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Introduction
The human body is capable of distinguishing self from non self
and this is most apparent in rejection of grafted organs skin
and blood transfusions. The immune surveillance system constantly
checks the type of molecular structures present on cells and tissues
throughout the body. So long as these cell surface antigens are
familiar to the immune system and are part of self no inflammatory
response is initiated. However, if the immune system finds cell
surface antigens that it does not recognize as self then immune
attack and destruction of the offending cells swiftly follows.
We have commented on the humoral immune system and the ability
of antibodies to recognize foreign antigens and help in their
destruction. However, in cell and tissue rejection, as in a graft,
blood transfusion and most autoimmune diseases the dominant method
of immune system rejection is cell mediated involving antigen
presenting cells, T helper and T cytotoxic cells. This chapter
looks at how these cell types recognize antigens and how they
interact with each other, the rest of the immune system and other
body cells via cytokines. First, we must consider the types of
antigens T cells recognize and the T cell receptors they use to
latch on to these antigens.
Major
histocompatibility complex
There are several different classes of cell surface antigens that
are important in acceptance or rejection of cells in grafts or blood
transfusions. The most important is the "Major Histocompatibility
Complex" or "MHC". The MHC goes under different names
in different species. In mice it is called H-2, in humans it is
called HLA for "Human Leucocyte Antigen". Whatever, we
will call it MHC which is universally applied to all species. MHCs
are coded for by a cluster of genes that in humans are situated
together on chromosome 6. There are several hundred genes involved
which are classically divided into three groups, genes involved
in class I, class II or class III complexes. We will focus on just
class I and class II. The class III gene group codes for some molecules
involved in the complement system we mentioned in chapter 5. The
genes are positioned in blocks adjacent to each other. In Humans
the Class II genes are subdivided into three groups called DP, DQ
and DR. Next, in the middle sits the class III genes and at the
other end of the gene cluster the class I gene are subdivided into
three groups A, B and C.
MHC class I type are distinct in structure from class II MHC.
Class I MHCs are made up of one large polypeptide chain, the alpha
chain which is coded for by MHC class I genes and about 45kilodaltons
in weight. A small beta chain of 12kilodaltons sits on the alpha
chain but is coded for by non-MHC genes. An alpha chain may come
from genes in the A, B or C subgroup and so we can have more than
one type of MHC molecule in our bodies. Class II MHC molecules are
coded entirely by MHC genes and consist of two similar polypeptide
chains each about 30kilodaltons, again one called alpha the other
beta. The chains may come from the DP, DQ, or DR gene groups so
again we can have more than one subtly different type of class II
molecule. Throughout the human population there are around 40 different
MHC class II molecules that we know about so far. All have the same
basic structure but vary subtly in their molecular structure. In
the same way there are at least 80 known variants on the Class I
type MHC molecule.
It is possible to tissue type a person by serological or genetic
analysis to define which MHC class I or II molecules each person
has. MHC genes are a focus of extensive research because their the
MHC structures they code for are so important in the immune system.
When you hear about MHC molecules at conferences or in research
reports you might hear one called for example HLA-B17. This means
it is a human leucocyte antigen from the B gene group (hence a class
I type MHC) gene position (known as a gene locus) number 17. Or
gene HLA-DR11, this means Human Leucocyte Antigen coded by a gene
from the DR region (hence a class II type MHC) locus number 11.
For each gene position on a chromosome there can be several possible
bits of DNA code that can be present and each is called an allele.
For example, some people have an allele that codes for green eyes.
A different allele that fits in the same gene position on a chromosome
may code for brown eyes, another allele for blue eyes and so on.
Also remember we have two alleles for each gene position because
we get one from each parent.
Because MHC antigens are so fundamentally involved in the immune
defense system they are also important in determining the overall
response level of the immune system to an antigen. From the pool
of different MHC genes available some genes code for MHC molecules
with superior stimulatory properties compared to others. The reason
for explaining this is that MHCs are probably involved in autoimmune
conditions. Certain gene alleles seem to make people more susceptible
to developing an autoimmune disease than others. MHC gene analysis
in alopecia areata is being conducted by several research groups.
