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, though, 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 might 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.
Adaptive immunity is also diverse, meaning it can recognize almost an infinite number
of specific antigens and mount a specific response against each of them.
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 the 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 primarily takes place in the bone marrow.
Hematopoiesis starts with a multipotent hematopoietic stem cell which can develop into various cell
types - its 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, and basophils are considered granulocytes, because they
contain granules in their cytoplasm, and neutrophils in particular are also referred to as polymorphonuclear
cells, or PMNs, because their nuclei contain multiple lobes instead of being round.
During an immune response, the bone marrow produces lots of cells, many 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 species
like hydrogen peroxide.
These molecules start to destroy nearby proteins and nucleic acids within the phagolysosomes,
which are the components of the pathogen that has been ingested.
The net result is that the pathogen is eliminated.
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 not phagocytic, and they’re best known for fighting large and unwieldy
helminthic parasites, or “worms,” because eosinophils produce molecules that can poke
holes in the outer layer of helminths.
These cells are also involved in allergic reactions, such as atopic dermatitis and allergic
rhinitis, also known as hay fever.
When involved in allergic reactions, eosinophils degranulate, meaning they release various
enzymes and proteins within their granules, and this causes an inflammatory reaction.
Next you have basophils, and they stain blue with the dye hematoxylin, and unlike neutrophils,
basophils are non-phagocytic.
On the flip side, they have granules that contain histamine and other proinflammatory
molecules; therefore, they are important in initiating allergic responses.
Finally, there are the mast cells, which live in tissues (not in the blood), and are very
similar to basophils.
They are also non-phagocytic and are involved in allergic responses.
Next up are the monocytes, macrophages, and dendritic cells which are also phagocytic
cells - they gobble up pathogens, present antigens, and release cytokines - which are
tiny molecules that 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.
Dendritic cells are the prototypical antigen presenting cell.
Dendritic cells are usually found in sites that are in contact with most external antigens
- like the skin epithelium, or the gastrointestinal mucosa.
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 - it’s a life-changing, coming of age moment.
Mature dendritic cells will destroy the pathogen and break up its proteins into short amino
acid chains.
Dendritic cells will then move through the lymph to the nearest lymph node, and they’ll
perform an 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, as
well as monocytes- which is why all of these cells are referred to as antigen presenting
cells.
Dendritic cells are the best at this process because they are the only cells that live
where pathogens enter (through epithelia like the skin, gut and airways) and they are the
only cells that can traffic from these tissues to lymph nodes, where T cells circulate.
Now, only T cells with a receptor that can bind to the specific shape of the antigen
will be activated - and 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 on an MHC molecule and display it
to T cells - and when the right T cell comes along - it binds!
The final group of blood cells, the lymphocytes, includes B cells, T cells, and natural killer
cells.
B and T cells make up the adaptive immune response, while natural killer cells are part
of the innate immune system.
B cells and natural killer 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.
Natural killer 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.
Natural killer cells kill their target cells by releasing cytotoxic granules.
These granules contain some molecules that punch holes in the target cell’s membrane
by binding directly to the phospholipids and creating pores; and some that get inside the
cell and cause target cells to undergo apoptosis which is a programmed cell death.
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 do not need antigens to be presented to them on an
MHC molecule, they can simply bind to an antigen directly.
When a B cell binds to a protein antigen that’s on the surface of a pathogen, it is capable
of internalizing that antigen, degrading it, and presenting it to T cells - so technically,
they’re also antigen presenting cells as well.
Like other antigen presenting cells, the B cell loads the antigen onto an MHC molecule
called MHC II, and displays 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
the plasma, 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 it’s in charge of cell mediated
immunity.
T cells are antigen specific, but they cannot 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 different cells apart.
For example, all T cells are CD3+, because CD3 is part of the T cell antigen 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 and B cells.
Helper T cells can only see their antigen if it’s 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 natural killer 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 natural killer 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, natural killer 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 residing under the epithelium
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 response, bridges the innate and adaptive
immune responses when it presents the antigen to the T cell - which is part of the adaptive
immune response.
Sometimes, if the infection is spreading, bacteria might find its way to a lymph node
without the help of the dendritic cell.
In this case, B cells - part of the adaptive immune response - might directly phagocytose
the bacteria and present it to a naive CD4+ T 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 into
the bloodstream.
The antibodies will tag pathogens, making it easier for phagocytes to eat them.
Some cytokines will activate macrophages to kill bacteria that have been phagocytosed
but cannot be killed by the macrophage alone unless it gets help from its friends (the
T cells, of course).
If the pathogen was a virus living and replicating in the cytoplasm of the infected cells, 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 they’re
needed in the future.
Alright, as a quick recap - the immune system has an 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.