Your Adaptive Immune System | Episode 3
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Hello, everyone. Welcome back.
This is Dr. Kara Wada, the Crunchy Allergist. I'm a board certified allergy immunology and lifestyle medicine, physician certified life coach and systemic Sjogrens patient. Busy mama three. And today I am your teacher.
I am bringing you part three of immunology, 101 where we are going to continue to learn how our immune system works.
There are many different ways to proceed in teaching now that we know the basic components of the immune system and understand the limitations of our innate immune system. This though is where the science can get really complicated really quickly.
My Introduction to Immunology - Story Time!
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I always like to share the story of my introduction to immunology. Initially I was introduced to the field as an undergraduate student. I was a student at Rockford college now known as Rockford university. It's a really small, wonderful liberal arts school located in Northern Illinois. It was about 30 minutes from my family's home. I love the atmosphere there. One of the really neat things about going to a school that is so small is that they are able to cater to the needs and the interests of the students.
My biochemistry, professor Dr. Brighter who I was a total fan girl of, although that term was not probably even invented in the early odds, is married to an immunologist. He worked at a local immunology firm, a firm you may have heard of Thermo Fisher scientific. They are responsible for creating and providing a lot of the lab studies and lab tests that I will order for patients actually now.
What they realized was that our class had a lot of folks who were interested in Madison. This was one way that they were able to also collaborate as a couple and provide a really neat educational experience for us to learn the science and the mechanisms of how we evaluate tests for and use our immune system both clinically and in research.
Fast forward then, got that basic introduction to the immune system. Fast forward to medical school. We actually used a similar textbook that we had used during that undergraduate course. This particular textbook is the basic immunology textbook. Really enjoyed that course as well.
As I then embark on the first few weeks of fellowship. We're now using the big kids version of this textbook. Not the basic version, the full fledged version. I'm going through the first several chapters of the book each week, we were responsible for reading kind of digesting and then teaching each other, a chapter from these books. These textbooks.
The first few weeks. I had this sense of, " oh yeah, this is why I love this. I get it. This is gonna be great. I remember this stuff." I felt in control. Like I had a good command of what I was learning.
Then we hit week four, week five. We're about a month in. It's like September. The proverbial" what" hit the fan. I said, " I don't think we're in Kansas anymore. Like what direction is up or down right or left?" Everything got really complicated really quickly.
What I want to do is to help keep things organized and understandable.
We're going to go through how our bodies fight off bacterial and viral infections.
Then we're going to cover how do we make lasting memory, hopefully after we've experienced those infections and we'll compare kind of contrast those along the way.
But I also want you to remember that this is a topic I spent two full years reading about writing on teaching others about and using practically in my clinical practice during my fellowship training and we're just covering the basis. We are just scratching the surface.
My hope though, is that you will have a greater insight into how your body works. Also as we move on next week, in how it misbehaves at times too. When these processes don't go according to plan.
Timeline of a Typical Infection
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Before we hop into specific infections, I think it is helpful to realize and think about the timeline that occurs when we are exposed to a microbe, a microbe being a bacteria, a virus, a fungi, parasite, and what happens along the way.
This is going to be a little bit of a recap from what we've talked about thus far.
The Incubation Period
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When we are first exposed to a microbe, there may be a period of time where we don't realize we're sick. *This is an incubation period.*
The microbe is in your system. It's doing some things behind the scene. Your immune system may or may not have recognized that it's there yet or responded to that yet.
When you start having symptoms, this is when we say that this is *the disease state*. You're having maybe fever or pain or runny nose redness, skin rash, whatever it may be.
It's during that incubation period that we see an increase in the number of microbes present. That may continue to increase as the disease progresses. Especially if the disease goes unchecked by our immune system or other treatments. That's when, if it progresses and this is serious enough that you see persistent disease and/or death.
