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Despite being surrounded by harmful microorganisms, toxins, and the threat of our own cells turning
into tumor cells, humans manage to survive; largely thanks to our immune system.
The immune system is made up of organs, tissues, cells, and molecules that all work together
to generate an immune response that protects us from microorganisms, removes toxins, and
destroys tumor cells - hopefully not all at once!
The immune response can identify a threat, mount an attack, eliminate a pathogen, and
develop mechanisms to remember the offender in case you encounter it again - all within
10 days.
In some cases, like if the pathogen is particularly stubborn or if the immune system starts attacking
something it shouldn’t like your own tissue, it can last much longer, for months to years,
and that leads to chronic inflammation.
Your immune system is like the military - with two main branches, the innate immune response
and the adaptive immune response.
The innate immune response includes cells that are non-specific, meaning that although
they distinguish an invader from a human cell, they don’t distinguish one invader from
another invader.
The innate response is also feverishly fast - working within minutes to hours.
Get it?
“Feverishly” - that’s cause it’s responsible for causing fevers.
The trade off for that speed is 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 that line
the airways to keep invaders out.
In contrast, the adaptive immune response is highly specific for each invader.
The cells of the adaptive immune response have receptors that differentiate one pathogen
from another by their unique parts - called antigens.
These receptors can distinguish between friendly bacteria and potentially deadly ones.
The trade off is that the adaptive response relies on cells being primed or activated,
so they can fully differentiate into the right kind of fighter to kill that pathogen, and
that can take a few weeks.
But the great advantage of the adaptive immune response is immunologic memory.
The cells that are activated in the adaptive immune response undergo clonal expansion which
means that they massively proliferate.
And each time the adaptive cells see that same pathogen, they massively proliferate
again, resulting in a stronger and faster response each time that pathogen comes around.
Once the pathogen is destroyed, most of the clonally expanded cells die off, that’s
called clonal deletion.
But some of the clonally expanded cells live on as memory cells and they’re ready to
expand once more if that pathogen ever resurfaces.
Now, it’s time to meet the soldiers - which are the white blood cells or leukocytes.
Hematopoiesis is the process of forming white blood cells, as well as red blood cells, and
platelets and it takes place in the bone marrow.
Hematopoiesis starts with a multipotent hematopoietic stem cell which can develop into various cell
types - it’s future is undecided.
Some become myeloid progenitor cells whereas others become lymphoid progenitor cells.
The myeloid progenitor cells develop into myeloid cells which include neutrophils, eosinophils,
basophils, mast cells, dendritic cells, macrophages, and monocytes, all of which are part of the
innate immune response and can be found in the blood as well as in the tissues.
The neutrophils, eosinophils, basophils, and mast cells are considered granulocytes, because
they contain granules in their cytoplasm, and the trio of neutrophils, eosinophils,
and basophils are also referred to as polymorphonuclear cells, or PMNs, because they’re nuclei contain
multiple lobes instead of being round.
The mast cells, aren’t considered PMNs because their nucleus is round.
During an immune response, the bone marrow produces lots of PMNs, most of which are neutrophils.
Neutrophils use a process called phagocytosis - that’s where they get near a pathogen
and reach around it with their cytoplasm to “swallow” it whole, so that it ends up
in a phagosome.
From there, the neutrophils can destroy the pathogen using two methods - they can use
their cytoplasmic granules or oxidative burst.
First, the cytoplasmic granules fuse with the phagosome to form the phagolysosome.
The granules contain molecules that lower the pH of the phagolysosome, making it very
acidic, and that kills about 2% of the pathogens.
Now, the neutrophil doesn’t stop there.
It keeps swallowing up more and more pathogens until it’s full of pathogens, and at that
point, it unleashes the oxidative burst.
During an oxidative burst, the neutrophil produces lots of highly reactive oxygen molecules
like hydrogen peroxide.
These molecules start to destroy nearby proteins and nucleic acids - a bit like the neutrophil
dumping bleach on itself and then lighting itself on fire.
