Innate Immune System: Second Line of Defense

okay so now moving on to the second line of defense of our innate or internal defense system um when we're talking about the second land of Defense it's predominantly just going to be cells and chemicals so things like fosic cells natural killer cells antimicrobial proteins fever and even inflammation all contribute to the second line of defense we're going to talk about these individually here shortly um many second line of defense cells they have what we call pattern recognition receptors and these are going to help um recognize and bind tightly to structures on microbes and they're actually able to disarm them before they can cause any harm so one type of pattern Rec recognition receptor are what we call uh tolllike receptors and these play a huge role in triggering our immune response we have about 11 uh different types of tlrs and each of these can recognize a particular class of attaching microbe so not just macroasia have toake receptors actually a variety of cells including epithelial cells lining our GI tract and our respiratory tract also have tlrs and tlrs really just allow us to help recognize Invaders and then sound an alarm that is eventually going to initiate inflammation so let's move on to our first um cell and those are aiic cells and if you remember from our blood chapter chapter 17 we mentioned neutrophils so neutrophils are one of the fosic cells that play a role in the second line of defense they were our most abundant um fosy as well as our most abundant Lucy um the downside to these neutrophils is that they pretty much die fighting um and they become itic on exposure to any type of infectious material and again they're going to destroy themselves in the process when we're talking about phagocytes because there's another type of aiic cell are basically just are two white blood cells that are capable of ingesting and digesting any type of foreign microbe that we have so neutrophils was one and our second one would be macroasia and if you remember from our blood chapter our macro phases actually develop from our monocytes um and um in our monocytes they were able to leave the bloodstream and when they leave the bloodstream and enter our tissues that's where they're going to actually develop into much larger cells that we call macras we typically classify our macras into two different categories one would be free macroasia and the other one's fixed macroasia our free fre macroasia are free to wander throughout all the tissue spaces and they keep wandering until they come or encounter um some sort of debris or foreign Invader our fixed macroasia are just that they're fixed um the permanent residence of a specific organ so for example our stellate macroasia are always going to reside in our liver so when we're talking about our two aiic cells again our macroasia and our nutrifil um the way they kill these microbes is by a process called phagocytosis and it has a couple different steps but the overall goal is to basically bring in the microbe into um this the macras itself I'm sorry the fago side itself and basically digest it um and break it apart and kill it so phagocytosis is pretty much the process is going to start when our it is going to recognize or adhere to some sort of pathogens carbohydrate signature so if we're talking about our cells we mentioned this a little bit with our red blood cells but all cells have different things on the surface of their membrane so when our fago sites recognize some of these things on the surface of a microbes um plasma membrane it lets them know that it's foreign um so one downside is is is some of our microorganisms actually have a capsule surrounding them so like this and that can lead to our fago sites not recognizing their carbohydrate signature because it's hidden beneath that capsule so then our immune system does something else it does something called opsonization and it's pretty much where we take antibodies or other proteins that we call opsonins and we coat the cap um of the pathogen so that we can use it to go in and bind to and basically fze the organism still so the second step after we adhere the fagos sites able to adhere to the carbohydrate signature or we undergo opsonization so we can adhere to one of those antibodies or absam opsonins the next goal is to basically bring in the microb into a vesicle the vesicle that we bring the microb into is what we call a fagone it's really great that we're able to bring in the microb in this fagone inside of the cell but the fome doesn't contain anything to actually kill the microb so we have to fuse the fagone with an organel that does contain things that can break it down and that organel is our lome so once we fuse our phagosome with our lome we form what's called a fago lome and then we can go and use those enzymes that are present in the lome to help acidify and digest whatever is inside that we brought in some of the things that we um digest or bring in um the fagone are not digestible so we consider those indigestible materials we don't want to keep them in the cell so we will actually exocytose those from the phagocytes so again here's a a good little illustration um we can see the side adheres to the pathogen using some sort of receptor so here's a little um receptor that's going to cause it to bind to the microb here represented as the little green oval um we start to pretty much engulf or invaginate the plasma membrane of the fosite um until we pinch it off and form a vesicle the vesicle that's containing our microbe is what we call the fagone but again there's nothing in the fagone that can actually help break down the microbe that we brought in so we have to fuse it with an organel that contains the enzymes that are able to digest it and that's the lome once we fuse the fagos to the lome we form the fago liome and now we're capable of going in and degrading down what was whatever we brought into the cell some of the stuff we're not able to break down it's indigestible so we're actually going to refuse our vesicle that we made with our with the plasma membrane and exocytosed any of that residual material so phagocytosis is helpful for a lot of different microbes but in some cases um pathogens that are brought in can't be killed by the Lal enzymes because the Lal enzymes basically turn the inside of the fagly into a very acidic environment some BAC IIA and microbes are able to thrive in this acidic environment so instead we have to have our helper tea cells help trigger the macras to uh produce what we call a respiratory burst which is going to help kill pathogens that are resistant to