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The
adaptive immune system
All the above cells we have described are part of our innate
defense system. The cells of the innate system respond to general
stimuli and the same cell is capable of defending against a variety
of microorganisms. It doesn't matter to a phagocyte, neutrophil
etc. whether the threat comes from a bacteria, fungi or parasitic
worm, they will still attempt to respond as best they can to the
challenge. For the adaptive system a key difference is that each
cell is only able to respond to very specific challenge. Each
cell of the adaptive immune system can only target a single antigen.
Different cells target different antigens so as a whole the adaptive
immune system is capable of responding to almost all bacterial,
fungal and parasitic challenges.
So, the adaptive immune system is comprised of lymphocytes that
together recognize thousands of antigens. However, this means
there are only a very few cells floating around or blood system
that are able to recognize any one specific antigen. Clearly we
need a lot of immune cells to fight off an infection so there
needs to be some form of mechanism that will promote the proliferation
of just those cells that are capable of responding to a particular
infection as and when it occurs. In other words the immune system
shifts or "adapts" to the challenges it receives, specifically
reinforcing some sections of the defense barrier as appropriate
to the particular microorganism that is the current threat.
Although they didn't know it, this is what enabled Edward Jenner
and Louis Pasteur to develop vaccines. The ability of the adaptive
immune system to learn what is dangerous permits its education
through vaccination techniques. The adaptive immune system is
able to learn from its successes and mistakes unlike the innate
immune system. Innate system is the first line of defense. The
holding barrier while the adaptive forces muster and organize
them selves ready for the counter offensive against the pathogenic
challenge. The adaptive immune system is comprised of lymphocytes.
The lymphocyte population is grouped into two types, T lymphocytes
and B cells. At any one time we have around 1,000,000,000,000
lymphocytes either circulating or deposited in our lymphoid organs.
This represents 2% of our total body weight and lymphocytes only
account for 20% of our cellular (adaptive and innate) defense
system. So, the immune system as a whole takes up 10% of our body
weight. There is a high turnover rate of production with 1,000,000,000
new lymphocyte cells being produced every day. However, given
the vast bulk of mature lymphocytes this should suggest that most
lymphocytes are robust and capable of long life. Human lymphocytes
have been confirmed to have the ability to live up to 10 years.
Lymphocytes
Ok. I'm going to have a big problem explaining all the subdivisions
of lymphocytes we know about. Lymphocytes are a very heterogeneous
population of cells in size shape and function. Many of the groupings
described below are loose collectives. Also consider that lymphocytes
can and do switch function so they readily move between the groupings
defined below (One of the disadvantages of looking at an adaptive,
learning immune system). One crossover that does not occur, T lymphocytes
will not become B cells or vice versa, but within these two groups
pretty much anything goes.
T Lymphocytes (so called because they are "thymus dependant"
or thymus derived" cells) vary widely in their size, anywhere
between 6-10micrometers in size. Typical non-activated T lymphocytes
have very large round nuclei in cells with very little cytoplasm
and the cytoplasm has no obvious granules. Next we have the non-activated
"large granular lymphocytes" (LGLs) with much more cytoplasm
and numerous granules. These cells look a bit like granulocytes
of the innate immune system but they are very different cells in
function. Cutting across both visually distinct T cell populations
we have two main groups, the T helper (Th) and T cytotoxic/suppressor
(Tc/s) cell populations. About 20% of non-activated Th and 35% of
non-activated Tc/s cells have the granular type of appearance, the
rest have the non-granular presentation. In our understanding of
lymphocytes there has been much investigation into the cell surface
molecules these cells express. So, just to confuse the issue, Th
and Tc/s cells are also defined by the type of cell receptors they
carry on their cell surface. Th cells have what are called CD4 receptors
(CD=cluster designation) so they are also called CD4 positive (CD4+)
cells. Tc/s cells have CD8 receptors on their cell surface and so
are also called CD8 positive. The equivalence is not quite exact.
It is rare, but possible to find Th or Tc/s cells that do not express
these particular receptors. However, for our purposes we can describe
the Th cells as CD4+ cells and Tc/s cells as CD8+ cells. See below
for a brief word about CD labels and how we further subdivide T
cell populations into subgroups based on cell surface molecule expression.
T
helper CD4+ cells
Ok, so T helper and CD4+ cells are one and the same thing. They
constitute about 30% of the mature T cell population and their one
and only role is to promote the activity of other immune cells be
they macrophages, B cells or T cells. Th cells themselves need to
be activated before they function properly and this activation comes
from stimuli produced by antigen presenting cells (see below). The
bulk of antigen presenting cells are members of the innate defense
system. So, note here that the innate immune system, our first line
of defense against pathogens, is also communicating with and educating
our adaptive immune system. Our adaptive immune system could not
function without input from the innate defense cells. The adaptive
immune system requires intelligence reports from the front lines
to determine its response to the pathogenic threat. We will discuss
how T cells are activated in another chapter. For now accept that
Th cells need to be activated by antigen presenting cells. Each
Th cell can only respond to one particular antigen. Different cells
respond to different antigens so in total the immune system should
be able to defend against a wide range of pathogens.
Activated Th cells stimulate other cells in to action by producing
chemical signals (cytokines) and by making physical contact with
other cells via cell surface receptors. Th cells can thus control
the response level of cells in the adaptive immune system, namely
Tc/s cells and B cells. Their chemical signals will also stimulate
cells of the innate system. Th cell regulation of innate system
cells is less exact as the innate system is capable of acting independently
of the adaptive system. The CD4+ or Th cell population can be further
subdivided in to specialist subpopulations with different functions.