In a healthy human body MHC class I molecules can be found on
just about all cell types and vary in density from cell to cell.
However, class II MHC molecules are much more exclusive limiting
themselves to B lymphocytes, phagocytic cells especially ones involved
in antigen presentation, occasional epithelial cells and a few T
cells. However, while class II molecules are normally found on a
few particular cell types, they can be induced and expressed on
all almost any cell type under certain prolonged inflammatory or
autoimmune conditions.
MHC molecules are first and foremost a method for immune systems
to detect what is part of self and what is foreign tissue. Immune
cells check the MHC molecules on cells. If the molecules tally with
what is expected then the immune cells will not be activated. If
the MHC molecules are foreign then the immune cells will respond.
Of course this MHC molecule marker for self non-self distinction
is not the only antigen system used to define histocompatibility.
When blood or tissue is transplanted from individual to another
doctors must check other histocompatibility molecules involved such
as those in the ABO blood grouping, rhesus system.
MHC
class I
MHC molecules have another function within our own body, they
present other cell surface antigens to T cells for checking to see
if they are self or non-self. T cells are practically blind. Although
they can detect different MHC molecule types they can rarely independently
recognize any other type of antigen, viral, bacterial or otherwise.
They must have antigens presented to them and this is done by MHC
molecules. The class I MHC molecules found on almost all cell types
present antigens to T cytotoxic cells whereas Class II MHC molecules
on antigen presenting cells present antigens to T helper cells.
The cell membrane is a very fluid structure. Molecules within
it can move around and come in to contact with other. Class I MHC
molecules migrate over the surface of cells and find other antigenic
molecules. They have a particular preference for binding to viral
antigens which of course will only be present if the cell is viral
infected. MHC molecules associate themselves with other antigenic
molecules too, they make no distinction between self and non-self
antigens. MHC molecules are not like antibodies which only recognize
one type of antigen. Each MHC molecule will attach to and present
a wide range of antigens just not all antigens. As described above
we have each have a number of subtly different types of MHC molecules.
Each type will have a preference for what form of antigen they are
best able to present to T cells.
Because MHC molecules are fairly flexible in how they bind to
antigens different parts of the same antigenic molecule may be presented
to T cytotoxic cells. Some MHC molecules will be more effective
in their interaction than others because of their binding preferences.
This will determine the ability of Tc cells to respond to the antigen
and will help define how potent the immune response against an antigen
will be. MHC molecule presentation of different parts of an antigen
will ensure more than one type of Tc cell will be activated to target
the same antigen.
MHC
class II
MHC class I molecules are found on almost all cells and alert
the Tc cells to any infection or damage in body tissues. MHC class
II molecules have a different role as they are normally restricted
to presence on antigen presenting cells (APCs). APCs are phagocytic
cells that ingest any cellular debris or potentially antigenic particles.
APCs make no distinction about what they phagocytose, it can be
self or non-self material. The material is broken down inside the
cells into small fragments and these are then released to the APCs
cell surface. Here, MHC class II molecules bind to the antigenic
fragments ready for presentation.
Because the antigens have been processed, they are much smaller
than the antigens that MHC class I molecules present. Indeed, Structural
differences in MHC class II molecules mean they can only present
small, extensively processed antigens. As with MHC class I molecules,
MHC class II molecules are quite flexible in how they bind to an
antigen and what part of it they present. The same antigen can be
presented in several different ways to elicit an immune response
from different cells. The responding cells to MHC class II presentation
are T helper cells. Th cells are involved in helping Tc cells in
their activity and also in B cell production of antibodies. Th activation
by MHC class II is therefore extremely important in our overall
defense from pathogens.
T
cell receptors
We know that B cells use antibodies attached to their cell surface
to detect foreign antigens that they should respond to and start
to produce more antibodies for release in to the blood stream. T
cells also have receptors to detect foreign antigens. These T cell
receptors (TCRs) are somewhat similar in their structure and antigen
binding mechanisms to antibodies. Indeed antibodies and TCRs are
evolutionary related to each other. In fact MHC class I and class
II, TCRs, antibodies, CD4 and CD8 T cell receptors are all similar
in structure and are described as belonging to the "immunoglobulin
superfamiliy". You might remember I mentioned some confusion
over calling antibodies immunoglobulins. Strictly speaking although
immunoglobulins are antibodies, they are also TCRs, MHCs etc. The
word immunoglobulin describes the nature of the molecular structure.
