HLA MHC Genetics Evolution Epidemiology Biostatistics Glossary Homepage
Major
Histocompatibility Complex
M.Tevfik Dorak, MD, PhD
The major histocompatibility
complex (MHC) is a set of genes with immunological and non-immunological
functions and present in all vertebrates studied so far 1;2. It was
discovered during transplantation studies in mice (as the H-2 complex) by Peter
A Issac Gorer in the Lister Institute in London in 1937 who later collaborated
with George Snell of the Jackson Laboratories in Ben Harbor 3;4.
Jean Dausset described the first human MHC antigen MAC (HLA-A2) as part of the Hu-1
system 5 followed by the discovery of the FOUR series 4a and 4b
(HLA-Bw4 and -Bw6) by the Leiden group led by Jon van Rood in 1963
6;7. Rose Payne and Walter & Julia Bodmer identified the LA
series (1964).
Bernard Amos, who had originally worked with Gorer, organised the first
International Histocompatibility Workshop in 1964 and the first WHO
Nomenclature Committee Meeting in 1968 (see IHWG website; Marsh,
2004). See full references for early MHC-HLA work.
The function of the MHC can be
described as pleiotropic, i.e., multiple unrelated ones 8-11. It is
best known with its role in histocompatibility 12 and in immune
regulation 13-17 with many
other functions not much appreciated yet 2;18-22. The main
function of the main MHC molecules is peptide binding and presentation of them
to T lymphocytes. Among the non-immune functions, the noteworthy ones are
interactions with other receptors on the cell surface 23;24, in
particular with transferrin receptor (TfR), epidermal growth factor 25
and various hormone receptors 26-28, and
signal transduction 29.
In nature, different taxa of
multicellular organisms have unrelated compatibility systems such as the
protozoan pheromone system 30;31, the fungal compatibility system 32-35,
angiosperm (flowering plants) self-incompatibility system 33;36, and
the invertebrate allorecognition systems 37-39. All of
these systems are primarily involved in prevention of matings between
genetically similar individuals to avoid the harmful effects of inbreeding. The
MHC also prevents inbreeding through its influence on mate choice in mice 40;41
and humans 42;43; and on reproductive processes in rats 44,
mice 45;46 and humans 47;48. The reproductive mechanisms
are varied and range from selective fertilization to selective abortion. A
major common feature of the compatibility systems is that they favour genetic
dissimilarity between mates and the gametes (mate choice, selective fertilization);
but similarity in co-operation (kin recognition, dual recognition, transplant
matching) 49;50. All these functions are based on the provision of a
phenotype for the genetic identity of the individual by the MHC: either cell
surface molecules or chemosensory signals.
MHC
structure
The MHC in humans is called Human
Leukocyte Antigens (HLA). It is located on chromosome 6p21.31 and covers a
region of about 3.6 Mbp depending on the haplotype 1;51. The longest
haplotype is the HLA-DR53 group haplotypes because of the 110-160 kb extra DNA
in their DR/DQ region 52-56. The HLA
complex is divided into three regions: class I, II, and III regions as first
proposed by Jan Klein in 1977 57. The telomeric region to the
classical HLA complex is now called the class Ib region; and there has also
been a suggestion for a class IV region located at the telomeric end of the
class III region 2. The classical HLA antigens encoded in each
region are HLA-A, -B, and -C in the class I region, and HLA-DR, -DQ and -DP in
the class II region. All class I genes are between 3 and 6 kb, whereas, class
II genes are 4-11 kb long 58. The 1998 Nomenclature Committee
recognized more HLA genes all of which are in the class I and Ib regions:
HLA-E, -F, -G, -H, -J, -K and -L 59.
Among those, only HLA-E, -F and -G are expressed 60. The massive
sequencing project of a human MHC haplotype has just been completed and the map
positions of all of these genes are known 51. The class III region
has the highest gene density but some of the genes are not involved in the
immune system 2;61. Among the genes which are of interest, HSP70,
TNF, C4A, C4B, C2, BF and CYP21 should be mentioned. The HSP70 genes encode
cytosolic molecular chaperons and might have donated to the PBR region to the
ancestor MHC gene 62. It has also been proposed that HSP70 may be
the functional forerunners of MHC molecules because of their peptide binding
and presenting abilities 63. By presenting intracellular contents of
a cancer cells to the immune system, HSP70 behaves like a tumour rejection
antigen 64-68 similar
to the other molecular chaperons, calreticulin and grp94/gp96 67-69. An
important feature of HSP70 alleles makes this locus a useful one in disease
association studies. They show strong linkage disequilibrium (LD) with HLA-DR
alleles 70-72. TNF(A)
and TNFB (LTA) genes encode cachectin and lymphotoxin-a
molecules, respectively 2;73. C2, C4A and C4B are the genes for some
of the complement proteins, whereas, BF codes for factor B which is also
involved in immune response 74;75. CYP21 is the gene for
21-hydroxylase which is an important enzyme in corticosteroid metabolism. Its
complete deficiency causes congenital adrenal hyperplasia which was the first
disease identified to be the result of a structural change in an HLA-linked
gene 76. Other genes of interest in the class III region are the
human homologue of the mouse mammary tumour integration site Int-3, NOTCH4, and
the homologue of a homeobox gene similar to PBX1 involved in t(1;19)
translocation in pre-B cell ALL encoded on chromosome 1q23, PBX2 (or HOX12) 2;77-79.