How we fight off a typical bacterial infection like a staph or strep infection (extracellular bacteria)
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When your immune system recognizes initially that something's wrong. Something is there that is not supposed to be there. It says dangerous signal. That will be the innate immune system that initially recognizes that. Then you'll have a transition into our *adaptive immune response* in memory.
That's what we're going to cover primarily today.
It's when we have that immune response, both innate and adaptive that then we see a decrease in the number of microbes and hopefully eradication.
Which then would result in improvement in your symptoms. Full recovery, hopefully. Or we may have instances where the immune system is only partially controlling our disease or the number of microbes present. That's when you can see recurrent illness.
We are going to focus on the simple today.
When we think about a bacterial infection, we are going to talk about what may happen if you have a strep throat infection or a staff skin infection. When we're thinking about viral infection, we will be talking about what may happen. When you have a cold, for instance.
Just to clarify a little bit, when we talk about bacterial infections, bacteria can be in two different places. They could be outside of ourselves, or they could be inside of ourselves. That is called either extracellular or intracellular bacterial infections.
Extracellular Bacterial Infections
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We're going to focus on extracellular today. Those are the typical ones, like a strep or staph infection and how that type of immune response to that sort of infection may proceed.
When we initially are exposed to the strep or the staph, you will see initially activation of those phagocytes. Those are the cells that the white blood cells that engulf and gobble up those bacteria. They are usually pretty efficiently killed by those neutrophils and macrophages. In part because they haven't adapted to surviving inside of those cells.
The immune system though, when they recognize that and start gobbling those bacteria up, are going to recruit and activate additional phagocytes to bring them to that site of infection. They're going to recruit more troops in part, because when a phagocytes engulf says bacteria many times they will self-destruct as a result of gobbling up too many of those bacteria.
Inside of those phagocytess remember they're creating substances like hydrogen peroxide and oxygen to help kill those bacteria. The same time we're seeing those dendritic cells. Those are the cells with the real long arms and finger like projections.
Those are going to also be bringing those bacteria or even bits and pieces of those bacteria back to the immune system factories, which are the lymph nodes in order to help transition the response from the innate immune system response to the adaptive immune system response.
The same time we have complement activation. Those are those proteins that help make that bacteria appear more yummy to those phagocytes.
We have some of those innate lymphoid cells and natural killer cells that we talked about as well. Part of the response to extracellular bacteria is the production of proteins or antibodies that help us clear fight and clear these infections. We term this part of the immune system, the* humoral immune system*.
That not only helps kill the bacteria, it also functions to block further infection to eliminate the microbes like we talked about, but also neutralize their toxins. In particular, strep and staph are both known to potentially secrete some of these toxins.
How bacteria try to fight back?
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*So how do we end up creating antibodies? *
First of all, we need to do a little immune system matchmaking. Those dendritic cells or other antigen presenting cells.
During this process, and as they are heading back to the lymph node, they are digesting and processing the bacteria that they ingested. They are breaking down that bacteria into bits and pieces and creating little bite-sized chunks that the immune system then can represent out and use to find a match in our immune system cells.
*How does that happen? *
We'll head back to the closest lymph node. In that lymph node, they are going to undergo speed dating. They are looking for a match between a helper T-cell and B-cell these are lymphocytes. When that match is made, then the immune system is able to start creating antibodies.
Immunoglobulins
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Antibodies are proteins that we also call immunoglobulins. These are what provide our immune system a type of immune system memory. They take the form of four, technically five, but we're going to talk about the four main classes.
So these include, IgM, which is the immature kind of first made immunoglobulin. IgA is the type of immunoglobulin that is going to line our sinuses, our respiratory, the rest of our respiratory track, our gastrointestinal track ,and our urinary track. Then we also have IgG. IgG is the main workhorse part of our humoral immune system.
Just to add another layer of complexity, there are actually four subtypes of IgG, each with a different purpose. The main portion of these antibodies is the same. They are shaped like typically like the letter Y. Up at the top of the Y. So if you're doing your YMCA- type moves up on your hands are the receptors.
