Your Innate Immune System | Episode 2
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Welcome back everyone to the Crunchy Allergists Podcast. If this is your first time meeting, Welcome. Hello. My name is Dr Kara Wada.
I am a practicing pediatric and adult allergy immunology and lifestyle medicine physician. I'm a certified life coach. I'm a mom of three, a wife and a systemic Sjogrens patient.
It's because of everything I learned and went through as a patient that I've made it my mission to use the privilege I have as a physician to help us all navigate our health and wellness more effectively and efficiently. To find ways to ensure that we are fully seen and cared for as patients and as people.
One of the ways I love to do that is empowering people with education. If we can understand how our bodies work and what happens when they are not working properly.
When we're communicating with the healthcare professionals, we entrust to take care of us, there is at its core a power imbalance. By becoming more educated in how your body works and what happens when it's not working, it helps you feel a little bit more confident and clear as you're going into that visit to be able to advocate for yourself. To get the care that you need and you deserve.
This season on the Crunchy Allergist Podcast, we are tackling all things, allergies and autoimmunity, but really digging into allergy immunology 101. Last week we kicked off this series by talking about some of the pieces of the puzzle. Those parts of our immune system that are present and talking about the framework of the innate and the adaptive immune system.
This week, we are going to dig in to the innate immune system. This is the system that is the early defense we have against infections.
When billions of years ago, we as a life forms emerged from single celled organisms into multi-celled organisms, we ended up requiring mechanisms to protect ourselves from other things that we're trying to harm us. To also eliminate damaged and dying cells that were a part of us as organisms as well.
These mechanisms are then what evolved first in invertebrates, as I mentioned in the first podcast episode. Starfish, even. And still persist in all higher forms of life i.e. humans. These are always present and functional within us as humans and ready to recognize and eliminate microbes and dead cells just by being there.
This is the host defense that we describe as innate immunity. It's natural to us. It's just part of who we are. It's the first line that we have in defense against infections. This functions in a few different ways. It can block those invaders from coming in. It can destroy the ones that make their way in.
It's even capable of controlling and even eradicating certain infections.
What it doesn't do is it doesn't create memory on its own. So that innate response remains the same from essentially the time we're born until the time that we die.
We are going to focus on answering three main questions today.
How does the innate immune system recognize microbes and damaged cells? How do the different parts of the innate immune system function to combat different types of microbes? And how does this innate immune response help signal and stimulate the adaptive immune system, which we'll talk about next week.
Our basic defense against infection
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The most basic way that we fight infection is by preventing that infection from entering our body at the major interfaces between the outside and the inside the skin, the gastrointestinal track, our respiratory track, and our genital urinary track. We have layers of our skin or epithelium and our mucosa, we talked about those are the more moist surfaces, and how those areas are specifically structured is one of the many ways that we actually protect ourselves.
The presence of mucus. Mucus will capture those microbes in that sticky surface or the production of antimicrobial peptides, our little proteins that have specific components called defensins and cathelicidins, which will actually kill some bacteria and viruses upon contact.
We also have specific white blood cells called intraepithelial, so inside the skin: T-cells, that are a part of our innate immune system, but will help recognize infections that are trying to make their way into our skin.
This is why it's really important that we do our best to keep our skin barrier and our, mucosal barriers healthy. This is why using a nasal saline to help moisturize the nose, especially when it's cold and dry. Or maybe you have Sjogren's and your tissues are already dry. Or helping repair the skin barrier in someone who has eczema where the skin barrier is leaky and itchy and has breaks in the skin.
It can be really important because this is our first defense against particular bacteria and viral infections in particular.
As we get inside the body, then we move into our immune system proteins and cells so we're going to start with proteins and then we will move on to cells.
How does the innate immune system recognize microbes and damaged cells?
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So how exactly do these pieces, our innate immune system recognize foreign from self or damaged from self. There are particular structures that are found on bacteria, on damaged cells, on virally infected cells that clue in our white blood cells and the parts of our innate immune system into realizing that these are not normal, healthy human cells.
