Tuberculosis | Clinical Medicine

0:07 What's up, ninja nerds? In this video today, we're going to be talking about tuberculosis. And if you guys like this video, please support us. You can hit the like button, you can comment down in the comment section, you can subscribe, or you can go to our website. On our website, we got things like notes, illustrations, we got quizzes. Go check it out. There's a lot to learn. All right, let's get into TB. When we talk about TB, first thing we need to know is what's the thing that's causing it? What is that particular pathogen? The particular pathogen is actually called mcoacterium tuberculosis. That's really really important to remember. So the primary pathogen is called mcoacterium tuberculosis. Now there's a lot of different types of mcoacterium species, but mcoacterium tuberculosis is definitely it's a pretty scary one. When we talk about this one, what makes this one super unique is when you actually zoom in on its overall cell

0:54 wall, there's a couple different components that are really critical. So going from the most inner portion to the outer portion there's a couple different layers. One here we have just the overall cell membrane right that's kind of that just the phospholipid billayer if you will. Then after that we have this pepidoglycin layer. All right so then we have something called a pepido glycen layer. Then there's technically something called arabino galactin layer. And then the most important layer is called the micolic acids. So this is called micolic acids. Now the micolic acids are probably the most important thing to remember when we talk about this one. Micol acids really what's interesting

1:39 about these is that they allow for mcoacterium to be I'd say whenever you're doing your special types of staining. So when you go through different types of grandstanding procedures, use things like crystal violet, use things like carbal fusion. And generally what it's supposed to do is supposed to stain the bacteria kind of like a a reddish pinkish color. And then what you do is you actually undergo a process where you kind of use this kind of acid alcohol to decolorize it and remove that dye out. What happens with micolic acids is that they really resist that decolorization. And because they resist decolorization with what's called your acid fast kind of like staining, which is again we use acid alcohol, they don't get that red

2:24 color out. They remain kind of a well actually they kind of retain this reddish color with a bluish background. And so micolic acids make these bacteria what we call acid fast. All right, so let's write that down. This makes it a acid fast bacteria. And this is going to become pretty critical because when we actually start getting into um the actual testing process where we do something called acidfast basillus smears. One of the be things about you know generally mcoacterial species is that when you again go through them you give them this kind of reddish pinkish dye you give them an acid alcohol and that should wash all of that off. any kind of mcoacterial species exhibit a lot of these micolic acids and they resist that decolorization. So again

3:10 because of that they stay what does this mean when they're acidfast is they stay red. So let's actually write that out here they remain red and all that tells me is that there is the presence of mcoacterial species. Doesn't tell me if it's TB. It doesn't tell me if it's like avium or any of these other different types. It just tells me hey there's a mcoacterium present. Now, one of the other really important things about miccoacterium is not only just its cell wall, which is rich in these micolic acids. Micol acids makes it pretty pretty hardy types of pathogen, but also it's got other unique characteristics. Naturally, what we look at with these bacteria is something called their doubling time. And we look at this logarithmic scale, which looks at time on the x-axis and logarithmic number of cells on the y- axis. And

3:55 generally, bacteria have this type of growth pattern. What we notice about mcoacterium tuberculosis is it has a very very long uh doubling time or it has a very prolonged takes a really long time for this thing to grow. So it has a very long doubling time which means it has a slow growth process. One of the downsides about this is that well there's two things. One is whenever you try to do cultures to actually see if you can grow this type of particular bacteria, it takes a really long time. So often times when we try to do cultures for these patients, the clinical application is that it takes sometimes two sometimes like six weeks

4:42 for cultures to grow out. And that's kind of one of the potential downsides. And so that's kind of a clinical application of their really really long doubling time is since it takes super super long for these things to grow. When you try to culture these things, it just takes a really really really long time. But these are the gold standard. Another thing about tuberculosis is it's it's predilction. So mcoacterium tuberculosis is what's called an obligate a-obbe. All right, so let's write that down. So, it has a long doubling time, but it has an it's an obligate a-obbe, which means it really really needs and it really prefers to be in high levels of oxygen tension. If you look at the lungs and we kind of imagine

5:27 here for the lungs, all right, here we have the different parts of the lungs. You have your upper lobes, you have your middle lobe just here on the right side, and then you have your lower loes. Which of the loes has the highest oxygen tension? It's generally the upper lobes. And so what happens is mcoacterial species not only do they have a very long time period where we start off with this bacteria and then we double it right but also they prefer the upper lobes because that's where the highest oxygen tension is present. So, one of the other things about this is because it's an obligate a- robe, it has a preference for the apex of the lungs because of why that has the highest oxygen

6:15 tension. So, that's going to be where it wants to live. It wants to be in those areas where there's going to be a lot of oxygen. All right. So, so far we got mcoacterium tuberculosis. One of the most important things about it with respect to its overall structure is the micolic acid residues makes it pretty hardy. Also makes it really unique that whenever you take mcoacterial species and you uh undergo decolorization and then you try to again give them this new counter stain, they don't take that up. They remain that reddish color. Again, they have a really long doubling time, which kind of sucks when you got to culture these patients because it means it's going to take a while for you to actually get these to grow out. That also means that you got to put these patients on antibiotics for a really long time as well. So there actually another component to that. It's an

7:00 obligate a-ro which areas of the lungs? It prefers the apex of the lungs because of the high oxygen tension. There's a third component to these that makes them really scary. The other component is that they have a lot of what's called virulence factors. All these mean is that essentially the mcoacterium have really nasty kinds of weapons that make it able to evade the immune system and make it really hard for the immune system to try to be able to kill these species. So what are these? Well, one of them is here in this S. So it's called a sulfatide. So let's say here you have a macrofase, right? Here's our macrofase. And this macrofase generally what it wants to undergo

7:46 is it wants to undergo a process called uh making a fagosome. So in other words what happens is let's say you take this mcoacterium species up. It under goes fagocytosis. So what does that mean? It takes it from the outside which is out here engulfs it and brings it inside. That's called a fagosome. And the process by which we go to do this is called fagocytosis. Then it wants to fuse with this little green structure. What's that called? A lome. So then we should make a fagago, which is the fusion of the fagosome and the lome. And what happens is the purpose of doing this is that you take all of these really nasty harsh loal

8:32 enzymes and you mix it with the fagosome that contains the bacteria. And the goal is to do what? is to cause killing, right? It's to basically kill the mcoacterium tuberculosis. We'll put MTB. That's the goal is to kill the mcoacterium tuberculosis by using this fagalosome. Well, what happens is it has this thing inside of it and it's called a sulfatide. So again, what is it going to be over here? It has something called a sulfatide. And sulfatide is essentially the virulence factoring that inhibits. So they have the presence of this thing called a sulfatide. And the sulfatide inhibits at what point in this process?