These are the areas of the antibody that are specifically going to recognize the microbe parts and pieces of the microbe. That have been identified by the immune system and that is where that matchmaking comes into play.
The body part of the antibody, so this would be your trunk and legs. That's the part that is going to determine the purpose or how that antibody works. If it's an IgM antibody, many times there actually will be five of these antibodies in consort working together.
It would be like, if five of us were laying on the floor and had our feet all pointed together to central kind of circular area and had our arms all up. Looking a little bit like a dandelion. Or a little bit like the crunchy allergists logo that was intentional.
If you have an IGA, sometimes stable partner up, is it as two. IgGs typically are flying solo. The different subtypes of IgG have slightly different configurations of what their feet or legs may look like.
Now, what are those antibodies doing? They are helping neutralize. They are helping make those bacteria look more yummy and, helping those phagocytess recognize and find them similar to how complement is working, but in a more effective and a more specific way.
They also are going to be neutralizing any toxins that the bacteria are producing.
As the immune system response proceeds through this process. The system is becoming more and more refined. When we start off with that IgM type antibody, it's akin to a rough cut key. It works okay but it's not super specific. Over time through very specific and very elegant mechanisms.
The immune system will make various different alterations and variations in that initial pattern of the receptor. The stronger the bond between antibody and antigen or the piece of the microbe, the stronger response that is created.
There's some positive feedback where when that response and that bond is tighter, you will see more of that particular cell that's factory cell that's creating the antibodies. You'll see more of those developed.
That strengthens and solidifies that response over time.
That's then what results and what we call class switching. The immune response will go from that IgM and switch into an IgG response over the course of time that you were fighting off that infection. So if you have someone who is early in the course of a new infection and you were drawing a blood level of antibodies you would see igM spike initially. Then over time, you will see that switch over to an IgG spike.
Consequences of bacterial infections
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This is when everything is going right. But what happens when things go wrong?
One of the main consequences of bacterial infections are inflammation and sepsis. Sepsis is a consequence of severe either local or whole body infection by bacteria, typically bacteria.
It will manifest clinically in signs and symptoms of trouble getting blood flow, adequate blood flow to our tissues.
It results in problems with our ability to have our blood clot and, or stay thin enough to travel through the tissues. It results in problems with our metabolism and organ function.
*What does that all mean? *
It means you probably have a fever or a low temp, very low temperature, increased heart rate, maybe increased work of breathing, trouble breathing. Sometimes can have what we call respiratory failure. That's when people require a breathing tube and ventilator to help them breathe.
Usually we'll see blood pressure drop called hypotension or develop into circulatory collapse or shock. In worst case scenario, something called disseminated intravascular coagulation or DIC. This is when you form small little blood clots throughout the body and the results can be absolutely devastating.
This can happen as a result of bacterial infection because of the massive amount of cytokines. Those are those chemical messengers that are being used to help coordinate this immune system response and also can be activated by some of the bits and pieces in those bacterial cell walls. Including we talked about a couple of weeks ago, LPs or lipopolysaccharide and some of those peptidoglycan.
Essentially this is a spark that turns into a devastating forest fire incredibly quickly, and this is why in instances of severe bacterial infection, it is really important to get people medical care quickly. This is especially important, if you are someone who has a low immune system. You're immune suppressed or have an immune deficiency because your immune system may not be able to recognize infection as quickly and/or respond to infection as quickly as it should.
How bacteria try to fight back
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How are some ways that bacterial infections or bacteria themselves, try to evade our immune responses. One is that they can vary the look or the appearance of some of those antigens or other components on their cell wall. Many bacteria have strategies to inhibit the activation of complement. And some actually have resistance to being gobbled up or that phagocytosis.
Our bodies' response to extracellular bacterial infection vs viral infections
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Alright, now let's compare and contrast how our response to extracellular bacterial infections is the same and different to how we respond to viral infections.
First and foremost, viral infections are what we call obligatory intracellular microorganisms. They have to exist within a cell in order to exist and do their thing.