For example, certain types of bacteria express something called endotoxin which is also known as LPS or lipopolysaccharide.
Other receptors on white blood cells will recognize terminal mannose residues. These are specific types of sugars that are found on the outside of bacteria and fungi that are not found on human cells.
There also is the ability to recognize double stranded RNA which isn't made by humans. It's made by viral infections and will then be put on the outside of our own cells when a cell is infected by a virus, but would not be on a healthy human cell.
PAMPS: Pathogen associated molecular patterns
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All of these different microbial molecules that stimulate innate immunity are grouped together in called PAMPS, pathogen associated molecular patterns. These indicate that these are sequences or little receptors are clues that these infections are pathogens have, that our own bodies do not have. These are patterns that then our innate immune system will recognize through structures called pattern recognition receptors. So it's like a lock and a key. They're just fancy locks and keys.
DAMPS: Damage associated molecular patterns
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Now to keep with the same idea, we also have something called damage associated molecular patterns. These are molecules that are released from damaged or dying cells from our own body.
So if we have a burn or have surgery and have cells that are dying in that area that the body needs to call in the troops to start healing that area.
There'll be expression of these damps that then clue in the immune system through the innate immune system to say, "Hey, you got injury here. We need the repair team to head over. "
This'll happen after a heart attack, for instance, when the heart muscle tissues have died, then the innate immune response will call in the immune system to start trying to repair that damaged dead tissue, even though there's no infection there. It's considered a sterile injury cause there's no infection but that area has become damaged or is dying because it did not have adequate blood flow.
Pieces of this puzzle of the innate immune system are encoded in our inherited genes and they're identical in all of ourselves.
In particular, you'll see these in our macrophages, that's a type of white blood cell that does a really great job of gobbling things up. They are considered a type of phagocyte that we talked about last week.
What I think is a really pretty cool is that there are about 100 different types of innate immune cell receptors. Those are the pattern recognition receptors, PRRs, and they can recognize somewhere around a thousand or so of those pamps and damps. It's quite a few, right?
How does that compare to our adaptive immunity? Interestingly, there are only two types of receptors in the adaptive immune system. We're going to talk all about this next week, but these are *immunoglobulins*, or antibodies, and our *T-cell* receptors.
But the diversity that those two types of receptors are able to have in their ability to identify and recognize and remember different proteins, essentially protein structures, is far up out numbers what we see in our innate immune response.
We'll talk about how amazing, it's actually pretty astonishing, the diversity in our immune system's ability to adapt but we'll save that for next week. I think it is helpful to think about things in comparison and contrast sometimes.
How do the different parts of the innate immune system function to combat different types of microbes?
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So the innate immune system when functioning normally does not react against healthy cells and part of that is because the receptors of an aid immunity have evolved specifically for recognition of those pamps and damps. Those pathogen and damage cell signals and those aren't present on healthy cells.
Normal cells also express other molecules that downregulate or prevent these innate immune cells from recognizing them as damaged or foreign as well.
This is another way that the immune system works to help us, when functioning normally, understand what is self and what is not self? What is a dangerous signal and what is not a dangerous signal?
Receptors in our innate immune system
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Let's talk a little bit more about some of these specific cellular receptors that our immune cells have, our innate immune cells have, that are present and able to recognize these potential invaders.
TLR: Toll-like receptors
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One category that we have are called *TLR *or *toll-like receptors*. These were actually initially discovered in fruit flies. So if you remember back to high school biology, when maybe you did some fruit fly studies, these are actually originally described from work with fruit flies or drosophila.
There are multiple different types of toll-like receptors and they are specific in the types of patterns that they will recognize. For instance, TLR 1, 2 and 6, all do a really great job of recognizing gram positive bacteria. These are specific types of bacterial infections like that would cause strep throat or staph infections.
TLR type 4 recognizes that lipopolysaccharide, that LPS that's present in gram negative bacteria. So that's like e-coli, that is many times the cause of our urinary tract infections.