9:17 It inhibits the fusion of the fagosome and the lysosome. So you don't get this process. Therefore you can't have a really easy time killing the mcoacterium tuberculosis. And so this becomes more challenging. You see how that pretty much allows them to essentially kind of evade the immune system. Another thing is when you have just a couple of these by themselves, right, you just got one dude just hanging around and it's by itself. It's it's more susceptible to getting jacked up. So because of that, what these things do is they carry this kind of molecule on them. And this is called chord factor. And chord factor is essentially kind of like a glue. That's the way I want you guys to think about It's like a glue and essentially what it does is it does two things. One is it

10:02 really helps to enhance your macrofase involvement and it also helps to really inhibit neutrfils. But one of the biggest things about this chord factor is it really causes what's called serpentine kind of growth or serpentine formation is what I want you to remember. So it causes serpentine formation or serpentine cords of the mcoacterium tuberculosis. So essentially this thing acts like a little glue between these guys and then they can grow and almost give you like this. Well, if you kind of think about it, it's maybe a little bit of a stretch with my drawing, but the serpentine cord which is all of these mcoacterial species kind of linked

10:48 together. It's really hard for a macroofage to be able to defend against this. All right? As compared to just one of these by themselves. So, it's a whole group of friends taking on this kind of like macrofage versus just one or two of them by themselves. All right? So, that's kind of the benefit of this is that it just makes it harder for the macroofages to fight against them. So, what we get out of this is that mcoacterium tuberculosis is a pretty it's a pretty tough dude. All right. It has the capability of having micolic acids which makes it kind of resistant, right? But also it also really makes it kind of interesting with very unique features when it comes to diagnosis. We know about some very unique characteristics of it. One is it takes a long time for it to be able to grow and because of that there's two downsides.

11:35 One is that it takes a long time for us to get cultures and it also takes a long time for us to completely clear the infection. So we should actually write that down. So there's actually two components here. One is it takes time for it to grow and the other one is it takes time for the uh for the infection to clear with antibiotics. Takes time to clear the mcoacterium tuberculosis with antibiotics. You'll see whenever we get to the actual treatment section, people have to be on these antibiotics for sometimes 3 months, 6 months, 9 months. It really depends. That's an insanely long time and it probably has something to do with that lung doubling time. All right, we know it prefers the upper lobes of the lung. That's going to come in really really critical when we talk about what's called reactivation TB. And

12:20 also one of the big big things here is this thing is pretty hardy. Besides the micolic acids, it has these things called sulfatides and cord factor which basically allow for it to kind of become more hearty and make it harder for the immune system of the host to fight against it. Now we know the pathogen that basically can cause this problem. The question is is how do we get it and how does it actually cause disease? Because you don't hear about mcoacterium tuberculosis like a ton. Well, one of the big things is exposure. When we talk about risk factors for exposure, it's really how you I would say how you get the bacteria. And so so this is basically how you get the bacteria.

13:07 into the lungs. That's really what it comes down to. It's how you get the bacteria. Now, when we talk about this, how do you how do you actually get it? Well, it's via respiratory droplets. And so whenever a person is nearby somebody else who has maybe mcoacterium tuberculosis and they cough, they sneeze and that respiratory droplets move into the lungs, they find an opportunity to get down here and start causing some potential damage. If the person's immune system, for whatever reason, doesn't have the capability of being able to fight back. So how this thing gets in is via the processes called respiratory droplets. So, you have to be relatively close to someone who probably has TB or

13:52 has a very high risk, you know, scenario of potentially having TB. So, we're spreading this bad boy via respiratory droplets. How would I actually really increase my risk of getting the bacteria? Well, one is high prevalent areas. So, I would call this more specifically endemic exposure. That's really what it comes down to. It's endemic exposure. So what areas have a high kind of prevalence of tuberculosis? Asia, Africa, probably even like Latin America as well if we wanted to add that one in there as well. So here we'll actually we'll throw that one in there too. Latin America. So again, it's more particularly those who were kind of born into these particular areas or traveled to those areas. That's an exposure risk. The other thing is

14:38 going to be some type of like close contact exposure. Um and so what do I mean by this? This is could be a family member. This could be a friend, but it's someone who you were around and they had active TV. This is a pretty high-risisk component. So again, endemic exposure really, really important, especially for your exams. Um, but I'd say the close contact one is just anybody. This doesn't really matter, but this is like again it is the most likely one to have that highest risk of kind of inoculation. So close contact exposure was someone again it has to be it's someone who has active TB. All right. The other component here is going to be probably higher risk kind of areas. Um, and so what do I mean by this? The last one I would say is just going to be kind

15:24 of like overall high-risk regions or high-risk kind of like workplaces, facilities. So high-risk areas. Um, and so the ones that I would want you guys to think about for this one is probably going to be like the hospitals. So, anybody who's in the health care kind of like aspect probably going to is going to have some degree of risk here. So, health care would probably be a big one. Um, another one I would definitely want to think about is potentially like homeless shelters. That is a potential risk factor as well. So, the homeless shelters and we could even go down the line and sometimes they even include in like prisons if you really want. We could even add in like prisons as well. But I think the biggest ones that I would want you guys to remember is probably going to be a close contact