the LOM enzymes the respiratory burst includes things like releasing cell killing free radicals um producing oxidizing agents such as hydrogen peroxide and increasing the pH in osmolar of the flyone so again like tuberculosis it thrives in a very acidic environment but it's hindered in a basic environment so if we increase the pH we're making it more basic and that's going to help kill um the tuberculosis or at least help prevent it from replicating um very quickly because it's not in its an ideal environment and then of course we also have some defensin that are produced um and released especially for talking about nutrifil and this was our antimicrobial Protein that's capable of pretty much putting holes into a bacterial cell's um plasma membranes effectively licing it so those were our fagos sites and our fagos sites were our monocytes and our neutrophils now we can move on to another type of cell which is our natural killer cells so these are non fosic cells but they're very large granular lymphocytes um lymphocytes of the Adaptive immune system are specific these are not specific and they B basically act like the police um of our blood and Limp so they're constantly circula circulating around looking for any Intruders um they're capable of killing cancer and virus infected cells before our adaptive immune system is activated because remember our adaptive immune system is really slow and it takes a while um for us to build up those defenses so what do natural killer cells um kill they basically are going to attack cells that lack what we call Self cell surface receptors so all of our cells in our body have a specific receptor on their plasma membrane to let them know that that's our own cell that it's a good cell don't touch it it's fine any cell that doesn't have this self antigen on its receptor to let it know that it's belongs to us is going to cause the natural killer cell to go in and attack that cell so if it doesn't have the self um receptor then it's going to be attacked by a natural killer cell and it kills by apoptosis which is just programed cell death um it's the same method as cytotoxic tea cells which we'll see later um but they're not really picky or specific um and the natural killer cells really just reflects the non-specificity of the cell itself they're also capable of secreting really potent chemicals that are going to help enhance that inflammatory response and moving on inflammation so inflammation is going to occur anytime we have any um damage to our body tissues it's a non-res specific response um and it include like trauma intense heat um chemicals or any type type of infection infection I will say that a lot of people think inflammation is a bad thing but inflammation has several beneficial effects so for example if you have inflammation in a certain area inflammation is going to help prevent the spread of whatever damaging agent is in that tissues to other tissues so it's able to kind of help wall off that infection um it also is going to help dispose of cellular debris and pathogens and inflammation is going to alert our adaptive immune system and it's going to help set the stage for repair so how do you know um you have inflammation present well there's four cardinal signs and the four cardinal signs include redness heat swelling and pain and sometimes we consider impaired function to be a fifth Cardinal sign so for example if you have an inflamed joint say in your knee um that may like hinder you from being able to use that joint that's going to help force it to rest which is going to help it heal okay so stages of inflammation um when we're talking about the stages of inflammation the first stage is really going to be where we have a flood of inflammatory chemicals being released into our extracellular fluid and these chemicals are released by injured or stressed tissue cells so for example our mass cells are going to start to release um histamine which is a key component of the inflammatory response we're also going to have vasod dilation um and increased vascular permeability as well as fosite mobilization so let's talk a little bit more about the inflammatory chemical release so chemicals can be released by those extra into the extracellular fluid by those injured tissues or immune cells like I mentioned previously histamine being released from mass cells is a huge and crucial key inflammatory chemical um other than histamine we have some other things like kinin prostaglandins and cyto kindes I don't know if you've ever heard of a cocine storm um but all of those can help also initiate inflammation and then if we're talking about a pathogen being the result of the inflammation we have complement which we'll talk about a little bit later so all all of these chemicals including histamine cause vasodilation of those local arterials um if we have Vaso dilation and we're dilating those blood vessels it's going to stretch the blood vessel walls which means that we're going to be making those capillaries leaky making the capillaries leaky because we have those Str walls is a good thing um and we can also attract fago sites to that area so here's a table of some of the inflammatory CH chemicals I really just want you to know what the inflammatory chemicals are and what they do collectively as a whole you don't need to understand the specific source of each one of these or necessarily this specific physiological um effect unless we talk about it in more more detail so the second step of inflammation is we release all of this chemicals and now we have Vaso dilation and increased vascular permeability and we have that again because of Vaso dilation we've stretched the cell walls um we've stretched our blood vessel walls and we've increased the permability because we've made them a little leaky so Vaso dilation is going to cause a low hyperia which is going to increase the blood flow and that's going to lead to redness and heat and if you remember redness and heat are two of our cardinal signs um The increased capillary permeability also causes exudate which is basically fluid containing the clotting factors and antibodies is going to be leaked into the tissue spaces um as a result we get local swelling because of that fluid leak um swelling is also referred to as edema and this swelling is going to help push on nerve endings which is why we have pain associated with inflammation so pain can also be the result um from the release of toxins and bacteria toxins from bacteria or release prostaglandins and kinins um if you've ever taken aspirin aspirin actually inhibits prostag glin release which is going to help prevent this sense