This process kills the neutrophil - a bit of a suicide mission - but each neutrophil
takes out a lot of pathogens with it.
Now, in comparison to neutrophils, eosinophils and basophils are far less common.
They both contain granules that contain histamine and other proinflammatory molecules.
Eosinophils stain pink with the dye eosin - which is where they get their name.
Eosinophils are also phagocytic, and they’re best known for fighting large and unwieldy
parasites because eosinophils are much larger than neutrophils and have receptors that are
specific for parasites.
Unlike neutrophils and eosinophils, basophils are non-phagocytic.
They stain blue with the dye hematoxylin, and like eosinophils they can be helpful at
combating large parasites but also cause inflammation in asthma and allergy responses.
Finally, there are the mast cells which are also non-phagocytic and they’re involved
in asthma and allergic responses.
Next up are the monocytes, macrophages, and dendritic cells, which are phagocytic cells
- they gobble up pathogens, present antigens, and release cytokines - tiny molecules that
help attract other immune cells to the area.
Monocytes only circulate in the blood.
Some monocytes migrate into tissues and differentiate into macrophages, which remain in tissues
and aren’t found in the blood.
Other monocytes differentiate into dendritic cells, the prototypical antigen presenting
cell, which roam around in the lymph, blood, and tissue.
When dendritic cells are young and immature they’re excellent at phagocytosis, constantly
eating large amounts of protein found in the interstitial fluid.
But when a dendritic cell phagocytoses a pathogen for the first time - it’s a life-changing,
coming of age moment.
Mature dendritic cells will destroy the pathogen and break up it’s proteins into short amino
acid chains.
Dendritic cells will then move through the lymph to the nearest lymph node and they’ll
perform antigen presentation which is where they present those amino acid chains - which
are antigens - to T cells.
Antigen presentation is what connects the innate and adaptive immune systems.
Antigen presentation is something that can be done by dendritic cells, macrophages residing
in the lymph node, and monocytes which can travel to a lymph node after phagocytosing
a bloodborne pathogen - which is why all of these cells are referred to as antigen presenting
cells.
Now, only T cells with a receptor that can bind to the specific shape of the antigen
will get activated - that’s called priming.
It’s similar to how a lock will only snap open when a key with a very specific shape
goes in.
However, T cells can only see their antigen if it is presented to them on a silver platter
- and on a molecular level that platter is the Major Histocompatibility complex or MHC
for short.
So the antigen presenting cell will load the antigen onto an MHC molecule and display it
to T cells - and when the right T cell comes along - it binds!
Now the other group - the lymphoid progenitor cells - become lymphoid cells which are the
B cells, natural killer cells -quite a name huh?, and the T cells, which we’ve already
talked a little about.
B and T cells make up the adaptive immune system, while NK cells are part of the innate
immune system.
B cells and NK cells complete their development where they started - in the bone marrow, whereas
some lymphoid progenitor cells migrate to the thymus where they develop into T cells.
All of the lymphocytes are able to travel in and out of tissue and the bloodstream.
NK cells are large lymphocytes with granules and they target cells infected with intracellular
organisms, like viruses, as well as cells that pose a threat like cancer cells.
NK cells kill their target cells by releasing cytotoxic granules in their cytoplasm directly
into the target cell.
These granules contain some molecules that cause target cells to undergo apoptosis which
is a programmed cell death and some that punch holes in the target cell’s membrane by binding
directly to the phospholipids and creating pores.
B cells, like T cells, also have a receptor on their surface that allows them to only
bind to an antigen that has a very specific shape.
The main difference is that B cells don’t need antigen to be presented to them on an
MHC molecule, they can simply bind an antigen directly.
When a B cell binds to an antigen that’s on the surface of a pathogen, it is capable
of phagocytosis and antigen presentation - so technically, they’re also antigen presenting
cells as well.
Like other antigen presenting cells, the B cell will load the antigen onto an MHC molecule
called MHC II, and display it to T cells.