Antibodies, TCRs etc are all made from one or more polypeptide chains
linked and looped together by disulfide bonds. The loops of polypeptides
are "globular" domains and the overall structures are
important in the immune system, hence the word "immunoglobulin"
describes more than just antibodies.
TCRs bind to antigens but only when they are presented by MHC
molecules. Each T cell may express numerous TCRs on its cell surface
but the TCRs are only able to bind to one antigen. A different T
cell will have TCRs that bind to a different antigen structure.
So the T cell population is much like the B cell population. Each
cell can only recognize and respond to one type of antigen but as
a whole the T cell population can respond to practically all types
of antigen we are ever likely to be challenged by during our lives.
CD4
and CD8 molecules
TCRs will not recognize antigen on its own, it must be presented
physically attached to an MHC molecule. Plus of course TCRs on Th
cells will only recognize MHC class II and TCRs on Tc cells will
only recognize MHC class I. In addition there is another mechanism
to ensure this clear distinction between which class type MHC molecules
Tc or Th cells will respond to. When a TCR binds to an MHC molecule
and an attached antigen the CD4 or CD8 molecules come in to play.
As mentioned before Th cells are also called CD4 cells because they
have CD4 molecules on their surface. Tc cells are also called CD8
cells due to the presence of CD8 molecules. When a TCR binds to
MHC the CD4 or CD8 molecules must also bind to the MHC to make a
strong bond. CD4 will only bind to MHC class II. CD8 we are less
sure about but probably it only binds to MHC class I.
Enforcing this distinction between what MHC molecule a Th or a
Tc cells will recognize makes sense. Tc cells are destroyer cells
directly involved in removing damaged or viral infected cells. Class
I MHC is found on all cells and presents antigens on these cells
so Tc cells must be able to recognize MHC class I to ensure that
Tc cells can remove infected cells whatever or wherever they are
in the body.
Th cells are regulator cells they help amplify a Tc and/or B cell
response or stop an inappropriate one from developing. Its important
that Th cells are only activated by a limited set of specialized
APCs. If a wide range of cells were able to activate Th cells there
may be the possibility of an inappropriate immune response. Unfortunately
this can be the case in prolonged inflammatory events. All nucleated
cells of the body have a full set of chromosomes and genes. The
fate of a cell, whether it becomes a fibroblast, a brain cell, a
lymphocyte etc. depends on which genes are switched off or on inside
the cell. Some genes will dictate the cell should be a lymphocyte
other genes dictate it should be brain cell. Sometimes inappropriate
genes can be switched on in the wrong cells (as occurs in cancer).
MHC class II genes can be switched on in tissue cells if given the
right stimuli. Prolonged inflammation is one known method of inducing
MHC class II expression on tissue cells in the area of inflammation.
Sometimes this is a good thing as it may Further stimulate Th cells
in the area and encourage a more potent immune response to damaged
or infected cells. A prolonged inflammatory response suggests the
immune system is having trouble removing the antigenic challenge
so an extra boost from localized MHC class II expression can be
beneficial. However, MHC class II can equally promote inappropriate
immune activity such as in autoimmune conditions. Prolonged autoimmune
activity will stimulate expression of MHC class II on healthy tissue
cells. Cells of the hair follicle when inflamed in alopecia areata
are known to express MHC class II.
This promotion of MHC class II expression is the result of chemical
molecule stimulation by inflammatory cells in the area. So far we
have looked at communication between cells in terms of physical
contact or presentation of antigen and activation of immune cells
through cell surface receptors. However, the immune system has a
long distance communications network involving production of numerous
different molecules. Different types of molecule have different
actions on other immune cells, tissue cells and even directly on
invading pathogens. These molecules are "cytokines".
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