TLR 3, 7, 8, and 9, all do a much better job of recognizing infections that are inside of the cell. So these do a better job of recognizing some of those viral infections or intracellular infections and they specifically will pick up on double-stranded RNA, single-stranded RNA. Those different genetic pieces that are more in line with a viral infection. Those are located within the endosome or inside a specialized package within the white blood cells in particular.
What happens when our toll-like receptors encounter bacterial infection?
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What happens when our toll-like receptors encounter bacterial infection?
This then triggers a series of events, a cascade of sorts, that essentially turns on signaling within the cell. It recruits other proteins.
One in particular that will come up time and time again are transcription factors. Including NF Kappa B and other interferon regulatory factors.
These essentially are different messages that are going to go inside of the cell, into the nucleus, where our DNA is present and it's going to increase expression of those chemical messengers. Those *cytokines*, that are going to allow our immune system to talk and communicate with one another.
It's going to increase expression of different adhesion molecules. This is going to allow white blood cells to stick to one another, or stick to other parts of the body so that they can communicate better and function better.
*Co-stimulators.* These are other proteins that are going to essentially upregulate this response so that our immune system has the tools and capabilities that are there in order to stimulate the adaptive immune response and start killing these invaders.
In the case of a viral infection, especially, we will see production of the type 1 interferon. This is interferon alpha, interferon beta. These are in large part part of what is responsible for causing us to have a fever. This essentially makes it more challenging for viruses to replicate. It decreases their ability to invade more cells and decreases their ability to make more of their genetic material, which is how they propagate and make us sicker.
NLR: NOD-like receptors
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In addition to those TLRs or toll-like receptors, we also have another family called nod-like receptors. These are another family of innate immune system receptors that will recognize damps and damps and again stimulate these downstream effects that upregulate or increase our immune system's response to infection or damaged cells.
These will result in similar activation of things like that NF Kappa B, which is that transcription factor, that's going to turn on our body's ability to use our genetic code and create proteins from that instruction manual.
Inflammasomes
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One of the things that is created when these different proteins are turned on and our immune system is upregulated and our body is in that mode of trying to eliminate that microbes and clean up damage are inflammatory homes. These are really complex, multi protein factories that are assembled in our cells.
They're hanging out in the cytosol, which if you remember, it's like the goo that's inside the cells, that's where it's not in the nucleus where the DNA is, it's just in the rest of the cell.
These are factories that are going to generate active forms of the chemical messengers, our body is going to use to up-regulate all of this. It is like adding fuel to the fire and this in particular will create active forms of interleukin 1 and interleukin 18.
These are then further turned on by more enzymes. They're clipped and made active and then these are released into our system and promote inflammation.
The reason I wanted to mention the inflammasomes specifically is because we have discovered that there are some people that have genetic variations in their inflammasomes. They have a tendency towards having overactive response and this is the part of the body that is problematic in people who have auto-inflammatory syndromes.
These folks will have uncontrolled spontaneous inflammation. So many of these conditions are a little more rare, like familial cold auto-inflammatory syndrome or Muckle-Wells . But these are also implicated in more common conditions like gout and type 2 diabetes. Vitiligo and crohns and even maybe multiple sclerosis as well.
RLR: rig-like receptors
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Another part of our innate immune system are the sensors that are within the cell. So within that cytosol or that goo within the cell. These many times will recognize RNA or DNA. Bits and pieces of the genetic material that viral infections will create. These are called rig-like receptors, ILRs. Or cytosolic DNA receptors or sensors, cBS's. As I mentioned before, those TLRs also can play a similar role inside the cell.
Back on the outside of the cells. The last other type of sensor that we have are lectins and glucans. These will recognize carbohydrates and fungal components, respectively.
Different types of white blood cells
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We've talked about these different sensing components. Let's talk a little bit more about the different types of white blood cells that make up our innate immune system. There are two types that we call phagocytes.