16:10 exposure or some type of like especially for the exams because it's a perfect vignette to set you up. They just came back from traveling or they were born in some area of Asia, Africa. So they had that exposure risk. All right. So the first thing is they get the bacteria in. The second component is we have to then determine okay is a person they got the bacteria in. Are they having a primary infection that progresses right that progresses or are they having a primary infection that goes dormant and then in certain scenarios it reactivates

16:55 and that's really kind of the step here that's critical. So you have a person who gets a primary infection. Either they progress and they continue to have active disease or they get a primary infection, it goes dormant and then it reactivates. So let me explain something for a second. In most patients, I'd probably say greater than n g greater than equal to 90% of cases, they go to a stage called latent. So in other words, this means that they have latent TB. latent TB means that they don't really have an active infection. What kind of happens here in just a simplistic way because I'm going to go into detail more there in a second is they get the bacteria in. So here's the bacteria. Then what happens is if you have a good enough immune system, your immune

17:41 system's capable, it's functioning in the normal individual, you'll wall this thing off. And when you wall it off, it kind of goes into this dormant state where it's still there. It's still there. It's actually present in your lungs. you maybe didn't completely eradicate it, but you walled it off and so it's in this sleepy state. That's called latent TB. In about probably whatever the remaining portion of this is, so less than 10% of cases, they can progress. So in other words, you get this kind of infection, the pathogens get here, maybe you try your best to kind of wall it off, but it doesn't really do a great job because your immune system isn't as strong. And because of that, it spreads to a bunch of different areas. And maybe it spreads throughout the lungs. Maybe this even

18:27 gets into the bloodstream. It gets into your lymphatics. And this thing starts to kind of go haywire because you just don't have maybe that proper immune system to wall this thing off. And so because of that, this thing spread throughout the lungs or it spread to the bloodstream and it became disseminated. In this scenario, we call this primary progressive TB. So, primary progressive TB. All right? So, that is the first thing that I want you guys to remember is again most of the patients if they have a good enough immune system, they go into a state of dormcancy. Some of those patients who just don't have a robust immune system, they're probably in some way, shape, or form immunosuppressed, and we'll get into that. They can't kind of wall this

19:13 bacteria off. And so because of that it can kind of spread spread spread even get into the bloodstream and start to disseminate. In another scenario out of this patients that most often go into latency in certain scenarios sometimes you have something that pushes the individual to where they had it walled off but then what happened is is it decided to maybe come out of dormcancy. And I'll get into how this actually happens, but whenever they're in these areas, especially reactivation, reactivation typically likes to occur in the upper lobes of the lungs. Why? Remember I told you that this is an area of high oxygen tension. And so what we'll notice in patients who get reactivation TB is they end up getting

20:00 kind of this liquefactive necrosis that occurs in the apex of the lungs. And that my friend is called reactivation TB. All right? So this is called reactivation. Some even call it post primary. So reactivation TB or post primary TB in case you hear that. So what I want you to get at is you get exposure to the bacteria, gets its way into the lungs. If it gets into the lungs, it can either do one of two things. It can progress if you just don't have the robust immune system or you can go into a dormant state. But in certain scenarios, you can reactivate it. The question becomes not as much here. It can be a certain degree of a question, but I'd say a lot of it comes in here. What's really the reason why they come out of

20:47 latency and go into this reactivation state? And often times it comes down to a suppressed immune system. So, one of them is that you have a really diminished activity. And I promise you'll see what I mean by this a little bit later is you have a reduced activity of your tea cells. And particularly it's called your TH cells. Your technically these T- helpper cells are CD4 cells. That's really what we're going to call them. They're CD4 cells. And what is really really critical about our CD4 cells which are going to represent here is that they help to secrete a bunch of different types of cytoines that are really helpful for this TB. one that they release is really critical and what it does is it really kind of activates macrofasages makes them really really just beasties and try to try to really

21:32 focus on killing and destroying these microbacterium. It makes them a little bit more hearty. All right, that chemical that they release is called interferon gamma. All right, interferon gamma activates macrofasages and then what macrofasages do is they also pump out a particular cytoine to activate more tea cells bring in more macrofasages and that's called TNF alpha but TNF alpha is not only released by in this case the macrofase it's also released by these te- cells and what happens is in all of this is that te- cells really really whenever they get hit with interferon gamma It activates macrofasages. Macrofasages release TNF alpha. T- cells release TNF

22:17 alpha. What does this do? Brings more macrofasages to the area. All this is trying to do is is if I bring all of these immune system cells to the area, theoretically I should be strong enough to take this bacteria and push it into the jail. Put it into the prison. And I'll explain what that prison is over in the pathophysiology. For right now, what I want you to trust about this is that really what we're trying to make is this this prison is what we're going to refer to as a granuloma for right now. So, for right now, I just want you to trust me that this is what we're going to eventually push them into is a granuloma. All right? But we need sufficient amount of tea cells and we need sufficient amount of these like inflammatory cytoines. So what if I don't have te- cells and what if I have

23:03 a reduction in these cytoines and the inflammatory cytoines I'd say the most important one is going to be what? Well it definitely is interferon gamma but I'd say TNF alpha is probably going to be the biggest one that I want you guys to associate with this. So what conditions really reduces your te- cells? Come on think about it. If I have a condition called HIV or AIDS, what does that do to my te- cell levels? It drops them. So in patients who have HIV AIDS, you drop their T- cell levels. If you drop their T- cell levels, they don't make as much of the interferon gamma. Can they stimulate the macrofasages? No. If they

23:51 can't, they inhibit the macrofasages. Do they release TNF alpha? No. Because of that, do you put them into the prison? No. And so what ends up happening is unfortunately these little suckers escape and they grow and they grow and they grow and they grow and this is basically what pushes the bacteria to grow and cause more damage and that's what we don't want right so out of this you're getting more of this bacterial growth. If I have patients who have really really low levels of these cytoines what would be a reason for this happening? Well, I think the biggest one is any kind of amunosuppressant. That's really the case is any amunosuppressant drug is probably going to be a pretty strong trigger here. So, we'll write this one out. So, this is really any kind of amunosuppressants.

