody mediated, and it starts with C1 and it goes all the way to C9 producing C3 and C5A, which enhance inflammation.

Alternative is not antibody-mediated, it's directly binding C3B with the foreign pathogen. And that causes that whole process again, right? And then lectin, you just need a mannose and a lectin-binding mannose, to trigger this entire cascade. What's the overall effect of these pathways right here? To produce the membrane attack complex, to initiate lysis of the bacteria, or to enhance opsonization by the C3B, or to enhance the inflammatory response to C3A and C5A. So that's the complement system. Still in the innate.

Now what else? We also said, what if we have these cells here, our macrophages, our general tissue cells, what if they're infected by a virus? So they're affected by some type of viral molecules, right? If they're infected by the virus, so this is these cells are infected by a virus. What can happen? They can activate genes to produce specific types of molecules called interferons, like alpha, beta and gamma. What do alpha and beta do? They activate what? They come over here to a nearby healthy cell and tell those nearby healthy cells to produce antiviral peptides, for example, protein kinase R. What does that do? It actually destroys the actual virus or prevents the virus from attaching, right? And prevents this virus from causing damage in these tissue cells.

What does gamma interferons do? Well, the only one who really see [inaudible 00:05:47] gamma interferons, because we have more over here, remember? Alpha and beta interferons are produced by tons of cells, a lot of different cells. Beta interferons are usually specific to making platelets though, or they're made by platelets, right? gamma interferons are made by specific types of cells like your natural killer cells, your lymphocytes, your macrophages. What do those gamma interferons do? We already showed it over here, right? These gamma interferons, they're secreted by macrophages or natural killer cells or lymphocytes. They come over, activate other macrophages, and then do what? Cause these macrophages to proliferate, get bigger, get hungrier and increase the expression of class I and class II molecules, all designed to enhance the inflammatory response, right? Then what else? Alpha and beta, they can also cause the activation of natural killer cells who can come in and start killing some of these virus infected cells. So it's a beautiful thing, right? And that is a part of our innate immune system still.

Now last thing for our native immune system, we have these toll-like receptors and these toll-like receptors, we have 11 different types, right? So many different types. But there's 10 that we only talked about here because we don't know the function of toll-like receptor 10. What is the overall result of all these? Because they're all responding to different types of pathogens. The overall result is the production of specific types of signaling proteins for chemotaxis, right? Or the production of interferons like alpha, beta and gamma interferons, and the production of Tumor Necrotic Factor Alpha, interleukin-1 beta, interleukin-18, and remember these guys have to be acted on by [inaudible 00:07:16] to become in an active form because then they're preformed right now, or they're pro form. What do all these guys do? They enhance the inflammatory response, enhance chemotaxis, and try to be able to eliminate the foreign pathogens from the body, right? That's the desire.

Now then we go on to the adaptive immunity. What was the adaptive effect? You remember, we took these macrophages with the MHC-II molecules and we also took these free antigens and we take them into a lymph node. What was the effect here? So again, what do we do? We take this macrophage and we take these free antigens and we bring them inside of the lymph node, right? Because we already went through the phagocytosis process and we know that the neutrophils exocytose what? Those free antigens. The macrophages are good antigen-presenting cells. Those as well as lymphocytes and specifically, I'm sorry, dendritic cells. They come in and what happens?

Let's say we follow the free antigens first. The free antigens are the exogenous antigens bind onto a naive B lymphocyte, activating that B lymphocyte, right? That B lymphocyte then can bring in the receptor-mediated endocytosis, bring that antigen in, and produce MHC-II molecules against it, right? And expose it on the membrane surface. But that activated lymphocyte, which also has all these BCR receptors specific to that antigen, he can't get stimulated to proliferate yet. Why? Because he needs some type of stimulation from other cells.

So what's those other cells? Remember the macrophage? The macrophage is going to be coming over here, it's having its MHC-II and the foreign antigen, it brings it to a naive T cell, T helper cell, right? That T helper cell will have CD4 positive proteins, it will have a TCR or T cell receptor specific to that foreign antigen, which will interact. When they interact it activates a CD3 molecule, which sends this primary signal into the nucleus. There'll also be key co-stimulation signals between B7 and CD28. And then there'll also be the secretion of interleukin-1. What does this do? Interleukin-1, that third signal will activate this T helper cell to produce interleukin-2. And there'll also be the production of interleukin-4 from other cells, which will bind onto this actual T helper cell. Then what will happen? whenever this interleukin-4 and interleukin-2 bind, it triggers the T naive cell to start proliferating and becoming specialized and differentiating into what's called TH2 lymphocytes. Because remember, interleukin-4 converts the naive T cell to TH2, interleukin-12 converts the naive T cell into TH1, or T helper one cells.