Phagocytes
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*Phagocytes* are cells that like to gobble up things. These include neutrophils and monocytes. *Neutrophils*, which we also call PMNs are the most abundant type of white blood cell that we have in our body.
We have anywhere typically from 4,000 to 10,000 on a given day. Those numbers will increase and decrease depending on if we're fighting infection, the time of day, if we've had any steroids or other immune system suppressing medications.
Or in the case of some folks who are undergoing treatment for cancer, they may receive something called CSF, which essentially will stimulate production of these cells. Because the chemotherapy many times folks are receiving wipes out these cells. These are most often the first and most numerous types of cells to respond to infections. Particularly, they are really good at recognizing bacterial and fungal infections. The cells that are most prominent in acute inflammation.
Neutrophils do a great job of gobbling up microbes and bacteria and then they digest them and destroy them. Within these neutrophils, there are specific little packets of that contain chemicals that help digest those bacteria.
This is actually where our body will create in part hydrogen peroxide and oxygen to help kill some of these bacteria within the cell, which is really pretty amazing.
*Monocytes* are not as numerous as neutrophils. They are maybe somewhere in the order of 500, 10,000 per microliter of blood. They also ingest microbes and that's why they are in the phagocyte family.
When they leave the bloodstream and enter the tissues, they become macrophages. Macrophages can stay in a particular area for long periods of time.
These when found in the nervous system are called microglial cells. In the liver, they're called Kupffer cells. In the lung, they're called alveolar macrophages. In the spleen, they're called sinusoidal macrophages.
Those hang out there can be as Donna Jackson-Nakazawa calls them in the case of the brain macrophages, they can both be angels in healing our damaged tissues and assassins by destroying microbes or causing more influent inflammation as well.
These can be turned on in different ways and cause inflammation in different ways as well. They can both clear dead tissue and initiate the process of tissue repair. They also can produce a lot of those cytokines or those chemical messengers. We talked about that induce and regulate inflammation, so they can essentially add more fuel to the fire in some instances as well.
You can imagine that in a situation where the immune system was out of whack or dysregulated. And macrophages were turned on when they needed to be turned down or turned off. That this could then create ongoing inflammation that was not helpful, but instead harmful to the body.
Dendritic Cells
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Another category of innate immune cells are the dendritic cells. As I mentioned in part 1, these are the cells that have these long arm-like processes. Little fingers that then capture cells and proteins, and they're always sampling the environment.
There are a lot of dendritic cells found in our skin and our mucosal membranes in particular. If they send something that is foreign or potentially harmful, they will then pack up and they will migrate from wherever they are and they will take that back to a lymph node. That's then where this interface occurs between the innate and the adaptive immune system.
Dendritic cells are a big part of a group of cells. We call antigen presenting cells. So we'll talk more about that next week.
But this is all about sampling the environment and then bringing it back to home base where they can then continue that immune response.
Mast Cells
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Mast cells are another type of white blood cell that are made in the bone marrow. They have inside of them pre-packaged little packets or granules. Different substances that are really good at killing bacteria or parasites. They're pretty toxic. They are things that are called like histamine and tryptase. There are prostaglandins and leukotrienes. They will stimulate the production of more of those cytokines that we talked about, those communication signals.
Mast cells are found again throughout our body, in our skin and our noses and our respiratory track in our gut. They are now known as allergy cells. But when we were back in cave people days, we didn't have allergies.
So their main purpose was to defend us against intestinal worms or snake and insect venoms. Because more often than not, we don't encounter these things any longer, not in as often for sure. We describe the symptoms they create when these cells are triggered as the signs and symptoms of allergic disease. So more to come on that in the coming weeks.
Innate Lymphoid Cells
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Last, but not least we have our innate lymphoid cells. So we talked about our Faygo sites. Those were. One type of one big grouping. And now we have lymphoid cells which are lymphocytes as T and B cells, and there are some types of those T and B cells that are also still innate cell.