of pain um some of the benefits of swelling or edema is that the surge of the fluid into the tissue is going to help sweep that foreign material into our lymphatic vessels um and we want it be swept there so it can be processed by our lymph nodes it's also going to help deliver clotting factors because again we have some sort of uh tissue damage um and blood vessel damage as well as comp complement to that area and um the coling factors like we talked about in chapter 17 they're going to form that fiber mesh that's going to act as a scaffold for repair and the mesh is really important that we created because it's also going to help contribute to isolating the in injury so that we can't have movement of those microbes to other tissues and the last thing is really fosite mobilization so remember our aiic cells um we have neutrophils and macras the first ones on the scene are actually going to be our nutrifil um and then are going to come our macrofiles and there's pretty much four steps in which our fago sites are mobilized um to help Infiltrate The whatever site of damage we have so the first step is going to be what we call lucose cytosis and that's going to be the release of the neutrophils from the bone um so we're going to increase the number of lucaites that we have anywhere from four to fivefold of what we would if we didn't have any sort of tissue damage at all um how do we initiate lucco sitosis well those injured cells are going to release what we call increase 4 to 5-fold and we're going to see an increase in white blood cells in general as well the second step um is going to be margination so margination is where we have um endothal cells of our capillaries in the inflamed area are going to project what we call cams and cams are just cellular adhesion molecules um these cams are really important because once they start projecting these cams they're going to basically help stop um nutrifil that are flowing by in our blood and cause them to kind of slow and Roll Along and clean to the blood vessel and once we have that nutrifil can also Sprout cams on their surface once they're activated the third step is diapedesis um so we have more chemical signaling basically prompts those neutrophil to help flatten and squeeze through the endal cells of the capillary walls so the process of them leaving the bloodstream and entering into the tissues is called diapedesis and the fourth step is chemotaxis I mentioned this to you before in chapter 17 but chemotaxis is basically the method in which cells um sense a concentration gradient of chemicals to help know where they're supposed to move to so those inflammatory chemicals that are being released act as kind of like a signal for them to know where to go so those nutrifil and other white blood cells will basically move to a higher concentration gradient of those signals of those chemicals so here's a good picture or an overview um illustration um where we have uh four to fivefold more neutrophils and white blood cells entering into our bloodstream from the bone marrow then we have margination where these cells are going to um start sprouting what we call cams or cellular adhesion molecules that cause the um neutrophils to kind of slow down a little bit and kind of stick so that they're signaled that this is the site where they need to leave then we have diapedesis where our neutrophils are actually going to change their shape so they can squeeze through um the endoral cell wall so that they can leave our bloodstream and enter to the site of the tissue once they're in the tissues they have no idea where to go so they actually have to use what we call chemotaxis so chemot taxis is where they're following a high concentration of chemicals that basically signals hey this is where the damages come here so pretty much the goal of inflammation as a whole is to clear that injured area of the pathogens um clear it of the tissue cells and other debris so that we can set the stage for the tissue to come in and be repaired here's a good overview of kind of what happens um I recommend you kind of follow through this flow chart starting with tissue injury you can also see where we have the four cardinal signs of inflammation down here um and everything that kind of happens I love these flowcharts so if you see them I definitely recommend going through them and kind of following along okay something else that's involved in our second line of defense of our innate immune system is antimicrobial proteins so these are going to help enhance the innate defense by one attacking microorganisms directly or by hindering their ability to reproduce Two really important antimicrobial proteins are what we call called interferons and these are proteins that are going to be released by virus infected cells or complement proteins which is really just a group of bloodb proteins um when they're activated they lice microbes via opsonization so let's start with interferons um the interferons are family of what we call immune modulating uh proteins and what happens is that when we have cells that are infected with viruses they're going to secrete something called ifns these interferons and the interference are going to warn the healthy neighboring signals that hey there's a virus around how do they do this they can enter into the neighboring cells they stimulate the production of proteins that are actually going to block the viral reproduction and they help degrade viral RNA so we have three different types um ifin type A and B work this way and we'll talk work this way and we have interferon Alpha and beta that also help activate natural killer cells our other type of interferon that's really important is interferon gamma um and it's actually secreted by lymphocytes and it has widespread immune mobilizing effects because it's able to activate macroasia so when we're talking about interferons um they can activate natural killer cells if they are are alpha or beta interferons and macroasia if they're gamma interferons so they can also help directly fight cancer um we've used artificially made interferons to help treat disorders such as hepatitis C uh genital warts and multiple sclerosis so here's a good picture to kind of explain what's going on here's a cell right here this one right here this is infected via virus so here's our virus virus is going to come in bind to a receptor on the surface of the cell inject its nucleic acid this nucleic acid is going to cause the cell that it infected to turn on its interferon genes when it turns on its interferon genes they're going to go through transcription and translation to produce the MRNA and