Classical
genetics
A highly relevant feature of the
MHC antigens is their co-dominant expression. Since both alleles contribute to
the phenotype equally, it is important to investigate the genotypes in disease
association studies rather than the alleles on their own. If susceptibility to
a disease is a recessive trait, allelic association studies may not yield a
positive result. Also important is the fact that the MHC is inherited en
bloc as a haplotype with the exception of the rare recombinational events.
Recombination occurs at 1-3% frequency mostly at the HLA-A or HLA-DP ends,
i.e., in 100 meiosis the haplotype will be broken and reconstituted in one to
three of them. The large segment from HLA-B to HLA-DQB is almost always
inherited as a whole. This also has important implications in disease
associations. A haplotypical association is usually stronger and more
meaningful than an allelic association.
The co-dominant expression and
haplotypical transmission have an important consequence: within a family,
HLA-identical sibling frequency should be 25% according to Mendelian
expectations. This has been, however, found to be higher than that in leukaemia
80-84. This would suggest preferential
transmission of leukaemia-associated HLA haplotypes 85. The fact
that HLA-identical sibling frequency is higher than 25% in leukemic families
should not be confused with the overall chance of having an HLA-identical
sibling which is correlated with the family size (equal to [1 - (0.75)n]
where n is the number of siblings). This probability may go up to 55% in areas
where families are traditionally large 86.
Despite the enormous number of alleles
at each expressed loci, the number of haplotypes observed in populations is
much smaller than theoretical expectations. This is to say that certain alleles
tend to occur together on the same haplotype rather than randomly segregating
together. This is called linkage disequilibrium (LD) and quantitated by a D value 87;88.
The public specificities, also
called supertypes and sometimes wrongly broad specificities, group a number of
private specificities. In the HLA class I region, all HLA-B private specificities
are grouped into two supertypical families: HLA-Bw4 and -Bw6. In recent years,
the nature of HLA-B supertypes has been better understood. They are not encoded
by a different gene. The antigens HLA-Bw4 and -Bw6 reside on a unique epitope
on each HLA-B molecule and are distinctly different from the epitopes that
determine the HLA-B specificity. Each HLA-B molecule expresses either the Bw4
or Bw6 supertype (residues 74 to 83 of the a 1 helix) in addition to a
(private) HLA-B specificity. The amino acid residues 80 IALR 83 represent the
Bw4 specificity, whereas, 80 NLRG 83 represent Bw6 (Ref 89).
Likewise, HLA-DR alleles are also
associated with supertypes. However, the HLA-DR supertypes are not allelic with
each other 90. They are encoded by separate genes (HLA-DRB3, -B4,
-B5) and are distinct molecules (HLA-DR52, -DR53, -DR51, respectively). Only
one or none of these genes occurs on a haplotype.
The private specificities in each
supertypical family are as follows:
DR51 (DRB5): DR2 (DRB1*15/16)
DR52 (DRB3): DR3 (17/18; DRB1*03), DR5 (DRB1*11/12), DR6
(DRB1*13/14)
DR53 (DRB4): DR4 (DRB1*04), DR7 (DRB1*07), DR9 (DRB1*09)
Although all HLA-DR4 / 7 / 9
haplotypes carry the structural gene HLA-DRB4, not all of them express the
HLA-DR53 molecule 91. The non-expression, however, is restricted to
the HLA-(B57) : DR7 (Dw11): DQ9 haplotype 92 due to a G to A
substitution in the acceptor splice site at the 3' end of the first intron,
changing the normal AG dinucleotide to AA 93;94. In fact, the null
allele of the HLA-DRB4 gene is expressed but it is an aberrant protein 95.
An exception has been reported as an unexpected expression of HLA-DR53 in a DR7
(Dw11) : DQ9 - positive leukaemia patient 96. A difference between
HLA-B and -DR supertypes is that not all DR alleles are associated with a
supertype. These are HLA-DR1, -DR8 and -DR10. Thus, no supertypical gene is
present on these haplotypes.
An interesting group of MHC
haplotypes is the ancestral or extended haplotypes (also called supratypes).
These are specific HLA-B, -DR, BF, C2, C4A and C4B combinations in significant
linkage disequilibrium in chromosomes of unrelated individuals. They extend
from HLA-B to DR and have been conserved en bloc 97-101. In some
Caucasian populations, the extended haplotypes constitute 25-30% of all MHC
haplotypes and together with recombinants between any two of them, they account
for almost 75% of unselected haplotypes 97;98;100. Particular
extended haplotypes are identical by descent. The evidence for this is that in one
study, 22 of 26 unrelated extended-haplotype-matched subjects had similar mixed
lymphocyte reactivity to HLA-identical siblings 99. Matching for
extended haplotypes significantly improves survival in kidney transplantation 102.
