Book: Don't Touch That Doorknob!
What does the word, histocompatibility, mean?
The level of histocompatibility between and among individuals is
primarily dependent upon the similarity of the pattern of structures of
the MHC molecules uniquely expressed by the individuals involved. To be
histocompatible literally means that if skin is grafted, one individual's
skin is compatible with another, i.e., the donor skin will be accepted
and will not be rejected by the recipient's immune system as foreign. The
term "histocompatibility" therefore originally involved
only
skin compatibility between animals of varying degrees of genetic
difference. However, as we know today, this term applies not only to the
acceptance of foreign skin but also to the acceptance of foreign tissue
of all types such as a liver, kidney, lung, heart, etc., - all manner of
organ transplants. When an organ transplant is planned, both individuals
must be carefully examined for their relative degree of genetic
similarity. In this case, the degree of genetic sameness depends not
only upon the blood group to which an individual belongs, but also
depends upon the particular forms of MHC molecules among humans that are
expressed upon the cell surfaces within each individual. Therefore, it is
the expression of the various forms of MHC molecules unique to the
individuals that ultimately determines whether or not the graft will be
accepted by the recipient's immune system.
Are all MHC molecules identical to one another?
MHC molecules fall into two basic classes - known as MHC Class I (Roman
numeral "one") and MHC Class II (Roman numeral "two") molecules.
Every
individual inherits two sets of each class, one set from the mother and
one set from the father. Both sets of either MHC Class I or MHC Class
II, or sometimes, both MHC Class I and MHC Class II, are expressed by
cells within an organism. These molecules subsequently appear on the
surface of each cell within the individual and participate in induction
of an immune response against an invader. The class of each MHC molecule
expressed on a given cell's surface, however, depends upon the type of
cell involved.
Which cells within the individual express these molecules?
All nucleated cells (mature erythrocytes, i.e., red blood cells, within
humans do not have a nucleus) equally express on their surface, both sets
of inherited MHC Class I molecules. However, only certain cells of the
immune system, i.e., B-lymphocytes, macrophages and certain dendritic
cells additionally express both sets of MHC Class II molecules on their
surface. Because of their capacity to express MHC Class II molecules,
each of these three categories of immune system cells are also known as
an antigen-presenting cell, or APC. This last term means that
B-lymphocytes, macrophages and the appropriate dendritic cell can each
present parts of proteins taken up (internalized) by the APC, to T
lymphocytes.
How is the immune response dependent upon MHC molecules?
1. Humoral (antibody production) immune response
Here is how MHC molecules and the immune system work together
to remove or kill foreign substances, cells, or microorganisms such as
viruses and bacteria. We'll first take a look at how the immune system
removes a foreign protein, such as something like tetanus toxin, a
protein produced by the bacterium, Clostridium tetanii. If a deep
puncture wound (little to no oxygen at the bottom of the wound because of
trauma-induced cell death and lack of oxygen flow) becomes infected by
this bacterium, the toxin will be produced and will enter the
bloodstream. Once into the blood, the toxin will eventually be taken up
by a neutrophil through a process known as phagocytosis (cell eating).
If there is any material remaining, the toxin can eventually land inside
a lymph node. There, dendritic cells and macrophages as well as
toxin-specific B-cells can bind and internalize the toxin. Inside these
cells, the toxin will be chopped into fragments by special enzymes and
these fragments will finally associate with MHC Class II molecules.
These MHC Class II molecules with their associated toxin fragment will be
transported and displayed on the surface of these cells. At this point,
a particular kind of T-cell, a helper T cell, with receptors that
interact specifically and simultaneously with MHC Class II shapes and the
toxin fragment shape will be activated to divide and to produce
substances. These substances, known as cytokines, can stimulate
activated B cells to produce antibody molecules - soluble molecules that
bind specifically to molecular shapes on substances. The only B cells
that will be activated are those B cells that reacted with the toxin in
the first place. Therefore, the overall response will lead to production
of millions of antibody molecules specific for various toxin fragments
and similar shapes on the native toxin molecule. Once antibody binds to
the native, non-fragmented toxin molecule anywhere the toxin is in the
system, the toxin can easily be engulfed by macrophages and destroyed.