eventually to produce the interferon molecules so the cell that's infected will release what we call these ifns or interferons they're going to go and bind to neighboring cells as you can see here the interferon bound the neighboring cell to kind of warn them that there's a virus around so how do they warn them once we have the interferon binding to the receptor it's going to stimulate the healthy cell to turn on its antiviral protein genes so we produce the antiviral mRNA and produce the proteins that can help go in and block reproduction so the cell that was infected with the virus to begin with we can't do anything for that but we can help preserve and maintain the health of all the neighboring cells by using this inner feron the second thing is the compliment system and the compliment system like I said is a group of blood proteins that are constantly circulating in the blood but they're circulating in what we call an inactive form and it's going to include proteins that are just numbered um C1 through C9 as well as factors like B DP and some other regulatory proteins um compliment is pretty much going to provide a major mechanism for destroying foreign uh substances in the body once we activate compliment is going to help um release inflammatory CH chemicals that will help amp ify all of the inflammatory process and once we have that activated complement it's also going to help lice and kill bacteria and some other cell types that we have it's nonspecific defense system because we're still in our innate defense system but it helps complement or enhance the effectiveness of both RNA and our adaptive immune system so we have three different Pathways of our complement um one is called the classical pathway and the classical pathway is going to use antibodies so antibodies are going um to bind to the invading organism and then bind to a complement Pro component activating them once we have this double binding is called complement fixation the second pathway is called the lectin pathway um and it's going to use lectins not antibodies to help produce the Nate system or produced by the Nate system to help recognize as foreign Invaders the third pathway is alternative pathway so the compliment Cascade is activated spontaneously doesn't require binding of anything specific when certain complement factors bind directly to a foreign Invader um so when we're talking about activation of these three different Pathways I thought I had a slide in here on might later I really just want you to understand um all of these Pathways classical lectin and alternative they all converge at the same end point but what activates each one of the pathways so classical again is going to be activated by antibodies lectin pathway is going to be activated by lectins alternative Pathways activated spontaneously that's kind of what I want you to get from the three Pathways and again all three activation pathways are going to converge um to something specific which we call C3 so each pathway involves activation of proteins in an orderly sequence um each step is going to catalyze the next kind of like in a Cascade fashion and each pathway is going to converge it doesn't matter again which one of the three Pathways we take on compliment protein C3 once we um activate C3 it's going to cause it to cleave into C3 a and c3b so we split C3 um once we split C3 it's going to enhance inflammation um promote fagocitosis and cause cell Lis so cell liis begins when c3b binds to a Target cell um when C3 binds to a Target cell it's going to cause this tunnel to or pour kind of to be inserted into the plasma membrane of that cell and that pore or that tunnel that's inserted is what we call the membrane attack complex or the mat complex so this is that hole I was telling you about before being able to go in and Pierce holes into a bacterial cell membrane that hole that it pierces is actually this matte complex and because you put a hole or a pore into the plasma membrane of a bacterial cell it's going to cause an influx of water and ultimately it's going to cause Lis of the micro so that was one of the the components of this C3 that we split that was c3b c3b also causes opsonization so opsonization if you remember we talked about it earlier um basically c3b can coat a microb um and it acts like a handle for our phagocytes so our nutrifil and macrophases to help grab onto it to help undergo phagocytosis in the event that we have a capsule around um the bacterial membrane so c3a is a little bit different um c3a and other compliment protein cleavage products help amplify the immune response and inflammation so c3a is going to go on to stimulate mass cells and basil cells to release histamine um and this is going to cause neutrophils and other inflammatory cells to be attracted to the site so here's a really good picture um we have our three specific Pathways classical again activated by antibodies lectin Pathways activated by lectin alternative pathway is spontaneously doesn't matter which pathway we take they all converge at C3 and they're going to cause C3 Lis into c3a and c3b um c3b can go on to cause opsonization that's one of the things it can do again so c3b is going to actually go and bind to the surface of pathogens and enhance phagocytosis or c3b can go on option two and complex with other complement proteins which you do not need to know the specific names of um to form that matte complex or that pore or hole that's going to go into a bacterial cell membrane to cause its lcis the other component of the C3 split which is c3a is a little bit different C3 is going to go in to help enhance inflammation by doing things like stimulating histamine release um attracting fago sites by chemotaxis and increasing blood vessel permeability okay antimicrobial proteins um we're still here let's talk a little bit about fever so if we're talking about fever um in response to some sort of invading microorganism lucaites in our macroasia that are exposed to some sort of microb are going to secrete what we call pyrogens and pyrogens are going to act on our body's thermostat which is located in our hypothalamus um to help raise our body temperature there are some benefits of fever um because it's going to cause um the liver and the spleen to help sequester iron and zinc if our liver and swing sequester iron and zinc that's going to help inhibit bacterial growth because a lot a lot of bacteria need both iron and zinc in order for it to replicate um fever can also help increase the metabolic rate of tissue cells which is going to help speed up the repair process if we have any damage

