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The Major Histocompatibility Complex
The major histocompatibility complex (MHC) is another example of historical
nomenclature in immunology. The name stems from work in the early 20th
century on transplant experiments. It was demonstrated that transplants
between species always failed, transplants between animals of the same
species almost always failed, but transplants within one animal (almost) never
failed. The molecules found to be important for this were named as tissue
compatibility complexes. However the name MHC does not give any
indication as to their normal function, namely presenting antigen to Tlymphocytes. The MHC is sometimes referred to as HLA (Human Leukocyte
Antigens) but the terms are essentially synonymous.
One of the important differences between T- and B- lymphocytes is the type of
antigen that they respond to. B-cells respond to native antigens on the surface
of pathogenic organisms. T-lymphocytes were demonstrated to respond to
short contiguous sequences of amino acids. These amino acids are derived
from the invading organisms and then presented by the MHC molecules on
the cell surface. Strictly, the T-cell receptor does not bind antigen, instead it
binds the combination of antigen and MHC molecule.
The genes for the MHC molecules are found in one region of chromosome 6
that contains more than 100 genes.
The MHC molecules
The MHC molecules are glycoproteins and are part of the immunoglobulin
superfamily. There are two classes of MHC that have a slightly different
function. They have very different amino acids sequences but very similar
three-dimensional structure. They are known as MHC-I and MHC-II.
MHC-I is made up of four domains. Three of these domains are formed by one
peptide - the -chain (an MHC glycoprotein) - and the fourth domain is
provided by a non-MHC encoded molecule named 2-microglobulin. The
three domains of the -chain are named andandform the
peptide binding cleft where the antigen is presented to the T-cell receptor and
contains a trans-membrane region that binds the whole molecule to the cell
membrane. (See diagram below).
MHC-II is very similar and is made up of an and achain, both of which are
coded for by the MHC region in chromosome 6. Each chain has two domains;
1 and 1 form the peptide binding cleft and both 2 and 2 are membrane
bound.
MHC-I is found on all nucleated cells and is central to anti-viral immunity.
MHC-II, by contrast is found on a small number of specialist cells known
collectively as antigen-presenting cells (APCs). Antigen presenting cells
include macrophages, B-lymphocytes, cytotoxic T-lymphocytes and several
others. Cytotoxic T-cells express the molecule CD8 with the T-cell receptor.
CD8 binds to MHC-I and not MHC-II. For this reason Cytotoxic T-cells bind
to MHC-I. T-helper cells do not express CD8 but do express CD4 which works
in a similar but contrasting way – it binds to MHC-II only and thus T-helper
cells only bind to MHC-II. Hence the molecules CD4 and CD8 are very
important in defining the function of different T-lymphocytes. This is why Thelper cells are also know as CD4 cells and cytotoxic T-cells as CD8 cells.
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Antigen Processing
The peptide antigens are small (~6-8 amino acids) and non-covalently bonded
to the MHC molecules. Hence they use van-der-Waals interactions, ionic
charge etc. to bind. Proteins are broken down to peptides continuously by
mechanisms within the cell. These peptides are then bound to MHC molecules
that then move to the cell surface. The process of antigen processing is slightly
different between MHC-I and MHC-II but the principal is the same that
peptide antigens are produced that are then expressed on the cell surface. In a
non-infected cell the antigens presented by MHC-I will be self-antigens and
the T-lymphocytes will not bind to the cell. If however the cell is infected then
peptides presented will be viral peptides and the T-cell receptor will bind and
initiate killing of the infected cell. In a similar way APCs such as Blymphocytes will process antigen and present it on their MHC-II molecules.
The binding of the B-cell to a T-helper cell induces the T-helper cell to release
certain cytokines that trigger various parts of the immune response.
MHC Genetics
The genetics of the MHC are very unusual and have been intensely studied.
Unusually, instead of having two genes for the MHC-Ichain, each
individual has 6 (3 on each chromosome). These are known as HLA-A, -B and
–C. They are all co-expressed, so that each individual has 6 different MHC
molecules on each cell. Similarly the MHC-II has multiple genes; they are DP,
DQ and DR. Each chromosome 6 has a DPand a DPSimilarly, each has a
DQand a DQas well as a DRand one or two DPgenes. This concept
(called polygeny) means that each individual expresses a range of MHC
molecules.
Polygeny is functionally very significant as each MHC molecule binds a
different range of peptides. MHC-I molecules present viral antigen to
cytotoxic T-cells, enabling the virally infected cell to be killed. It is very
possible that if each cell had only one MHC type, a virus could evolve proteins
that, when broken down by the cell's machinery formed peptides that could
not be presented by that MHC molecule. Such a virus would be lethal as it
would be 'invisible' to the immune system. By expressing 6 different MHC-I
molecules the cell is able to present to T-cells a very wide array of antigens.
For example, some MHC molecules present positively charged peptides;
others, negatively charged and others, non-charged peptides.
An inevitable question that arises at this point is why only 6 MHC molecules
per cell – why not 10, 20, 100? The answer is thought to be self-tolerance. A
cytotoxic T-cell that binds to an MHC-A molecule (for example) plus foreign
antigen may bind to a MHC-B molecule plus a self-antigen due to structural
similarities. Any T-cells that do respond to self-antigens are eliminated and
thus if there were a large number of MHC molecules, the repertoire of T-cells
would be dramatically reduced and thus the immune system would not be able
to respond to these infections. It is generally thought that the number of
molecules of MHC expressed is a balance – enabling as many antigens as
possible to be presented whilst maintaining as large a repertoire of T-cells as
possible. This cross-reactivity of T-cells is the mechanism of transplant
rejection. T-cells respond to the MHC molecules that are non-self as though
they were presenting foreign antigen. For this reason ‘transplant matching’ is
about matching the MHC types between the donor and recipient. The reason
that transplants still fail is that the matching is imprecise and even if two
individuals have apparently the same MHC types, they may still differ because
the MHC is an incredibly variable region of the human genome.
The concept of polymorphism of the human genome is an important part of
immunity on the species level. There are 25 known variants of the HLA-DQ
locus and 16 of the DQ, meaning that there are literally hundreds of different
DQ MHC-II molecules in the human population. The same principal applies to
each of the MHC genes (except that DRhas only one known allele). This
variability means that whilst some pathogens may be lethal to the individual,
it is much more difficult for the said pathogen to be able to evade the immune
system of entire populations.
As well as the MHC genes, included in this region of chromosome 6 are several
other genes (and also pseudogenes). Examples include the genes for
complement proteins C4, C2 and Factor B, the cytokines tumour necrosis
factor  and  and TAP genes. The TAP genes (Transporters associated with
Antigen Processing) encode for the proteins TAP-1 and TAP-2 that function in
antigen processing, breaking down intracellular proteins to the small peptides
that MHC molecules present.
Fighting Viral Infections
The MHC plays a central role in fighting viral infections: MHC-I on all cells
presents peptides from intracellular proteins that necessarily will include viral
peptides if the cell is infected. It is this combination of MHC molecule and
viral peptide that cytotoxic T-cells respond to.
The MHC-II molecule has a different role and is important in fighting both
bacterial and viral infections. Its function is discussed more fully in the section
on T-helper cells.