In part, because they use our own cell machinery to make more of themselves.
How our bodies respond to viral infections like a cold or the flu
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They essentially hijack are the nuclei of ourselves to make more of themselves.
Viruses will typically infect various cell types by allowing themselves to be endocytosed or brought within the cell using kind of normal mechanisms where that would normally occur.
In the meantime, they will also typically cause tissue injury and disease through several different mechanisms, but that is what is going to result in the signs and symptoms of a viral infection that we may experience.
When a virus takes over a cell and kind of hijacks it. It messes up the normal cellular responses, the production of proteins and the function of that cell. That will lead to the injury and ultimately the death of that infective cell. This is considered a *cytopathic effect of viral infections*. In this case, if the cell bursts open. It's called *cell lysis*.
Virus is also can stimulate inflammatory responses that will also damage tissues as well.
How our bodies respond to viral infections like a cold or the flu
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Let's go back to when that virus is initially infecting us and how is the innate immune system going to recognize it and respond to it.
The principal and main primary innate immune response against viruses is going to be the inhibition of infection by those type one interferons. Those natural killer cells killing infected cells, those are the assassin white blood cells.
That identify that a cell has been infected. It's been hijacked and it takes it out.
Okay. So those interferons are going to inhibit viral replication and cytokines will help do that as well.
As that's going on, our adaptive immune system is going to start kicking in along the way. Adaptive immunity against viral infections in part, it's going to be mediated by antibodies, similar to what we discussed with the bacterial response. In those instances, antibodies are going to help block viruses from binding and entering host cells.
There's also another mechanism called cytotoxic T lymphocytes and these are going to act in a similar mechanism as those natural killer cells. But in a much more refined and specific way. This is also going to be a way that our immune system is able to have memory to the infection that we have fought off over time.
The way that we eliminate viruses that reside within those cells is really mediated by those cytotoxic lymphocytes. They are going to kill those infected cells and they also are going to help surveil or provide surveillance against viral infection as well. The most viral specific lymphocytes are CD8 T cells and these recognize, we call, viral peptides.
Some of the little pieces of the virus that are going to similarly be taken back to the lymph node presented and look for a match with another lymphocyte in order to do that kind of back and forth conversation and strengthen the response. In creating receptors that recognize that little chunk of virus.
Now, when we talked about that process with antibodies. We talked about it looking like the letter Y and that at the top of the hands of the letter Y that we had those receptors. When we talk about T-cells and specifically CD8 Tcells, we have a different type of receptor these are called MHC molecules.
They have a similar appearance, not quite the same. It's more like a goalpost instead of the letter y. But at the top of the hands are at the top of the goal post. You have similar structures that will recognize, within that goalpost, a segment of viral peptide and bind to it.
That is then how they are able to become much more specific to these virally infected cells. Similar to the process that occurs with the production of antibodies, you're going to see a preference for creating more of the better match. The stronger the bond, the more you're going to see that particular match being propagated, you'll see more clones of those CD8 cells out doing their job.
The CD8 cells will undergo massive proliferation during a viral infection and they will be specific for a few of these viral peptides that are the heavy hitters are the most common and they are going to then take out those infected cells throughout the body.
Now, if you have a situation where you're not able to fully eradicate infection, that is when you may see a more chronic infection or relapsing remitting infection. Sometimes this is called a latent infection, and this is sometimes, what you more often would see in, for instance, like herpes viruses.
Like chickenpox becoming shingles, would be a common situation.
How viruses try to fight back?
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How do viruses try to evade the immune system and the immune system responses?
One great example that we have is the flu virus. A lot of folks will wonder why the heck do we need to get a new flu vaccine every year? And part of it is because of how this particular virus mutates over time.
Year to year, we will see minor shifts in the antigens of the flu virus. This we call antigenic drift. The surface proteins and these little peptides that we create when we're infected with that flu virus are slightly different than the year before and our immune system may not recognize them quite as well.
