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
combatting 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.