Innate immune system
Definitions & Key takeaways
The innate immune system is the first line of defense against invading pathogens. It's composed of a variety of cells and proteins that work together to detect and destroy harmful invaders.
The innate immune system is activated within minutes of exposure to a pathogen, and it responds rapidly and nonspecifically to any threat. Its main function is to halt the spread of infection until the adaptive immune system can come into play.
Your immune system is like the military - with two main branches, the innate immune response and the adaptive immune response.
Key features of the innate immune response are that the cells are non-specific, meaning that they don’t distinguish one invader from another invader, the response is really fast - occurring within minutes to hours, and that there’s no memory associated with innate responses.
In other words, the innate response will respond to the same pathogen in the exact same way no matter how many times it sees the pathogen.
The innate immune response includes things that you may not even think of as being part of the immune system. Things like chemical barriers, like lysozymes in the tears and a low pH in the stomach, as well as physical barriers like the epithelium in the skin and gut, and the cilia which line the airways to keep invaders out.
Now if a pathogen happens to get in, then the immune system kicks in and it usually begins with the macrophage - which is the garbage truck of the body.
Macrophages eat up dead and dying cells, so that the tissue doesn’t become cluttered with them, and that makes room for new cells.
They also eat invading pathogens. Since macrophages live in the tissue they begin recognizing pathogens within minutes of an infection.
And the way that a macrophage figures out if something is a healthy host cell or a pathogen is by the molecules that a cell or pathogen has on it’s surface.
This is because cells of the innate immune response don’t distinguish one invader from another invader. You see - pathogens have molecules that humans don’t have and they’re called pathogen associated molecular patterns or PAMPs.
PAMPs include bacterial wall components like peptidoglycan, lipopolysaccharide or LPS, and lipoteichoic acid, fungal wall components like mannan, and flagella proteins which can be found on some parasites and bacteria.
For intracellular pathogens, like viruses, PAMPs might include the viral RNA or DNA. Now, PAMPs are recognized by Pattern Recognition Receptors or PRRs which are receptors on various immune cells including macrophages, neutrophils, eosinophils, basophils, and mast cells.
There are two main groups of PRRs - phagocytic PRRs and signaling PRRs. Phagocytic PRRs bind to PAMPs so that a phagocyte can gobble it up, but they don’t allow for cytokines to be released to other cells.
This is important! - because it allows the macrophage to investigate and eliminate the threat before signaling that there’s an invader.
A little like investigating a noise before calling the cops - after all, it might just be a chicken wandering around on the roof.
So if there are just a few pathogens around, then the phagocytic PRRs will get activated, and phagocytes will eliminate the pathogens.
Going back to our garbage-truck macrophage let’s say that it’s PRR recognizes a PAMP on a bacterial cell. It will then swallow up the bacteria, and then trap it in a vesicle called a phagosome.
The phagosome then fuses with another vesicle called the lysosome and forms the phagolysosome. At this point the phagocyte will undergo a variety of chemical reactions to kill the pathogen.
First off, the phagolysosome contains two types of granules, specific granules and azurophilic granules, which help destroy the bacteria.
The specific granules go to work first - they contain proteases and hydrolases which are active at a neutral pH. As the organisms die, potassium and hydrogen ions are drawn into the phagolysosome decreasing the pH, this allows the enzymes in the azurophilic granules to go to work.
Overall, the enzymes in these granules kill about 2% of the pathogens that the macrophage eats. The other 98% of the pathogens that the macrophage ingests get killed by a process known as oxidative or respiratory burst - a process that’s so powerful that it eventually destroys the phagolysosome and the macrophage as well.
Phagocytes, like macrophages and neutrophils are capable of creating an oxidative burst, but neutrophils really excel at it!
An oxidative burst leads to the production of nitric oxide (NO) and reactive oxygen species, which are chemically unstable molecules that contain oxygen - like superoxide anion (O2-) and hydrogen peroxide (H2O2).
These molecules can bind to molecules within the cell and that can lead to tissue damage. The oxidative burst gets underway when the phagolysosome forms because that activates the enzyme NADPH oxidase.
NADPH oxidase transfers an electron to 2 oxygen molecules creating NADP+, 2 superoxide anions (O2- ), and a hydrogen ion (H+).
The enzyme superoxide dismutase then converts the hydrogen ion and superoxide anions into hydrogen peroxide (H2O2) which is highly toxic to microorganisms!
Also, in the presence of NADPH and O2, arginine is converted into nitric oxide (NO) by an enzyme called inducible nitric oxide synthase, or iNOS.
Nitric oxide and reactive oxygen species destroy pathogens, but also destroy the phagocyte as well. And as it turns out, being deficient in NADPH oxidase allows bacteria and fungi to escape getting killed by neutrophils and can lead to chronic granulomatous disease or CGD.
Now, let’s say that there are lots of pathogens around. In that situation, the tissue resident phagocytes will need some help to deal with this larger invasion.
This is where signaling PRRs come in. Both phagocytic PRRs and signaling PRRs will be activated, and if the amount of pathogens is high the signaling PRRs will signal to the body to send reinforcements to the location.
Signaling PRRs don’t help the macrophage to gobble up a the pathogen but they do get the macrophage to release cytokines - a bit like lighting a signal fire to start the immune response.
Cytokines are small secreted proteins that cells use to communicate with one another. The most important group of signaling PRRs are the toll-like receptors called TLRs.
TLRs are single polypeptide chains and each one makes a single pass through the plasma membrane. TLRs are found on all leukocytes, as well as on epithelial cells, and endothelial cells.
TLRs 1, 2, 4, 5, and 6 are located on the cell surface, and they bind to PAMPs like peptidoglycan, lipopolysaccharide, and flagella.
TLRS 3, 7, 8, and 9 are found within the cell and they bind to intracellular PAMPs like viral RNA. Now, when any of these TLRs get activated by a PAMP, they activate the transcription factor NFkappaB which stimulates the secretion of proinflammatory cytokines like TNFalpha, IL-1beta, and IL-6.
These cytokines cause vasodilation, bring more leukocytes to the area, and induce fever. If the pathogen is intracellular the cell starts to secrete interferon alpha and interferon beta, which interfere with the virus’s ability to replicate in nearby cells.
Phagocytic PRRs help phagocytes like macrophages and neutrophils ingest pathogens which they destroy using specific and azurophilic granules or the respiratory burst.
Signaling PRRs - like TLRs, help cells bind to PAMPs on the surface of a pathogen or bind to intracellular pathogens, and stimulate cytokine production which brings more immune cells to the site of inflammation.
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