So now our TH2 cells are activated. They're ready to start producing specific types of interleukins. What are those interleukins? One of them is interleukin-4, interleukin-5, and interleukin-6. Interleukin-4 is the very signal that these activated lymphocytes need to start proliferating. What is that proliferation called? It's called clonal expansion. And you're making all of these B cells with the BCR specific to that foreign antigen that we've started throughout this whole process. They expand, interleukin-5 stimulates these actual activated B cells to undergo differentiation. So again, what is this step right here called? This is actually differentiation.

So differentiation right here will convert these actual B cells into memory cells or plasma cells. Memory cells will stay in our body for a while, right? With that specific B cell receptor specific to any foreign antigen. The plasma cells will respond to interleukin-5 and interleukin-6 and they'll produce antibodies. And what will those antibodies do? These antibodies can either do a couple different things, right? We talked about it very briefly. They can bind with these foreign antigens and cause neutralization reactions, precipitation reactions, lysis, and we also said agglutination reactions too, right? So there's a lot of different things and opsonization. We'll go into more detail on those in antibodies, right?

All right. So again, they can undergo the opsonization reactions, right? Now that whole thing that we talked about is humoral immunity. What is humoral immunity? It's the effect again, one more time, of those exogenous antigens stimulating these actual B cells or these T cells, and the overall response is to produce antibodies in response to that, right? Or to produce memory B cells and we can also produce memory T cells. I didn't talk about those enough, but again, these are our effector T cells, but you also can make, as a response to this, whenever they proliferate, you also can make memory TH2 cells. And those memory TH2 cells will have a TCR specific to that foreign antigen. All right? Whenever the MHC molecule comes back, MHC-II molecule and the foreign antigen on the macrophage comes to him again, he'll be ready for it.

All right. That's humoral immunity. What is cell mediated immunity? Cell mediated immunity is due to the, it's going to be exerted by this cytotoxic T cells. And the cytotoxic T cells, they're going to act on cells that have already been virally infected, so they've been infected by a virus and there's no turning back, or they're cancerous. What's the overall result again? One is it can actually down-regulate the class-I molecules, or it can produce the expression of a viral peptide that combined with our own self peptide. And then what happens? Our T cytotoxic T cells recognize those either foreign peptides or they recognize the lack of class-I molecules as there's not that many, and then what will they do? They'll produce perforins, which will create holes in the membrane, and granzymes which initiates this apoptotic mechanism that we talked about, right? So that's killing the cell. Why is it cell mediated though? Because the actual infectious pathogen is already inside of the cell. It's not outside of the cell. It's inside of the cell and it's affected it inside of the cell, okay? That's the basic way of understanding cell mediated immunity.

We also talked about natural killer cells, but remember, just because I included them with the adaptive immune system that doesn't mean they are a part of them. They are not a part of the adaptive immune system. They're a part of our innate immune system. They're not specific, but their mechanism is very similar to the cytotoxic T cells.

How do they do this? What do they do? There's three mechanisms. One is they either recognize that there is no MHC-I molecules present, and if there's no class-I molecules present, they perceive it as foreign because all nucleated cells have class-I molecules. And then what? It'll produce perforins and granzymes and kill this cell. It'll also recognize an abnormal form of the MHC molecule, right? And again, we said the MHC molecules have alpha-1, alpha-2, alpha-3 chains, as well as a beta-2 microglobulin, but MICA or MICA has no beta-2 microglobulin. So therefore he's kind of like an MHC. If he's recognized by the natural killer cells, he'll actually release perforins and granzymes and kill him. And then again, if there's any type of foreign antigen with IgG antibodies bound, the natural killer cells release perforins and granzymes and kill him.

Again, guys, this pretty much gives us everything we're going to need to know about the entire overview of what the adaptive and the innate immune system. All right, ninja-nerds.