This large and important set of genes owes its
rather clumsy-sounding name to the
fact that the proteins it codes for were first detected by their effect on
transplant rejection, i.e. tissue incompatibility. However, it is now
clear that their real purpose is to act as receptors binding and stabilizing
fragments of antigen and displaying them at the cell surface for T lymphocytes
to recognize, via their own receptors, and activate their adaptive
immunological functions.
Again, for historical reasons, the
MHC in the mouse (extreme bottom line in the figure) is known as H2,
while in humans it is called HLA (human leucocyte antigen). In fact the
basic layout of the MHC genes is remarkably similar in all animals so far
studied, consisting of a set of class I (shaded in the figure) and a set of
class II genes, differing slightly in structure and in the way they interact
with T cells (see Fig. 12). In the figure the names of genes are shown boxed, while the numbers below indicate the
approximate number of alternative
versions or alleles that can occur at each locus. Perhaps the most
striking feature of the MHC is the number of different variants that exist in
the human population. The number of possible combinations on a single chromosome
probably exceeds 3 × 106, so that an individual, with a set of
MHC molecules coded for by both chromosomes, can have any one of about 1013
combinations, which is part of the problem in transplanting kidneys, etc. (see
Fig. 39).
Since HLA typing became a routine
procedure, it has emerged that many diseases are significantly more common, or
sometimes rarer, in people of a particular HLA type. There are several
mechanisms that might account for this but none of them has yet been
established to everybody’s
satisfaction.
Peptide-binding cleft The classic MHC I and II molecules contain a
peptide-binding site at the distal end of the molecule from the membrane,
formed by two protein α-helices, lying on top of a β-pleated sheet. The binding
site, or groove as it is often known, can accommodate a peptide of about
9–10 amino acids in length, although for class II MHC molecules, the ends of
the groove are open allowing longer peptides to extend out of either end. A
wide variety of different peptides can be bound tightly, by interaction between
conserved residues in the MHC molecules and the amino acid backbone of the
antigen peptide. In order to accommodate the side-chains of the larger amino
acids, however, the floor of the groove contains a number of pockets. It is the
size and position of these pockets that limit the range of peptides that can be
accommodated, focusing the immune response onto only a few defined epitopes.
H2 The MHC of the mouse, carried on chromosome 17.
There are at least 20 other minor histocompatibility genes on other
chromosomes, numbered H1, H3, H4, etc. but H2 is by far the strongest in
causing transplant rejection and the only one known to be involved in normal cell
interactions.
HLA The human MHC, on chromosome 6, closely
analogous to H2 except that the class I genes lie together and there are three
class II genes.
Class I region Class I MHC molecules load peptides derived
from the cell cytoplasm (see Fig. 18) and have probably evolved to activate
cytotoxic T cells against viruses infecting the cell.
A, B, C The classic human class I genes that present
processed peptide antigens to the antigen receptor of CD8 T cells. A is the
homologue of K in the mouse.
K, D, L The class I genes of H2, coding for the α chain
(MW 44 000), which in combination with β2-microglobulin (see below) makes up
the four-domain K, D and L molecules or ‘antigens’. β2M β2-Microglobulin (MW
12 000), coded quite separately from the MHC, nevertheless forms part of all
class I molecules, stabilizing them on the cell surface. In the mouse there are
two allelic forms, but in general β2M is one of the most remarkably conserved
molecules known. It is also found free in the serum.
Class IB genes Both human and mouse MHC loci encode a large number
(around 50) of genes that code for proteins with a class I-like structure,
known as class IB genes. These include Qa and Tla in the mouse, and E, F, G, H,
J and X in the human. The function of many of these remains unknown, but some
may play a part in controlling innate immunity, perhaps by regulating NK cell
activation. Some class IB genes lie outside the MHC locus. One such is the CD1
family that is specialized for binding glycolipids, especially from
mycobacteria, and presenting them to some types of T cells and NK cells.
Class II region As well as the classic class II genes involved
in antigen presentation (see below), the class II regions of both mouse and
human genome contain genes encoding a number of other molecules involved in the
antigen processing pathway (see Fig. 18). These include DM and DO (H2-O and
H2-M in the mouse), class II MHC-like molecules that regulate the loading of
peptide fragments onto DP, DQ and DR. The region also contains the LMP genes
and the TAP genes (see Fig. 18). region
also contains the LMP genes and the TAP genes (see Fig. 18).
A, E The classic class II genes of H2, which present processed peptide
antigen to the antigen receptor of CD4 T
cells (see Figs 18, 19 and 21). A and E contain separate genes for the α (MW 33
000) and β (MW 28 000) chains of the four-domain molecule. Unlike class I,
class II molecules are expressed only on a minority of cells, namely those that
CD4 T cells need to interact with and regulate (see Fig. 12).
DP, DQ, DR The classic human class II genes, which present
processed peptide antigens to the antigen receptor of CD4 T cells. The
distribution of these different class II molecules within the body is slightly
different, but it is still unclear whether each one has a distinct role in the
regulation of T-cell responses.
Polymorphism The classic MHC genes in both human and mouse
exist in many different alternative (allelic) variants, making these genes the
most polymorphic known. The differences between allelic forms lie mostly within
or close to the peptide-binding groove, and result in the different alleles
binding to different peptide fragments from a particular protein antigen.
However, there is also a great deal of polymorphism in the promoter regions of
class II MHC, suggesting that the levels of MHC expressed at the cell surface
may also be very important. Because MHC molecules are expressed codominantly
(i.e. each cell expresses both paternally and maternally inherited alleles),
this increases the number of antigens from each pathogen that can be presented
to the immune system, and hence makes the immune response more vigorous. Some
HLA alleles (e.g. A1 and B8) tend to ‘stay together’ instead of segregating
normally. This is called ‘linkage disequilibrium’ and may imply that such
combinations are of survival value. For example, some HLA alleles have been
shown to be linked with a more effective control of HIV, and a slower
development of AIDS (see Fig. 28). Not all species show equally great MHC poly-
morphism: the Syrian hamster, for example, shows little class I variation,
perhaps reflecting its isolated lifestyle and hence decreased susceptibility to
viral epidemics.
C2, C4, FB Surprisingly, a large number of genes that are
structurally unrelated to the classic MHC genes are coded for within the MHC
locus. These ‘class III’ genes include several with immunological function such
as complement components involved in the activation of C3, and members of the
TNF cytokine family important in inflammation. Although they are less
polymorphic than the MHC class I and II genes, some of the genetic association
between diseases and the MHC locus may be explained by genetic variation of
these class III genes.
HLA-associated diseases (see also Fig. 47). Many diseases show genetic
associations with particular HLA alleles. The most remarkable example is the
rare sleep abnormality narcolepsy, which virtually only occurs in people
carrying the DR2 antigen; the reason is quite unknown. After this, the most
striking example is the group of arthropathies involving the sacroiliac joint
(ankylosing spondylitis, Reiter’s disease, etc.) where one HLA allele (B27) is
found in up to 95% of cases, nearly 20 times its frequency in the general
population. But numerous other diseases, including almost all of the autoimmune
diseases, show a statistically significant association with particular HLA
antigens or groups of antigens, especially in the class II region. The
explanation probably lies in the ability or otherwise of the HLA molecule to
present particular microbial peptides or, alternatively, self-antigens.