There is at least one subdivision you should be aware of, the Th1
and Th2 populations. Occasionally you may hear investigators in
alopecia areata talking about these populations. Th cells can be
Th1 or Th2 depending on the type of cytokine communicating chemical
signals they produce. Some cytokines promote the activation of Tc
cells and the Th1 population produces these cytokines. Other cytokines
promote the Ts cells and these cytokines are produced by the Th2
subpopulation. Th cells can switch from being Th1 into being Th2
and vice versa.
T
cytotoxic/suppressor CD8+ cells
Older terms for cytotoxic cells include "killer" or
"effector" cells. As the different names suggest, Tc cells
are the destructive force of the adaptive immune system. It is these
cells which seek and destroy pathogens. Like Th cells they need
to be presented with antigens before they become active. Otherwise
they innocuously float around in our blood stream or sit in our
immune organs waiting for their orders. Antigen presentation to
Tc cells can be done by almost any tissue cell unlike Th cells which
must receive their stimulation through antigen presenting cells.
Any cell of our body that becomes infected or damaged has its cell
surface antigens altered in some way. If it becomes infected with
a virus then viral antigens will start to appear on the cells surface.
Tc cells patrol through out our body and they can be attracted to
sites of infection by macrophages and Th cells that may already
be on the scene. When Tc cells come into contact with tissue cells
they look at the cells surface molecules. If the Tc cells find non-self
antigens on these tissue cells then they become fully activated
and destructive. Tc recognition and binding is help enormously if
the offending cell is covered in antibodies.
So Tc cells require a two step method of activation. First Tc
cells must receive chemical cytokine signals, usually from Th cells.
This stimulates them and attracts them to the site of infection.
Then Tc cells need a second activation signal which comes from recognizing
foreign antigens via physically binding to the cell.
Once T cells are have found a target cell to destroy and are fully
activated they have a vicious arsenal of weapons to turn against
the offender. Activated Tc cells will release enzymes to digest
the cell surface. They also release cytokines TNF (Tumor necrosis
factor) and IFNgamma (interferon). As the names suggest these cytokines
can be disruptive. The cytokine chemical molecules bind to receptors
on the cell to be killed. This binding modulates the cell's protein
synthesis slowing it down or stopping it altogether. With the ability
to produce proteins the cells structural integrity degrades until
it is no longer viable. The most potent method of cell destruction
comes from the release of "perforin". Like the name suggests
it perforates, literally punches holes in the cell surface membrane.
Perforin is stored in several component parts in vesicles of the
Tc cell. On activation the Tc cell releases the parts that make
up perforin and they then form together on the surface of the offending
cell. The perforin components form into a cylinder and as it forms
it pushes through the cell surface to make a hole. The cell can't
take this kind of abuse and structural damage and disintegrates.
Don't mess with a Tc cell.
An active immune system responding to a pathogen is doing us a
favor. However, left to its own devices the immune system can become
highly destructive. It does not automatically know when to switch
off after successfully removing a pathogenic threat. Even when a
microorganism is completely removed from our bodies the immune system
can just keep on going and start to cause a lot of damage to perfectly
healthy tissue. Hence the need for a set of brakes on the immune
system which come in the form of T suppressor (Ts) cells. Ts cells
act on Tc and Th cells and B cells. Ts cells depress an immune response
by producing certain cytokine chemicals that soothe an active immune
system. Clearly there is a fine balance here. You don't want too
many Ts cells otherwise the immune system would be so depressed
that it won't fully protect us. On the other hand too few Ts cells
might allow an active immune system to become self destructive.
Tc cells can become Ts cells and vice versa depending on the state
of the immune system.
Got all that? Oh yeah one more thing, there is such a cell as
the "T contra suppressor" cell. It works against Ts cells.
So the regulating Ts cells are in turn regulated by T contra suppressors.
Just when you thought you had it all sorted out huh?
Natural
killer cells / third population cells / delta-gamma T lymphocytes
Just to confuse the issue even more, one designation which you
should be aware of (and is probably very important in alopecia areata)
is the distinction of T cells as alpha/beta or delta/gamma cells.
What we are referring to are the molecules that make up the T cell
receptor (TCR). Now there are many receptor molecules on a T cell
that will link to other molecules and trigger different functions,
but the TCR is THE key receptor. We will discuss the T cell receptor
in more detail later but for now recognize that the TCRs on a T
cell surface are the method by which Tc cells bind to target antigens
they are seeking to destroy and the receptor that Th cells are stimulated
through by antigen presenting cells.
There are two types of TCR. Naturally enough, TCR-1 and TCR-2.
TCR-1 is made up of two polypeptide molecules called delta and gamma
polypeptides. TCR-2 is made from two molecules, alpha and beta polypeptides.
95% of T cells have TCR-2 on their cell surface, the other 5% have
TCR-1. The TCR-2 bearing cells can be divided into the Th or Tc/s
populations described above. The big question for alopecia areata
is whether the delta/gamma T cells are a rogue population that are
part of the initial trigger response. delta/gamma T cells are probably
primitive T cells and they congregate at the site of initial pathogen
entry into the body. They have a particular propensity for accumulating
in the skin. These primitive T cells are relatively non-specific
in their attack and destruction of pathogens.
These cells don't fit into the standard classification method
using CD markers to define them as CD4+ or CD8+. Their cytotoxic
activity suggests they should be CD8+ and sometimes they are (hurrah),
but sometimes they're not (boo). Note that the mechanisms of killing
described for Tc cells above also applies to natural killer (NK)
cells. Natural killer cells are able to directly kill certain tumor
cells, viral infected cells and anything coated in IgG antibody.
Natural killer cells are regarded as loose cannons. They can be
extremely useful but they don't always follow the rules of the game
which makes them dangerous in the eyes of some immunologists.
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