okay so now moving on to the second line of defense of our innate or internal defense system um when we're talking about the second land of Defense it's predominantly just going to be cells and chemicals so things like fosic cells natural killer cells antimicrobial proteins fever and even inflammation all contribute to the second line of defense we're going to talk about these individually here shortly um many second line of defense cells they have what we call pattern recognition receptors and these are going to help um recognize and bind tightly to structures on microbes and they're actually able to disarm them before they can cause any harm so one type of pattern Rec recognition receptor are what we call uh tolllike receptors and these play a huge role in triggering our immune response we have about 11 uh different types of tlrs and each of these can recognize a particular class of attaching microbe so not just macroasia have toake receptors actually a variety of cells including epithelial cells lining our GI tract and our respiratory tract also have tlrs and tlrs really just allow us to help recognize Invaders and then sound an alarm that is eventually going to initiate inflammation so let's move on to our first um cell and those are aiic cells and if you remember from our blood chapter chapter 17 we mentioned neutrophils so neutrophils are one of the fosic cells that play a role in the second line of defense they were our most abundant um fosy as well as our most abundant Lucy um the downside to these neutrophils is that they pretty much die fighting um and they become itic on exposure to any type of infectious material and again they're going to destroy themselves in the process when we're talking about phagocytes because there's another type of aiic cell are basically just are two white blood cells that are capable of ingesting and digesting any type of foreign microbe that we have so neutrophils was one and our second one would be macroasia and if you remember from our blood chapter our macro phases actually develop from our monocytes um and um in our monocytes they were able to leave the bloodstream and when they leave the bloodstream and enter our tissues that's where they're going to actually develop into much larger cells that we call macras we typically classify our macras into two different categories one would be free macroasia and the other one's fixed macroasia our free fre macroasia are free to wander throughout all the tissue spaces and they keep wandering until they come or encounter um some sort of debris or foreign Invader our fixed macroasia are just that they're fixed um the permanent residence of a specific organ so for example our stellate macroasia are always going to reside in our liver so when we're talking about our two aiic cells again our macroasia and our nutrifil um the way they kill these microbes is by a process called phagocytosis and it has a couple different steps but the overall goal is to basically bring in the microbe into um this the macras itself I'm sorry the fago side itself and basically digest it um and break it apart and kill it so phagocytosis is pretty much the process is going to start when our it is going to recognize or adhere to some sort of pathogens carbohydrate signature so if we're talking about our cells we mentioned this a little bit with our red blood cells but all cells have different things on the surface of their membrane so when our fago sites recognize some of these things on the surface of a microbes um plasma membrane it lets them know that it's foreign um so one downside is is is some of our microorganisms actually have a capsule surrounding them so like this and that can lead to our fago sites not recognizing their carbohydrate signature because it's hidden beneath that capsule so then our immune system does something else it does something called opsonization and it's pretty much where we take antibodies or other proteins that we call opsonins and we coat the cap um of the pathogen so that we can use it to go in and bind to and basically fze the organism still so the second step after we adhere the fagos sites able to adhere to the carbohydrate signature or we undergo opsonization so we can adhere to one of those antibodies or absam opsonins the next goal is to basically bring in the microb into a vesicle the vesicle that we bring the microb into is what we call a fagone it's really great that we're able to bring in the microb in this fagone inside of the cell but the fome doesn't contain anything to actually kill the microb so we have to fuse the fagone with an organel that does contain things that can break it down and that organel is our lome so once we fuse our phagosome with our lome we form what's called a fago lome and then we can go and use those enzymes that are present in the lome to help acidify and digest whatever is inside that we brought in some of the things that we um digest or bring in um the fagone are not digestible so we consider those indigestible materials we don't want to keep them in the cell so we will actually exocytose those from the phagocytes so again here's a a good little illustration um we can see the  side adheres to the pathogen using some sort of receptor so here's a little um receptor that's going to cause it to bind to the microb here represented as the little green oval um we start to pretty much engulf or invaginate the plasma membrane of the fosite um until we pinch it off and form a vesicle the vesicle that's containing our microbe is what we call the fagone but again there's nothing in the fagone that can actually help break down the microbe that we brought in so we have to fuse it with an organel that contains the enzymes that are able to digest it and that's the lome once we fuse the fagos to the lome we form the fago liome and now we're capable of going in and degrading down what was whatever we brought into the cell some of the stuff we're not able to break down it's indigestible so we're actually going to refuse our vesicle that we made with our with the plasma membrane and exocytosed any of that residual material so phagocytosis is helpful for a lot of different microbes but in some cases um pathogens that are brought in can't be killed by the Lal enzymes because the Lal enzymes basically turn the inside of the fagly into a very acidic environment some BAC IIA and microbes are able to thrive in this acidic environment so instead we have to have our helper tea cells help trigger the macras to uh produce what we call a respiratory burst which is going to help kill pathogens that are resistant to the LOM enzymes the respiratory burst includes things like releasing cell killing