24:41 And again, I'll give you guys a couple examples of these, but I think the most common one that I would want you guys to think about for the exam is what type of drug? A TNF alpha inhibitor. So steroids, transplant rejection meds, TNF alpha inhibitors, which we use in a lot of different types of conditions, especially things like inflammatory bowel disease. We use it in a lot of like rheumatic diseases. So these are these are things that we really want to consider. If you drive down their kind of overall immune response, you don't keep them in these granulomaas. And so if we can't keep them in the granulomaas, either they progress, right? That's one of the other concept here is that again same it's kind of a similar concept here they don't put them in the granulomaas or they don't

25:26 maintain the granulomaas they break free and when they break free their predilction is for what area for the apex of the lungs and then for the primary progressive it's usually middle and lower lobe which I promise we'll get into so again what I want you to understand here is when a person gets exposed to something like mcoacterium tuberculosis the exposure is getting the bacteria In the reason why it even becomes active, which is either primary progressive or reactivation, is you have to have something that's suppressing the immune response. HIV AIDS dropping your tea cells or immunosuppressants shutting down the cytoine response. That could be steroids, that could be transplant rejection meds, that could even be TNF alpha inhibitors. HIV AIDS is probably going to be one of the highest risk,

26:12 probably about 50fold increased risk in tuberculosis with HIV AIDS. All right, that's the big thing. Now, if you have a good immune system, you're going to probably be fine and you're going to go into a dormcancy state and you don't have to potentially worry about this. And now, these are the biggest risk factors for why this happens, but it could be a lot of other mild ones. I just wanted to give you the most probably extreme ones, but you can see this in patients who just have we can see these in patients who are just malnourished, acutely ill, periods of just overall physical stress. This can also drive this process. All right. So with that being said, we talked about the particular pathogen which is mcoacterium tuberculosis. We talked a lot about the risk factors for getting exposed and we talked about the risk factors that actually cause it to progress. What I need to do now, which

26:59 is going to take a little bit of time, but I want you guys to stick with me, is to go through once the moment this microacterium hits the alvoli, how does it cause these granulomaas, which is going to be, you know, a hefty discussion, but let's kind of dig into it. All right, so first thing is how do they spread again? Respiratory droplets. So there is some type of movement of these pathogens and basically they are going to be spread via respiratory droplets from a close contact exposure from being in an endemic population from being in a high-risisk area. Either way these things make their way into the lungs. I told you a little bit about what's the most common locations. I'm going to

27:44 recap that again. Often times these prefer to start off their initial infectious kind of process really in the lower loes and in the middle lobes. And again it could be the right or the left but again usually there's only a middle lobe on the right. All right? But it could be it's usually more in the middle lower loes. So that's the first thing I want you to remember is initial location is oftent times it's going to be middle lobes or lower loes. But there's another component that I have to add on to that. So first thing is often times the initial location where it's going to start all of its kind of process is middle or lower loes. But the other thing is look how close it is to this pink tissue that I'm going to draw here. So we have a piece of kind of

28:31 a pink tissue here. This is the visceral plura. And then what's this one here called? That's called the parietal plura. It's just beneath the visceral plura. So we call that a subplural type of location, right? So it's middle lower lobe and it's usually subplural. All right, we have a location of where these initially start once you get an exposure. Now once they get in there, guess what? Macrofasages say, "Hold my beer. I got you. I'm going to help you out a little bit here, bear, buddy." So what happens is the macrofasages are going to be a part of your innate immune response. And what they're going to do is is they're going to see these mcoacterium and they're going to undergo a process which I told you guys which is

29:18 going to be where they eat them. They undergo the eating of them. They bring them inside of them. And what's that called? This is called fagoscytosis. So the first step is going to be something called fagago cytosis. And that's going to take it inside and it's going to bring it inside of this little thing called a fagosome which is going to be right there. And again what's going to be inside of it? It's going to be the mcoacterium tuberculosis. Then what happens is this son of a gun, we already told you it's supposed to fuse. What is it supposed to fuse with? Well, then you have your fagosome and it's supposed to combine with something called a lo, right? So here's our lo and this is going to have all the looal enzymes. This fagosome is going to

30:04 contain the mcoacterium tuberculosis. And what is it supposed to undergo? it's supposed to undergo fusion. So then we should have something called fusion. So here we have again the fagosome which is basically the macrofase that contains the TB. Then after that we're going to have fusion of the fagaloo. Well we should have fusion of the fagaloome. So at this step we should have fagago lysosome fusion which is going to be at this step right here. So the first process was fagocytosis. The second process is going to be fagalizosome fusion. I told you though that there was something that happens at this step. We have something

30:50 inside of the mcoacterium species that prevents this. Do you guys remember what it was that inhibits this process? I'll give you a hint. It started with an S. It was called the sulfatides. Yeah. So the miccoacterium has something called sulfatides. And the sulfatides are pretty much a virilence factor that what it's going to do is is it's going to inhibit this fagago loome fusion. That's what it's going to do. So instead of these guys going and actually fusing together, what happens? We're going to inhibit that process. we're going to inhibit this fusion. And so now what happens is these were supposed to come together, but they don't. And so we kind of keep this unfortunately the fagosome never fuses. And so we're still stuck with

31:38 this this guy over here containing all of that TB and we're still unfortunately stuck with this loss over here which aren't able to fuse. What happens is this bacteria, it's not really undergoing destruction. So because of that, guess what it decides to do? It decides to replicate in the macrofase. So that's the next step. So the first thing was fagocytosis. Second thing is once we actually have the fagosome is to fuse it with the fagaloome. All right? To actually fuse it with the loome to make a fagosome. So these were supposed to come together, right? We're supposed to have the fusion of these two. And again, it's going to be the what two things? It's the fagago fagosome.