When a T cell gets activated it helps the B cell mature into a plasma cell, and a plasma
cell can secrete lots and lots of antibodies.
Typically, it takes a few weeks for antibody levels to peak.
The antibodies, or immunoglobulins, have the exact same antigen specificity as the B cell
they come from.
Antibodies, are just the B cell receptor in a secreted form, so they can circulate in
serum, which is the non-cellular part of blood - attaching to pathogens and tagging them
for destruction.
Because antibodies aren’t bound to cells and float freely in the blood, this is considered
humoral immunity - a throwback to the term “humors” which refers to body fluids.
Now the final type of lymphoid cell is the T cell and its in charge of cell mediated
immunity.
T cells are antigen specific, but they can’t secrete their antigen receptor.
A naive T cell can be activated or primed to allow it to turn into a mature T cell by
any of the antigen presenting cells, but most often it’s done by a dendritic cell.
Now, there are two main types of T cells, CD4 T cells and CD8 T cells - where “CD”
stands for cluster of differentiation.
There are hundreds of CD markers in the immune system, and these CD markers are useful in
telling them apart.
For example, all T cells are CD3+, because CD3 is part of the T cell receptor.
So, CD4+ T cells, are actually CD3+CD4+, and these cells are called helper cells because
they’re like generals on the battlefield, they secrete cytokines that help coordinate
the efforts of macrophages, B cells, and NK cells.
Helper T cells can only see their antigen if it is presented on an MHC II molecule.
CD8+ T cells are CD3+CD8+, and they’re called cytotoxic T cells because they kill target
cells, really similarly to how NK cells do it with one major difference.
CD8+ T cells only kill cells that present a specific antigen on an MHC I molecule - which
is structurally similar to the MHC II molecule, whereas NK cells aren’t nearly as specific
in who they kill.
So now let’s go through a complete immune response with a bacterial pathogen in the
lungs.
To start, the bacteria will have to get breathed in, slip by your nose hairs, past the cilia
in the airways, and will then have to penetrate past the epithelium layer of the lungs.
Once it’s in the lung tissue, the bacteria will start to divide and might encounter a
resident macrophage in the lung tissue which will ingest the bacteria and start releasing
cytokines.
Those cytokines start the inflammatory process by making blood vessels leaky and attracting
nearby eosinophils, basophils, and mast cells, which release their own cytokines and granules
amplifying the inflammation.
Neutrophils from the blood as well as fresh new ones from the bone marrow dive into the
tissue and join the battle.
If the pathogen was a virus, NK cells would help destroy the infected cells at this point.
This is all part of the innate immune response.
Around this point in the infection, immature dendritic cells digest the pathogens and move
from the lung tissue over to a nearby lymph node where they present the processed antigen
on an MHC II protein to a naive T cell.
The dendritic cell, which is part of the innate immune system, bridges the innate and adaptive
immune responses when it presents the antigen to the T cell - part of the adaptive immune
system.
Sometimes, if the infection is spreading, bacteria might find its own way to a lymph
node without the help of the dendritic cell.
In this case, B cells - part of the adaptive immune system - might directly phagocytose
the bacteria and present it to a naive T CD4+ cell.
Either way, if the antigen is the right “fit” for the T cell it will begin to differentiate
and undergo clonal expansion.
Differentiated CD4+ T cells will release cytokines that will induce B cells to differentiate
into plasma cells which secrete antibodies that will go into the lymph and then the bloodstream.
The antibodies will tag pathogens making it easier for phagocytes to eat them.
Once again, at this point, if the pathogen was a virus, the CD8+ T cells would kill any
infected cells that express the viral antigen on an MHC I.
Over time, as the invading pathogen dies off, most of the B and T cells die of neglect,
but a few turn into memory B cells and memory T cells, which linger for years in case their
needed in the future.
So, to recap - the immune system has innate and adaptive response.
The innate immune response is immediate, but non-specific, and lacks memory, whereas the
adaptive immune response is highly specific and remembers everything, but it takes several
days to get started and almost two weeks to peak.