free radicals um producing oxidizing agents such as hydrogen peroxide and increasing the pH in osmolar of the flyone so again like tuberculosis it thrives in a very acidic environment but it's hindered in a basic environment so if we increase the pH we're making it more basic and that's going to help kill um the tuberculosis or at least help prevent it from replicating um very quickly because it's not in its an ideal environment and then of course we also have some defensin that are produced um and released especially for talking about nutrifil and this was our antimicrobial Protein that's capable of pretty much putting holes into a bacterial cell's um plasma membranes effectively licing it so those were our fagos sites and our fagos sites were our monocytes and our neutrophils now we can move on to another type of cell which is our natural killer cells so these are non fosic cells but they're very large granular lymphocytes um lymphocytes of the Adaptive immune system are specific these are not specific and they B basically act like the police um of our blood and Limp so they're constantly circula circulating around looking for any Intruders um they're capable of killing cancer and virus infected cells before our adaptive immune system is activated because remember our adaptive immune system is really slow and it takes a while um for us to build up those defenses so what do natural killer cells um kill they basically are going to attack cells that lack what we call Self cell surface receptors so all of our cells in our body have a specific receptor on their plasma membrane to let them know that that's our own cell that it's a good cell don't touch it it's fine any cell that doesn't have this self antigen on its receptor to let it know that it's belongs to us is going to cause the natural killer cell to go in and attack that cell so if it doesn't have the self um receptor then it's going to be attacked by a natural killer cell and it kills by apoptosis which is just programed cell death um it's the same method as cytotoxic tea cells which we'll see later um but they're not really picky or specific um and the natural killer cells really just reflects the non-specificity of the cell itself they're also capable of secreting really potent chemicals that are going to help enhance that inflammatory response and moving on inflammation so inflammation is going to occur anytime we have any um damage to our body tissues it's a non-res specific response um and it include like trauma intense heat um chemicals or any type type of infection infection I will say that a lot of people think inflammation is a bad thing but inflammation has several beneficial effects so for example if you have inflammation in a certain area inflammation is going to help prevent the spread of whatever damaging agent is in that tissues to other tissues so it's able to kind of help wall off that infection um it also is going to help dispose of cellular debris and pathogens and inflammation is going to alert our adaptive immune system and it's going to help set the stage for repair so how do you know um you have inflammation present well there's four cardinal signs and the four cardinal signs include redness heat swelling and pain and sometimes we consider impaired function to be a fifth Cardinal sign so for example if you have an inflamed joint say in your knee um that may like hinder you from being able to use that joint that's going to help force it to rest which is going to help it heal okay so stages of inflammation um when we're talking about the stages of inflammation the first stage is really going to be where we have a flood of inflammatory chemicals being released into our extracellular fluid and these chemicals are released by injured or stressed tissue cells so for example our mass cells are going to start to release um histamine which is a key component of the inflammatory response we're also going to have vasod dilation um and increased vascular permeability as well as fosite mobilization so let's talk a little bit more about the inflammatory chemical release so chemicals can be released by those extra into the extracellular fluid by those injured tissues or immune cells like I mentioned previously histamine being released from mass cells is a huge and crucial key inflammatory chemical um other than histamine we have some other things like kinin prostaglandins and cyto kindes I don't know if you've ever heard of a cocine storm um but all of those can help also initiate inflammation and then if we're talking about a pathogen being the result of the inflammation we have complement which we'll talk about a little bit later so all all of these chemicals including histamine cause vasodilation of those local arterials um if we have Vaso dilation and we're dilating those blood vessels it's going to stretch the blood vessel walls which means that we're going to be making those capillaries leaky making the capillaries leaky because we have those Str walls is a good thing um and we can also attract fago sites to that area so here's a table of some of the inflammatory CH chemicals I really just want you to know what the inflammatory chemicals are and what they do collectively as a whole you don't need to understand the specific source of each one of these or necessarily this specific physiological um effect unless we talk about it in more more detail so the second step of inflammation is we release all of this chemicals and now we have Vaso dilation and increased vascular permeability and we have that again because of Vaso dilation we've stretched the cell walls um we've stretched our blood vessel walls and we've increased the permability because we've made them a little leaky so Vaso dilation is going to cause a low hyperia which is going to increase the blood flow and that's going to lead to redness and heat and if you remember redness and heat are two of our cardinal signs um The increased capillary permeability also causes exudate which is basically fluid containing the clotting factors and antibodies is going to be leaked into the tissue spaces um as a result we get local swelling because of that fluid leak um swelling is also referred to as edema and this swelling is going to help push on nerve endings which is why we have pain associated with inflammation so pain can also be the result um from the release of toxins and bacteria toxins from bacteria or release prostaglandins and kinins um if you've ever taken aspirin aspirin actually inhibits prostag glin release which is going to help prevent this sense of pain um some of the benefits of swelling or edema is that the surge of the fluid