32:25 Actually, put this here. It's supposed to be the fusion of the fagosome and the lysosome. We're supposed to bring these together, but we're not going to. Because of that, all you end up having here is just bacteria that are going to replicate in the macroofase. These things are going to just replicate like bunnies. Because of that, now we get this infected macrofase. So now I have this infected macrofase and what does it have all the way filled inside of it? It's got all these mcoacterium species just growing within it. So again what is this here called? This is called a infected this is called an infected alvolar macrofase. Now that's the first thing that I want

33:12 you guys to remember in this step. So the first component here that happened is that you had inhalation via respiratory droplets gets into the airway causes its initial kind of sight of infection which is middle lower lobe. It's usually subpl. If we zoom in into the alvoli macrofasages are supposed to undergo fagocytosis that actually does occur. They get a fagosome. You're supposed to combine the fagosome and the loome to make a fagosome. But guess what the sulfatide does? The sulfatide inhibits that fusion. So now that never happens and then you just have all of these bacteria that replicate replicate in the micro macrofase. Now I got an infected macroofase. It's incapable of doing its job. So what does it need? It's got to call out onto its friend. So what happens is the infected macrofase

33:59 releases a couple different cytoines. It releases things like interlucan one. It releases things like TNF alpha. And that's going to get pumped out from this alvoli, which is where all of this process is occurring. It's going to get into the blood or it's going to get into the lymphatic circulation. Once it does that, these cytoines are going to go and activate different types of immune system cells, right? And generally the way I want you to think about them is just overall antigen presenting cells. And we're going to try to activate these antigen presenting cells. What are the two antigen presenting cells that I really want you guys to remember in this scenario? The two antigen presenting cells is going to be the dendritic cells. That's going to be kind of the heavy hitters in this scenario and then again it's going to be monocytes that come to the area and generally turn into

34:44 macrofasages. So these are the two ones that I want you to think about. But the heavy hitter in this scenario is going to be the dendritic cells. So they're going to come from the lymph, they're going to come from the blood and they're going to come to this area. All right? So we're going to activate those puppies. And again, who's really helping with it? It's these high levels of things like interlucan one and tumor necrotic factor alpha that's being released by the infected macrofasages. Once that happens these dendritic cells here's our antigen presenting cell. We're just going to use this. This is our antigen presenting cell. All right here is the mcoacterium tuberculosis. It undergoes fagocytosis. So once it under goes fagocytosis inside of this dendritic cell basically what happens is it will take some pieces of it and

35:29 expose it on its MHC2 complex. When it exposes it on the MHC2 complex you're supposed to have this interaction here which is the MHC2 complex with your T- cell receptor. These interact basically once you get this connection you have generally a co-stimulatory signal and this thing is ready to roll. what's ready to roll. This is a naive tea cell, which means it doesn't really it's it's not kind of it doesn't know what its job is meant to be. It doesn't know if it's meant to be a T-H helpper cell, a cytotoxic tea cell. It doesn't even know what kind of T- helpper cell it needs to be. So what happens is the macroofage is smart and some other cytoines that get released here is not just interlucan one and tumor necrotic factor alpha. So let's

36:14 actually kind of show that these are the cytoines first and then we'll bring these over here. But another cytoine that's also getting kind of pumped out here and causes some pretty uh helpful scenarios here is called interlucan 12. So that's another site that kind of gets released. So it's interlucan one TNF alpha and interlucan 12. Once the dendritic cell undergoes this fagocytosis, takes a piece of that mcoacterium and exposes it on side of its membrane, activates this interaction, then interlucan 12 comes in and really drives this naive tea cell to have an actual determination of what it's going to be. And so what it does is it says, "All right, folks. I know what

37:00 I'm meant to be when I grow up." and it turns into a very specific type of TE-C cell that underos an excessive amount of proliferation and this is called T-helper one cells and that's where these are becoming the big dogs the macrofase it just couldn't handle the it couldn't handle the heat and so what ends up happening is with this interaction with the antigen presenting cells and the interlucan 12 this naive T- cell it became TH1 cells TH1 cells I already told you they release a very very heavy amount of a very specific type of cytoine. Do you guys remember what that one is? It's called interferon gamma. Interferon gamma is the big cytoine in this scenario that is going to help us to

37:46 drive a particular type of immune response. One of those immune responses is it's going to tell this macrofase to become better. It says just come on bro, level up your game. And so the macrofase kind of goes from being like a fagocitic type of factory where it kind of eats things to where it becomes really really good at releasing things like reactive oxygen species and proteasis and tries to undergo a lot of intracellular killing. All of this is really trying to put this bacteria into dormcy. So one of the things that it does is it stimulates a lot of what's called intracellular killing by the macrofase. It basically just makes it like a beast. Makes it kind of like a a little bit more of a enhanced activated macrofase. So it under goes intracellular killing and that's one thing that it does to this

38:31 macroofage is it really really amps up its activity to be able to kill the pathogen. The other thing here is is it tells these macrofasages to start to undergo this kind of conversion and transformation process. And so it drives this kind of conversion and transformation process if you will where a bunch of these macrofasages kind of come together and fuse and it becomes one big giant cell. That's what we call them. We call them giant cells. So we actually call them Langghans giant cells. So Langghan giant cells. Some of them actually make what's called epithelioid hyocites. But I don't want you guys to go too crazy on that. I just want you to know that what we make is is we stimulate the formation of these things called langghan giant cells. It's basically I'm not kidding just a bunch

39:17 of macrofasages that are fused together and they may contain some of the mcoacterial tuberculosis in them. And what else is actually happening? interferon gamma not only is helping convert them but it's making them good at killing all of this is supposed to basically do two things one is to help the macrofasages be better at killing the pathogen and also start to kind of like wall this off this big cell becomes like a wall it's trying to keep the TV in one particular place not letting it spread around that's one of the benefits of this so in this scenario we started off we got the exposure That thing got into the lungs. It interacted with the macrofase. Macrofase couldn't handle it. Says, "Let me tell my buddies." Tells antigen presenting cells. They come in.