From year to year, everywhere, once in a while though, we will see a huge shakeup reassortment of these different antigens and that's what happened in around 2009 with the H1N1 pandemic.
There was a significant shift or antigenic shift within the virus itself, and that's why we saw much more severe disease. In part, because the vaccines that we had were not a great match for that H1N1 strain.
Other ways that the viruses will try to evade the immune system is some viruses are able to inhibit that MHC protein, that is the structure that is similar to antibodies, but more specific for viral immune system response, and T-cell related response.
There can be a block there. Some viruses produce molecules that will inhibit the effector of phases of immune responses.
An example of this is the Epstein-Barr or mono virus, which produces a protein that looks very similar to a human cytokine called IL-10. IL-10 typically is an inhibitory immune system chemicals.
It turns down immune system response. It inhibits activation of some of those phagocytess, so macrophages and some of the dendritic cells, and also may suppress cell mediated immunity.
This is one way that it evades our ability to recognize and respond to it. Some chronic viral infections also will result in something called exhaustion. Where the immune system will have so much exposure to particular antigens that the system actually starts down-regulating through kind of inhibitory receptors.
These include something called PD-1 or program cell death protein one. This is actually a target that is being used to help treat specific cancers. We know now with cancer treatment is sometimes if we're able to block PD-1 or blocking an inhibitory response, we're turning the immune system back on and then we're able to help the immune system fight off that cancer along with whatever other chemotherapies or treatments are being used. Super cool science.
We are coming to the end. I want to summarize a little bit and just really bring home the point that the interaction of the immune system with infectious organisms or microbes is really this dynamic interplay of the host, us, and our immune system and how we then use our tools to help eliminate infection while the microbes have their own strategies designed to promote their own survival.
It's this back and forth interplay of microbe versus human and we have evolved together. Different types of infections and microbes will stimulate distinct types of immune system responses and this has evolved over hundreds of thousands of years, millions of years, if we're even thinking back further before humans.
We start off with the innate immune system that is going to initially recognize that there is a danger signal. Then we're going to, hopefully, quickly start transitioning over that innate immune system is going to take pieces of the bacteria or the virus it's going to process them. Then it's going to play matchmaker. Looking for a match. The strongest survive and then go on to create effect or cells and our proteins that are going to help then eliminate hopefully the infection over time.
In bacterial infection, that's going to primarily be antibodies. These proteins that are going to neutralize toxins are going to help make those bacteria look more yummy to our white blood cells and help clean things up, help activate, complement better.
The cell responses, we have the MHC molecules that are going to act in a similar way, but they're attached to a CD8 T cell that is then going to identify those virally infected cells and take them out.
After all of this, we have immense numbers of antibodies of cells that are producing antibodies of the CD8 lymphocytes. All of these chemical messengers floating around. Everyone is in fight mode.
The immune system needs to learn then afterwards as it's the levels of infection, levels of microbes are decreasing. It then needs to downregulate and turn itself off. It needs to clean up the wreckage that is left in the wake of this infection. You can see where this requires significant energy.
You are creating tons of new proteins and other cellular structures. This is why we need more rests. We need more fluids. We need good nutrition to take care of ourselves when we're fighting off infection, or if we're dealing with chronic inflammation. For other reasons for fighting cancer, autoimmune condition.
Misbehaving Immune Systems: Allergies & Autoimmunity
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So as we are looking forward to next week, I hope you found this to be helpful. I look forward to next week starting to talk and teach you about what is going on with our immune system, when it starts misbehaving.
We're going to dig into what's going on in allergy, autoimmunity, immune deficiency in cancer. I hope again, that you are finding this helpful. You're finding this empowering.
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Modern medicine, lifestyle, the power that we have in using our minds and our mindset to put us on track for doing the best we can in treating our bodies with love, kindness, and respect. Really working to optimize this experience that we have in this one life we have to live. I appreciate all of you for your time. I can't wait to talk again next week.