into the tissue is going to help sweep that foreign material into our lymphatic vessels um and we want it be swept there so it can be processed by our lymph nodes it's also going to help deliver clotting factors because again we have some sort of uh tissue damage um and blood vessel damage as well as comp complement to that area and um the coling factors like we talked about in chapter 17 they're going to form that fiber mesh that's going to act as a scaffold for repair and the mesh is really important that we created because it's also going to help contribute to isolating the in injury so that we can't have movement of those microbes to other tissues and the last thing is really fosite mobilization so remember our aiic cells um we have neutrophils and macras the first ones on the scene are actually going to be our nutrifil um and then are going to come our macrofiles and there's pretty much four steps in which our fago sites are mobilized um to help Infiltrate The whatever site of damage we have so the first step is going to be what we call lucose cytosis and that's going to be the release of the neutrophils from the bone um so we're going to increase the number of lucaites that we have anywhere from four to fivefold of what we would if we didn't have any sort of tissue damage at all um how do we initiate lucco sitosis well those injured cells are going to release what we call increase 4 to 5-fold and we're going to see an increase in white blood cells in general as well the second step um is going to be margination so margination is where we have um endothal cells of our capillaries in the inflamed area are going to project what we call cams and cams are just cellular adhesion molecules um these cams are really important because once they start projecting these cams they're going to basically help stop um nutrifil that are flowing by in our blood and cause them to kind of slow and Roll Along and clean to the blood vessel and once we have that nutrifil can also Sprout cams on their surface once they're activated the third step is diapedesis um so we have more chemical signaling basically prompts those neutrophil to help flatten and squeeze through the endal cells of the capillary walls so the process of them leaving the bloodstream and entering into the tissues is called diapedesis and the fourth step is chemotaxis I mentioned this to you before in chapter 17 but chemotaxis is basically the method in which cells um sense a concentration gradient of chemicals to help know where they're supposed to move to so those inflammatory chemicals that are being released act as kind of like a signal for them to know where to go so those nutrifil and other white blood cells will basically move to a higher concentration gradient of those signals of those chemicals so here's a good picture or an overview um illustration um where we have uh four to fivefold more neutrophils and white blood cells entering into our bloodstream from the bone marrow then we have margination where these cells are going to um start sprouting what we call cams or cellular adhesion molecules that cause the um neutrophils to kind of slow down a little bit and kind of stick so that they're signaled that this is the site where they need to leave then we have diapedesis where our neutrophils are actually going to change their shape so they can squeeze through um the endoral cell wall so that they can leave our bloodstream and enter to the site of the tissue once they're in the tissues they have no idea where to go so they actually have to use what we call chemotaxis so chemot taxis is where they're following a high concentration of chemicals that basically signals hey this is where the damages come here so pretty much the goal of inflammation as a whole is to clear that injured area of the pathogens um clear it of the tissue cells and other debris so that we can set the stage for the tissue to come in and be repaired here's a good overview of kind of what happens um I recommend you kind of follow through this flow chart starting with tissue injury you can also see where we have the four cardinal signs of inflammation down here um and everything that kind of happens I love these flowcharts so if you see them I definitely recommend going through them and kind of following along okay something else that's involved in our second line of defense of our innate immune system is antimicrobial proteins so these are going to help enhance the innate defense by one attacking microorganisms directly or by hindering their ability to reproduce Two really important antimicrobial proteins are what we call called interferons and these are proteins that are going to be released by virus infected cells or complement proteins which is really just a group of bloodb proteins um when they're activated they lice microbes via opsonization so let's start with interferons um the interferons are family of what we call immune modulating uh proteins and what happens is that when we have cells that are infected with viruses they're going to secrete something called ifns these interferons and the interference are going to warn the healthy neighboring signals that hey there's a virus around how do they do this they can enter into the neighboring cells they stimulate the production of proteins that are actually going to block the viral reproduction and they help degrade viral RNA so we have three different types um ifin type A and B work this way and we'll talk work this way and we have interferon Alpha and beta that also help activate natural killer cells our other type of interferon that's really important is interferon gamma um and it's actually secreted by lymphocytes and it has widespread immune mobilizing effects because it's able to activate macroasia so when we're talking about interferons um they can activate natural killer cells if they are are alpha or beta interferons and macroasia if they're gamma interferons so they can also help directly fight cancer um we've used artificially made interferons to help treat disorders such as hepatitis C uh genital warts and multiple sclerosis so here's a good picture to kind of explain what's going on here's a cell right here this one right here this is infected via virus so here's our virus virus is going to come in bind to a receptor on the surface of the cell inject its nucleic acid this nucleic acid is going to cause the cell that it infected to turn on its interferon genes when it turns on its interferon genes they're going to go through transcription and translation to produce the MRNA and eventually to produce the interferon molecules so the cell that's infected will release