40:03 They help with fagosytosing them, presenting them to naive tea cells. And we turn this into a T-helper one cell. These things go ham and start pumping out interferon gamma. When they do that, activates the macrofasages, causes them to convert into big giant cells. We start kind of killing the pathogen and making a wall. So, let's talk about what that wall is. That wall, if you will, is called a granuloma. Now, this is what's really interesting. We're having the granuloma, which we're kind of just zooming in on here. It's really in this alvoli. It's where is it again? I told you usually middle, lower lobe, and subplural. If I zoom in on this and how all of this is happening in kind of a really cool sequence from the most outer part of

40:49 this granuloma is what? Well, the first one is the orange cells. These are called your T-H helpper one cells. What are the job of the T-helper one cells? Well, think about it. This thing is on the outside and it's just spewing out what type of cytoine to tell the Lang Hans giant cells to tell the macrofasages to be good at their job. What is that? Interferon gamma. So, it's just pumping out interferon gamma to feed what? The inner core. It's feeding the inner core of macrofasages and giant cells. All right. Then we get into the second component. What's that? Well, technically it's going to be the kind of the outer wall which is all those macrofasages that fuse together. Some of them are epithelioid hysteocytes and a

41:35 lot of them are lang giant cells. So that's the second part here is the lang hans giant cells. And again, I would even add in there if you guys want that these are also going to contain the epithelioid hysteocytes. These are basically a um basically I'd say a group of macrofasages that are fused and they're kind of helping to contain some of this pathogen. That's really their job. It's a bunch of them that help to contain that particular pathogen. And in the inner kind of core is the macrofasages. Now some of these obviously could be infected, some of them may not be infected. So but again I think the important thing is that a lot of these are the ones that are really

42:21 undergoing a lot of the killing process and some of them will contain the pathogen inside of them and even some of the Langhans giant cells may contain some of the pathogen inside of them. But the big component here is that we're containing it in this outer rim of tea cells. So again macrofasages are cool because they're supposed to do two things in this scenario. One is they're supposed to kill, but they're also they're really important to maintain this granuloma. And so they do two things. One is they kill the mcoacterium tuberculosis. The second thing is that they really pump out tons of something called TNF alpha. So that's another really really important thing that I want you guys to understand. We made the granuloma which was the macrofase

43:07 fagocytosed the mcoacterium couldn't really kill it told te- cells hey te- cells I need the t-helper one cells to come over here t- helpper one cells come over they activate the macrofasages make them better eating more of them then they have some of the macrofase turned into giant cells and come around them and then we end up with this kind of like nice little circular structure here that's containing a bunch of different types of cells now interferon gamma is keeping the wall in place. Tumor necrotic factor alpha is really really critical though. Let me explain why the tumor necrotic factor alpha there's there's released from actually here let's just let's zoom in it from outside here. When we take these cells here the tea cells they do also release TNF alpha but the macrofasages

43:52 are really that heavy source of TNF alpha. And so what happens is the TNF alpha is really cool because what it's trying to do is to keep more monocytes right which will come to the area and turn into macrofasages to keep the lymphosytes coming to the area and keep reinforcing that granuloma. So these are supposed to do that they're supposed to pump out things like TNF alpha to help to stimulate the macroofasages to come to the area to help to stimulate the tea cells to come to the area. Right? That's what we want. And because if they come to the area, we're going to reinforce and maintain the granuloma. I told you if you give someone TNF alpha inhibitors, you shut down that TNF alpha. TNF alpha is really critical for

44:38 maintaining the granuloma. These tea cells around the outer core are keeping the granuloma also in place with interferon gamma. So the maintenance of the granuloma is really primarily maintained by TNF alpha and T-C cells secretreting interferon gamma to keep the macrofasages intact. All right. What happens is when you have all of these cells clumped up together is oxygen requirements go up. So your tissue starts to become hypoxic. So the center core center of the granuloma experiences under goes hypoxia. That's one event that actually starts to take place. There's a bunch of different cells here, a lot of cells, not enough

45:25 oxygen to go around. And so the most susceptible area, which is the center portion of it, under goes hypoxia. That's one component here. All right. The second component here is that the macrofasages, they are releasing tons of reactive oxygen species, tons of proteasis. So there's going to be lots of reactive oxygen species and proteiases that are released by the macrofasages and attempt to kill the mcoacterium, right? And so there's lots of reactive oxygen species, lots of proteiases. And what that is designed to do is to kill the mcoacterium. But this stuff isn't selective. It says I'll damage whatever I have around me. And what it does is is since you have hypoxia to the center and all these reactive oxygen

46:11 species, it causes tissue necrosis in the center. And so the combination of these things lead to a tissue necrosis in the center. And that tissue necrosis starts to kind of look like it has it's like looks like a bunch of cheese like with holes in it like Swiss cheese. And we call this case necrosis. So it's technically called cacius necrosis. And when that happens, all of this center, which will represent, we'll do it here. We'll just do it in this kind of um let's just use the black actually. All of this, all of this is the case core. That is going to be the inner center gooey portion that contains all of that dead tissue. All right, that's the tissue necrosis. So what we

46:56 give this kind of thing is it's technically a granuloma but it's got a necrotic case core. So what do we call this thing? Technically this thing is called a caseiating. It's called a caseiating granuloma. And again if somebody were to say hey Zach what's a what's a granuloma again? It's an outer core of T- cells. Technically this would be your T-H helpper one cells. Then you're going to have your Langhans giant cells. Then you're going to have your macrofasages, right? And again, in the inner center of it, you're going to have some necrotic debris. Why? Because a bunch of the cells in the center start to undergo hypoxy because there's too much cells, not enough oxygen delivery. And on top of that, reactive oxygen species and proteasis that are being released by