These are not cells that have created memory, but they are hanging out, trying to be those first line of defense, recognize that infection has taken hold and these are actually a relatively newer area of immunology that we are continuing to learn a lot about these particular types of innate lymphoid cells. Where they are, what they do, and the role they play in infection and inflammation and disease.
Natural Killer Cells
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Natural killer cells are this group on their own. They do a really good job of recognizing infected and stress cells. And they respond by killing them by secreting something called interferon gamma.
They are related to those specialized lymphocyte cells that I mentioned. They only makeup about 10% of our lymphocytes and those similar to the mast cells also have these granules inside them that are really good at killing infected cells. These cells are really good at inducing something called apoptosis, which is essentially inducing a cell to self-destruct.
Complement system
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So we've talked about our epithelial barriers are the physical barriers that we have. We've talked about some of the ways that our body can tell self from non-self and damaged self we've talked about specific cells that make up our innate immune system. And last but not least, we're going to talk about some of the proteins.
In particular, we'll spend most of our time focusing on complement. Complement is a collection of circulating and membrane associated proteins. They're there floating around in our bloodstream, but they're also found on the surface of particular cells and tissues.
Three functions of the complement system
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Complement has three ways that it functions.
The alternative pathway
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The first is the *alternative pathway*, and this is when some complement proteins are activated on the surface of bacteria. This is a component of innate immunity.
The classical pathway
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The second way that it functions is what's called the* classical pathway*. This is going to be another interface between the adaptive and the innate immunity. Classical pathway is when complement is triggered by antibodies or immunoglobulins binding to the surface of microbes and complement helps improve the ability of those antibodies to do their job.
The lectin pathway
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The other way, the third way is the* lectin pathway*. We talked about mannose binding lectin or reluctance as being another way that the immune system is able to recognize a bacteria from a human cell.
Complement can bind to these particular carbohydrate structures and then make that bacteria look extra yummy to the immune system and our phagocyte cells.
Essentially complement is a series of multiple different proteins that cascade upon one another. When they all come together and form this structure called the membrane attack complex, it pokes holes in the membrane of bacteria. When there are holes in the membrane of the bacteria that causes the bacteria to die. So it is a really cool complex. System that works quite well.
When all of these pieces of the complement puzzle are coming together. There are little fragments that are chipped off. Those fragments are really great at up-regulating or turning on more inflammation. Once the system gets kicked off, it's like a single spark can become a forest fire quite quickly.
It helps magnify the response of the immune system. This is really helpful if your body is under the attack of a bacterial infection. This is not so helpful if your immune system is reacting to itself.
So we will talk about how the complement system comes into play with autoimmunity and if you are someone who suffers from an autoimmune condition, it may be part of your lab workup that you will have your complement levels monitored periodically. This is something that is commonly monitored in Sjogren's for instance.
Last, but not least as we're thinking about the innate immune system, we've talked a lot about cytokines. These are the chemical messengers that the immune system uses to talk to one another. These also help describe the flavor of inflammation that you can see based on what type of infection we're fighting.
Coming up next week: Your Adaptive Immune System
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We will talk a whole lot more about cytokines or we talk about the adaptive immune system. But I think it's just helpful to recognize and at least mention some of the names that you'll hear. So TNF, tumor, necrosis factor. Interleukins these are numbered one, two, so on so forth.
There are chemo kinds. They're interference like interferon gamma or alpha or beta. There is another one called TGF beta, which will come up in part because it inhibits inflammation.
So just wanted to introduce some of the names and the words, so that you'll have a little bit of additional context as we get into the weeds next week when we talk all about the adaptive immune system.
I would love to hear your feedback, your questions, your suggestions as we go through allergy immunology 101.
This first month, we are just digging into all things about the immune system and how it functions normally. I'm really excited in the next few weeks, I will be bringing on some of my esteemed colleagues to talk all about how the immune system shows up in our body and how sometimes it has a tendency to misbehave and how we deal with that in the office.
I hope y'all are having a great week. I look forward to sharing more with you all about how our bodies work and don't work next week.
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