what we call these ifns or interferons they're going to go and bind to neighboring cells as you can see here the interferon bound the neighboring cell to kind of warn them that there's a virus around so how do they warn them once we have the interferon binding to the receptor it's going to stimulate the healthy cell to turn on its antiviral protein genes so we produce the antiviral mRNA and produce the proteins that can help go in and block reproduction so the cell that was infected with the virus to begin with we can't do anything for that but we can help preserve and maintain the health of all the neighboring cells by using this inner feron the second thing is the compliment system and the compliment system like I said is a group of blood proteins that are constantly circulating in the blood but they're circulating in what we call an inactive form and it's going to include proteins that are just numbered um C1 through C9 as well as factors like B DP and some other regulatory proteins um compliment is pretty much going to provide a major mechanism for destroying foreign uh substances in the body once we activate compliment is going to help um release inflammatory CH chemicals that will help amp ify all of the inflammatory process and once we have that activated complement it's also going to help lice and kill bacteria and some other cell types that we have it's nonspecific defense system because we're still in our innate defense system but it helps complement or enhance the effectiveness of both RNA and our adaptive immune system so we have three different Pathways of our complement um one is called the classical pathway and the classical pathway is going to use antibodies so antibodies are going um to bind to the invading organism and then bind to a complement Pro component activating them once we have this double binding is called complement fixation the second pathway is called the lectin pathway um and it's going to use lectins not antibodies to help produce the Nate system or produced by the Nate system to help recognize as foreign Invaders the third pathway is alternative pathway so the compliment Cascade is activated spontaneously doesn't require binding of anything specific when certain complement factors bind directly to a foreign Invader um so when we're talking about activation of these three different Pathways I thought I had a slide in here on might later I really just want you to understand um all of these Pathways classical lectin and alternative they all converge at the same end point but what activates each one of the pathways so classical again is going to be activated by antibodies lectin pathway is going to be activated by lectins alternative Pathways activated spontaneously that's kind of what I want you to get from the three Pathways and again all three activation pathways are going to converge um to something specific which we call C3 so each pathway involves activation of proteins in an orderly sequence um each step is going to catalyze the next kind of like in a Cascade fashion and each pathway is going to converge it doesn't matter again which one of the three Pathways we take on compliment protein C3 once we um activate C3 it's going to cause it to cleave into C3 a and c3b so we split C3 um once we split C3 it's going to enhance inflammation um promote fagocitosis and cause cell Lis so cell liis begins when c3b binds to a Target cell um when C3 binds to a Target cell it's going to cause this tunnel to or pour kind of to be inserted into the plasma membrane of that cell and that pore or that tunnel that's inserted is what we call the membrane attack complex or the mat complex so this is that hole I was telling you about before being able to go in and Pierce holes into a bacterial cell membrane that hole that it pierces is actually this matte complex and because you put a hole or a pore into the plasma membrane of a bacterial cell it's going to cause an influx of water and ultimately it's going to cause Lis of the micro so that was one of the the components of this C3 that we split that was c3b c3b also causes opsonization so opsonization if you remember we talked about it earlier um basically c3b can coat a microb um and it acts like a handle for our phagocytes so our nutrifil and macrophases to help grab onto it to help undergo phagocytosis in the event that we have a capsule around um the bacterial membrane so c3a is a little bit different um c3a and other compliment protein cleavage products help amplify the immune response and inflammation so c3a is going to go on to stimulate mass cells and basil cells to release histamine um and this is going to cause neutrophils and other inflammatory cells to be attracted to the site so here's a really good picture um we have our three specific Pathways classical again activated by antibodies lectin Pathways activated by lectin alternative pathway is spontaneously doesn't matter which pathway we take they all converge at C3 and they're going to cause C3 Lis into c3a and c3b um c3b can go on to cause opsonization that's one of the things it can do again so c3b is going to actually go and bind to the surface of pathogens and enhance phagocytosis or c3b can go on option two and complex with other complement proteins which you do not need to know the specific names of um to form that matte complex or that pore or hole that's going to go into a bacterial cell membrane to cause its lcis the other component of the C3 split which is c3a is a little bit different C3 is going to go in to help enhance inflammation by doing things like stimulating histamine release um attracting fago sites by chemotaxis and increasing blood vessel permeability okay antimicrobial proteins um we're still here let's talk a little bit about fever so if we're talking about fever um in response to some sort of invading microorganism lucaites in our macroasia that are exposed to some sort of microb are going to secrete what we call pyrogens and pyrogens are going to act on our body's thermostat which is located in our hypothalamus um to help raise our body temperature there are some benefits of fever um because it's going to cause um the liver and the spleen to help sequester iron and zinc if our liver and swing sequester iron and zinc that's going to help inhibit bacterial growth because a lot a lot of bacteria need both iron and zinc in order for it to replicate um fever can also help increase the metabolic rate of tissue cells which is going to help speed up the repair process if we have any damage

Transcript for:Innate Immune System: Second Line of Defense

Transcript for:
Innate Immune System: Second Line of Defense