47:43 macrofasages cause a lot of innocent bystander destruction and all of that inner destructive tissue. Actually, we'll do a different color. Let's do for right now. Let's do kind of a pinkish color for right now because all the pink I want to represent like dead cells. This is like dead macrofasages. This could be some dead J uh um Langhan's giant cells. But what's in the inner center of it? the the actual mcoacterium that's kind of in this cheesy center that is really the inner center goo which is going to be containing dead cells inflammatory exidate and the mcoacterial species. But the beautiful thing about a caseating granuloma is I want you to think about this as the TB prison. This is

48:30 essentially going to be my TB prison. And if I have a proper immune system, I should be able to contain these things in that middle lower lobe portion of the lung just beneath the plura. If I don't have the immune system capable, it could then progress. If it goes into latency, it could potentially reactivate. So now let's go into the next step here. The next component is we've done a pretty good job at forming these caseing granulomaas. And again, it's really important to remember where is this? So what's this portion here? I'm just going to use the outer portion of the lung. We're going to call this the subplural portion. And it's going to be in the middle lower lobe. And again, it's going to have that outer core, which is the T-C cells. And it's going to have that

49:17 inner kind of uh portion with the laying on giant cells. And it's going to have all this case necrotic material. There's our caseating granuloma. Right? Here's the thing. There's all these lymph nodes that are in the hilum. This is connected, dude. So you got to remember there's there's lymphatic system channels that exist here and this can drain into this lymph node. And so all of these microbacterial species they had the opportunity to potentially spread over here and cause that same kind of concept over here in the higher lymph nodes. And so whenever they do that you get the same thing which will have the outer T- cell core then you'll have the Langhan giant cells and you'll have some macrofasages but a lot of dead cellular debris containing

50:03 the mcoacterium. All right. Now when this happens you have two components here. One is you have the caseing granuloma at this portion of the lung and you have a case seating granuloma here at the lymph node. These are two different components here. So the first thing is we have something called a gone focus. So what is a gon focus? The gon focus is one that's basically a caseiating granuloma that is usually near the middle lower lobe of the lung and it's a subplural structure. So that's the first thing that's going to be this part. All right. The second one is the hily node. So you have case eating granulomaomas that form within the hily node and makes it bigger and so that causes hiler

50:49 lympadinopathy. Now the combination of these two gives you something called a gone complex that is the next component here. So we have a gone complex. So a gone complex is essentially a gone focus which is a caseing granuloma at the subplural portion of the middle lower lobes of the lungs and hyolympinopathy which is due to caseing granulomaomas within the hily node. That's a gone complex. Now a gong complex can pretty much you're at this point these bacteria are pretty much dormant. They're kind of in a sleepy state.

51:35 They're not killed. they're still there. What happens though is that we try to show that this area of the lung healed and when it does that it kind of under goes some fibrosis and we call this when it under goes fibrosis and calcification of the gong complex we call that a ranky complex. So what is a ranky complex? It's essentially I mean honestly the simplest way of defining this is essentially this is a fibroalcification process. That's all it is. It's that the gong complex under goes fibro calcification. So let's example that. Here we're going to have the gon focus. Here we'll have a

52:22 caseing granuloma right there. again T-C cells outer core laying on giant cells and then the inner kind of portion which contains all of that dead cheesy necrotic material is the caseating portion and then what happens is it under goes fibrosis what color should we represent with let's do this kind of bluish color here so now it under goes some fibroalcification so now all of this under goes fibro calcification in these areas that is called a ranky complex And pretty much this thing is at a point of where we would consider it pretty much like healed. So it's kind of like a healed up gone complex. There's another thing that's really interesting. These gone complexes, again, this is technically dormant. This is technically

53:09 a healed dormant spot. There's another kind of thing that happens. And I actually found this super interesting because I always wondered whenever a TB reactivates, why does it how does it end up reactivating in the upper lobe of the lung? I just couldn't figure that out. like how does it actually get there? And so it does travel, but it had to be there even before you undergo the reactivation process. And so what's kind of cool here is you have here I'm going to say that this is our gone focus outer ring of tea cells langhan giant cells and for right now what I'm going to do is I'm going to have some purple which is again our mcoacterium. this mcoacterium, a lot of them before they just get ready

53:54 to go into this dormcancy state, some of them kind of hitch a ride via the bloodstream and they hitch a ride via the lymphatic system and they go to other areas of the body where they can also go and lay dormant. They can go to the kidneys, they can go to the brain, they can go to the heart, they can go all over the dang place. But this is before, right before they go into this dormcy state. One of the areas that it also loves to go to before it kind of decides to go to bed is into the apex of the lungs. So it uses the bloodstream, it uses the lymphatic channels to get to the upper lobes of the lungs. And then essentially what happens is they make these like tiny little like fosi. It's almost like a gone focus, but it's so tiny that you can barely see it on something like a chest X-ray, but you do

54:41 get kind of like a little a little granulomous formation here. There's like a little granulomous formation. So we started off with a gone focus right here. This is our gone focus and then what happened is it spread up here to the apex of the lungs via the lymph in the blood. This is called lymphohhematogenous seeding. This is called a simon focus. Let's actually write that down. This is called a simon focus. And that simon focus is basically some of the mcoacterium tuberculosis that traveled from the subplural middle lower lobe case granuloma to the apex and it goes into a dormcancy state. That's all this is my friends. So we have here a simon focus. So again a

55:28 ranky complex is basically fibroalcification of the gone complex. A gong complex that then breaks off and gives these small little like microscopic caseing granulomaas to the apex of the lungs before it goes into dormcy. Simon focus gone focus just that subplur portion of that case granuloma. Hilyinopathy is due to swelling that occurs in the hilymph node due to a case granuloma there. Wow. All right. So at this point we have become infected. The innate response with your macrofasages couldn't handle it. Who' they call in? They call the TH1 cells. TH1 cells really help to form the granuloma. You got the granuloma. Where do they like to form? In the middle lower lobe of the lung. Usually near the