In Caucasians, there are 10 to 12 common extended haplotypes that show
significant linkage disequilibrium. They are relatively population-specific 101;102
and are believed to represent the original MHC haplotypes of our ancestors
which are still segregating unchanged. They are easily recognized from their
characteristic class III polymorphisms called complotypes 100;102-104. Disease
associations with extended haplotypes are generally stronger than allelic
associations 100. The best examples of extended haplotype
associations are those with rheumatoid arthritis 105, multiple
sclerosis 106, insulin-dependent diabetes mellitus 100;107;108,
and systemic lupus erythematosis 109.
Polymorphism
One of the main characteristics of
the MHC is its extreme polymorphism. Among the expressed loci, the MHC has the
greatest degree of polymorphism in the human genome. The numbers of alleles
recognized at the classical loci by December 1998 are presented in Table 1 (for
the latest number of alleles, follow the link at the end).
Table 1. Number of alleles at the
classical HLA loci
|
Locus |
DNA-level
Alleles |
Serological
Equivalents |
|
HLA-A |
119 |
40 |
|
HLA-B |
245 |
88 |
|
HLA-C |
74 |
9 |
|
HLA-DRB1 |
201 |
80 |
|
HLA-DQB1 |
39 |
7 |
|
HLA-DPB1 |
84 |
(-) |
Data from Refs 59,91,110
This is at such a degree that it
is theoretically possible for each human to possess a different set of MHC
alleles. This feature of the MHC is shared by other compatibility systems in
different taxa (such as the fungal mating types, invertebrate allorecognition
system and plant self-incompatibility system). It is, however, important to
recognise that within the allelic polymorphism at the DNA level which seems
endless, there are ancient lineages which predate speciation and maintain
themselves in closely related species. This is the basis of the trans-species
polymorphism theory proposed by Jan Klein and has found widespread support 111.
Allelic lineages may be shared by related species, such as human and apes 112;113
or even human and mice 114, having been present in their common
ancestor. However, when primate and human HLA alleles are compared, there is no
identical (private) class I allele in great apes and humans despite the
similarities in polymorphic motifs 113;115-120. The only
similarity is that the human class I supertypes Bw4 and Bw6 are cross-reactive
with chimpanzees and gorillas (and even with rhesus monkeys) 113;117;121-123. This
conservation throughout hominoid evolution is attributed to the functional
importance of these two epitopes in CTL immunomodulation 89 and NK
cell function 124-126.
Similarly, in the HLA-DRB loci,
while no private specificity has an equivalent in another species, the DRB3 / 4
/ 5 loci seem to have remained as they are in all primates or even in rhesus
monkeys 127;128. Interestingly, these loci encode the class II
supertypes HLA-DR52, -53, and -51. The most ancient polymorphic class II locus
appears to be HLA-DQA1 129;130. The polymorphism of this locus also
correlates to the MHC class II supertypical groupings 131;132.
The haplotypical structure,
phylogenetic analysis and sequence comparisons agree on the presence of five
major haplotypical groups in the HLA class II region 59;128;133-135. These
are HLA-DR1, HLA-DR51, HLA-DR52, HLA-DR8, and HLA-DR53. It appears that the
oldest lineages are HLA-DRB1*04 (represented by the exon 2 motif 9 EQVKH 13)
and HLA-DRB1*03 (the motif 9 EYSTS 13) 136. The analysis of intron
sequences suggest that HLA-DRB1*03 first diverged from HLA-DRB1*04 more than 85
million years ago and later gave rise to HLA-DRB1*15 (Refs 133,137,138).
MHC class I and class II
supertypes are biologically as functional as private specificities. MHC
restriction of peptide presentation has been shown for HLA-Bw4 and -Bw6 139;140,
HLA-DR52 141;142 and HLA-DR53 143-147. HLA-Bw4
appears to be more immunogenic than HLA-Bw6 judged by the antibody response in
the case of mismatching in transplantation 148. Similar to the
cross-reactive HLA-B supertypes between humans and chimpanzees 117,
HLA-DR supertypes are cross-reactive with chimpanzee 142 and even
with mouse class II supertypes 149. Particularly striking is the
cross-reactions between HLA-DR53 and H-2Ek 145;150.
Furthermore, HLA-DR53 has its own peptide binding motif 151;152. The
most abundant peptide eluted from the DR53 molecule is derived from an
intracellular protein, calreticulin, which is involved in MHC class I
biosynthesis, heat shock response and tumour rejection 69;153-155.
HLA Biosynthesis (Animations) MHC
Animations (Serotec) KEGG
Antigen Processing and Presentation Pathways
See also Immunology in a Nutshell PowerPoint
Presentation
Thomson
Lab LGD @ NCI Trowsdale Lab Parham
Lab Kulski Lab
Cytokine
Gene Polymorphisms Cytokine Reference Cytokine
Immunogenetics Group (Gallagher) HUMIGEN
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