2. Cell mediated immune response
In this instance foreign cells or cells infected with an intracellular
agent like a virus or intracellular bacterium will be eliminated from the
body. This process of elimination of infected cells depends upon MHC
Class I molecules - as well as MHC Class II molecules. When a virus
infects a cell, viral proteins necessary for new virus particle assembly
will be produced inside that cell. These viral proteins are treated
exactly like all other intracellular proteins the cell makes for its
survival. This treatment is to fragment a portion of all of the proteins
that are synthesized inside the cell - no matter the origin of the
protein. Some of these fragments end up associating with MHC Class I
molecules and the complex is transported to the cell surface and
displayed there. Consequently, each nucleated cell in a person's body is
constantly displaying parts of itself. These parts are recognized by
another kind of T cell, a cytotoxic (cell killing) T cell. Some of these
cells will have receptors that can bind to MHC Class I shapes and
simultaneously bind to foreign protein shapes that are complexed with MHC
Class I molecules. There should not be any such T cells that can bind to
any fragment shapes that belong to the cell itself. Therefore, whenever
a fragment of a virus protein appears on the cell's surface in complex
with a MHC class I molecule, there will be a cytotoxic T cell that can
specifically interact with this complex. The interaction leads to
activation of the cytotoxic T cell and this activation step prepares the
cell to release cell killing substances. However, the cytotoxic T cell
will not release these killing substances without
"permission" from a helper T cell. Therefore, if a helper T
cell has been activated by interaction with an antigen presenting cell
that is presenting viral protein fragments via MHC Class II molecules,
this T cell will release cytokines that will signal the cytotoxic T cell
to release the killing substances. Then, the cytotoxic T cell will
therefore kill the cell that contains the virus, and thus eventually will
rid the body of the virus.
What does all of the above have to do with organ transplants?
Tissue - human or otherwise - genetically foreign to our body, means that
the MHC Class I and II molecules expressed on the surface of the
tissue that is foreign to us, are molecularly recognized by our helper and
cytotoxic T cells. It is a quirk of nature that foreign
histocompatibility molecules are recognized by our own immune system
cells as if the histocompatibility molecules were our own that are
presenting foreign protein fragments. Among all animal species
and indviduals within species, histocompatibility molecules are actually
very, very similar with respect to the variety of similar shapes.
Because they possess so many similar shapes among them, each
individual will have T cells that can interact with a portion of these
molecules as if they were our own. But, the fact that histocompatibility
molecules among species and individuals within a species also possess
shapes that are different among them, these different shapes are responded
against as if they were fragments of foreign protein being held by one of
our own MHC molecules. Thus, the immune system is "fooled" into
"thinking" that a foreign protein or fragment is beng presented
by our own APC via Class II molecules, and/or by our own tissue via MHC
Class I molecules. Foreign tissue is therefore "perceived" as
our own tissue that is infected with a virus or intracellular bacterium.
Consequently, the tissue wil be killed and therefore rejected. It is for
these reasons that tissue transplants must be as closely matched as
possible with respect to the inherited MHC molecules' shapes expressed by
the donor and recipient of the transplant. One reason liver transplants
are relatively more common is that liver cells for one reason or another,
do not express a high level of MHC Class I molecules on their surface.
Therefore, these cells are relatively more "hidden" from
cytotoxic T cells and thus more readily escape detection. If the
cytotoxic T cell cannot bind very well via its receptors to the target
cell, the cytotoxic T cell will not be activated and will therefore not
kill the target. Thus, the traspanted tissue can remain without harm.
Book: Don't Touch That Doorknob!