56:14 plura. When it underos that kind of process it, it can then spread via the lymphatic system and go to what? It can go to nearby lymph nodes. What's the lymph nodes? Hilo lymph nodes. When you get a case granuloma in that portion of the lung plus enlargement of the hily node, we call that a gum complex. This is pretty much is getting ready to go into dormcancy. It's getting ready to be controlled and go to bed. If we undergo fibroalcification, essentially all this means is it's undergone a healing process. And this generally kind of takes some time, but it's basically healed. It's healing. It's a healing up of that gong complex. Some of them will hit your ride via the lymphhematogenous seating process and get to the apex of the lung and create a simon focus. And this becomes really critical. This is

57:00 critical to reactivation TB because they are hanging out there already. They are ready whenever the opportunity arises. You give them the opportunity, they will take it and they'll start undergoing necrosis and liquefies of that case material in the upper lobe. If you let them reactivate, so we can't let them, but that's what will happen. All right, let's now take the time to talk about when a person gets infected, we undergo the exposure, we go through all of this immune response. How do I really really know if it's latent? How do I really know if it's primary progressive? How do I really know if it's reactivation TB? not just the

57:46 process of it but how do I truly understand them based upon the whole immune response and which one's causing lung tissue destruction which one's going to have an abnormal kind of chest X-ray etc let's do that all right so we started off here and we said again what happened here we had a person they get an exposure they undergo the immune response innate then they go through the adaptive which is the TH1 then from there we create granulomaas and generally these granulomaas are caseating and again they often times will form where initi Initially they'll form in this kind of middle lower lobe of the lung right that's where we said and then again it can also form here in the hiler lymph nodes right and I think the critical thing to remember here is again how do we kind of define this this was technically in this scenario this

58:32 was called that gone complex right now in most individuals we said what what percentage probably greater than 90% greater than or equal to 90% they go into this latent state. All this means is is that we were able to contain the TB. All right? So essentially what that means is you contained this. You had the proper immune response and whenever this happened, you were able to pretty much keep these kind of pathogens snoozing, if you will. So you kept them in the dormant state. You basically prevented them from constantly undergoing replication. So they're there but they're not actively doing any kind of problems and damage. All right. So you c

59:18 you created these case granulomomas in these areas and maybe maybe they even underwent fibrocalification and healed up. But in this scenario you have an individual who these bacteria are dormant but they're not replicating and causing tissue destruction. That's the key here. So latent TB, you got a good immune response. You go this way. You go into this dormant state. That's what I want you to remember. This is basically is the microacterium tuberculosis are dormant. They're there. They're not growing. They're not undergoing any tissue destruction, but they are there. The person does have the TB bacteria there. All right. In less than or equal to actually I would say less than generally in less than 10%

1:00:04 of cases if you just don't have that proper immune response right to be able to contain or to form these granulomaas they may not completely be maintained. So if you don't have the T-C cells that are able to keep that interferon gamma coming, you don't have the uh tumor necrotic factor alpha that's present for macrofasages because you're suppressing it in some way, shape or form. In those scenarios, you can't maintain the granulos. Here's what I want you to think about. Here's the granuloma, but we can't any longer keep it formed. And so because of that, all this mcoacterium basically starts to grow. And when it grows, it again can grow within this particular

1:00:50 portion of where it started its infection, which is usually like the middle, maybe even the lower loes. Again, middle lower loes. So what happened here is you had the case granuloma, but you couldn't contain it anymore. You couldn't maintain it. It bust out. The bacteria start causing further destruction. At that point, this is called primary progressive TV. So again, what's this one called? This is called primary progressive TB. You just basically you couldn't contain it. So in this scenario, the mcoacterium tuberculosis are active and the mcoacterium tuberculosis is

1:01:35 causing damage to the lung tissue. And usually what's interesting about this is that when we think about these like pathogens, they often times in this primary progressive one, they can kind of form like consolidations, basically kind of just damaged areas of fluid um exidate a lot of different types of immune system cells and dead tissue. It kind of accumulates within the alvoli and the bronchioles and it forms kind of like this consolidation, if you will. And so that's one thing that's really kind of unique about primary progressive TB is it's more of a middle a lower lobe consolidation. And so sometimes we'll get into this is this can kind of mimic like a pneumonia.

1:02:20 It's almost like an atypical pneumonia person who just keeps getting treated with antibiotics and they're just not getting better over recurrently. At least three more times they've been treated for this this pneumonia and they're just not getting any better. and you get a chest X-ray and they still have this consolidation that's present in a particular lobe of the lung middle lower loes that is pretty much consistent with that primary progressive TV and especially if they have the what else up here the hiler lympadinopathy because again the bacteria will also not be able to be contained here and it'll grow and potentially cause some enlargement within the lymph nodes. All right. Well, that's one thing. this patient you went this way because you just didn't have the immune response. This way you had the immune response but at some point you lost your

1:03:07 immune response. Maybe again person decided to get HIV AIDS. Maybe the person decided to take an imunosuppressant like TNF alpha inhibitor. They took a steroid. They got a transplant. They're on transplant rejection meds. They got acutely ill. Whatever it happened their immune system activity dropped. Their TNF alpha dropped. Their interferon gamma dropped. or T-C cell level activity dropped and they no longer could contain these granulomaas. But remember, I told you that there's a specific place for reactivation TB. What I want you to remember is that it's usually in these upper lobes. And so what happens is you had these kind of like little focus. What were they called? Come on. I want you guys to remember, don't you dare say a gone focus. It was a simon focus and they

1:03:54 could have a couple of these in the upper lobes of the lung. They had the mcoacterium tuberculosis that was there. What happens is you lose the immune activity. All right, you lose the TNF alpha, you lose that interferent gamma. macrofasages go into like this weird destructive state and they start releasing a bunch of like proteases, metalloprotein aces and all they basically do is they destroy all of that case material that was in there. There was some case and granulomaas even in the the dormant state and what happens is it gets filled with all of this necrotic liquid material. So all we're going to do is we're going to liquefy the case necrotic material in these granulomaas. Now we end up with these. Here's what

1:04:39 happens. They get close to a bronchi. They get close to a bronchi.

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