| Tissue
Typing Education Primer
Part
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1(Intro), 2(Antigens), 4(Methods),
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GENETICS
OF HLA
Routine Tissue Typing identifies the alleles at three HLA Class I
loci (HLAA,B,C) and three class II loci (HLADR,DP and DQ). Thus,
as each chromosome is found twice (diploid) in each individual, a normal
tissue type of an individual will involve 12 HLA antigens.
These 12 antigens are inherited codominantly that is to say, all 12
antigens are recognised by current typing methods and the presence of
one does not affect our ability to type for the others.
There are a number of genetic characteristics of HLA antigens,
for example:
POLYMORPHISM
The polymorphism at the recognised HLA loci is extreme. As the role
of HLA molecules is to present peptides from invasive organisms, it is
likely that this extreme polymorphism has evolved as a mechanism for coping
with all of the different peptides that will be encountered.
That is to say, each HLA molecule differs slightly from each other in
its amino acid sequence - this is what we see as different HLA antigens.
This difference causes a slightly different 3-dimensional structure in
the peptide binding cleft. Since different peptides have different shapes
and charge characteristics, it is important that the human race has a
large array of different HLA antigens, each with different shaped peptide
binding areas (clefts) to cope with all of these peptides.
However that is not all, as the polymorphism is population specific.
The frequent HLA antigens in different populations are clearly different.
For example, HLA-A34, which is present in 78% of Australian Aborigines,
has a frequency of less than 1% in both Australian Caucasoids and Chinese.
Thus HLA antigens are of great significance in anthropological studies.
Populations with very similar HLA antigen frequencies are clearly derived
from common stock.
Conversely, from the point of view of transplantation, which will be discussed
later, it is very difficult to match HLA types between populations.
Inheritance of HLA
The normal way to present a tissue type is to list the HLA antigens
as they have been detected. There is no attempt to show which parent has
passed on which antigen. This way of presenting the HLA type is referred
to as a Phenotype.
HLA PHENOTYPE example: HLA A1,A3; B7,B8; Cw2,Cw4; DR15,DR4;
When family data is available, it is possible to assign one each of the
antigens at each locus to a specific grouping known as a haplotype. An
haplotype is the set of HLA antigens inherited from one parent.
For example, the mother of the person whose HLA type is given above may
be typed as HLA-A3,A69; B7,B45; Cw4,Cw9; DR15,DR17; Now it is evident
that the A3, B7, Cw4 and DR15 were all passed on from the mother to the
child above. This group of antigens is a haplotype.
In the absence of genetic crossing over, 2 siblings who inherit the same
two HLA chromosomes (haplotypes) from their parents will be HLA identical.
There is a one in four chance that this will occur and therefore in any
family with more than four children at least two of them will be HLA identical.
This is because there are only two possible haplotypes in each parent.
Linkage Disequilibrium
Basic Mendelian genetics states that the frequency of alleles at one
locus do not influence the frequency of alleles at another locus. However
in HLA genetics this is not true.
There are a number of examples from within the HLA system of alleles at
different loci occurring together at very much higher frequencies than
would be expected from their respective gene frequencies. This is termed
linkage disequilibrium.
The most extreme example is in caucasians where the HLAA1, B8, DR3(DRB1*0301),
DQ2(DQB1*0201) haplotype is so conserved that even the alleles at the
complement genes (Class III) can be predicted with great accuracy.
Also, at HLA Class II, this phenomenon is so pronounced, that the presence
of specific HLADR alleles can be used to predict the HLADQ allele with
a high degree of accuracy before testing.
Because of linkage disequilibrium, a certain combination of HLA Class
I antigen, HLA Class II antigen and Class III products will be inherited
together more frequently than would normally be expected. It is possible
that these "sets" of alleles may be advantageous in some immunological
sense, so that they have a positive selective advantage.
CrossReactivity
Crossreactivity is the phenomenon whereby one antibody reacts with
several different antigens, usually at the one locus (as opposed to a
mixture of antibodies in the one serum).
This is not a surprising event as it has been demonstrated that different
HLA antigens share exactly the same amino acid sequence for most of their
molecular structure. Antibodies bind to specific sites on these molecules
and it would be expected that many different antigens would share a site
(or epitope) for which a specific antibody will bind. Thus crossreactivity
is the sharing of epitopes between antigens.
The term CREG is often used to describe "Cross Reacting Groups"
of antigens. It is useful to think in terms of CREG's when screening sera
for antibodies, as most sera found are "multi-specific" and
it is rare to find operationally monospecific sera.
The rarity of monospecific sera means that most serological tissue
typing is done using sera detecting more than one specificity and a typing
is deduced by subtraction.
For example, a cell may react with a serum containing antibodies to HLA-A25,
A26, A34 and be negative for pure A26 and pure A25 antisera. In this case,
HLA-A34 can be assigned, even in the absence of pure HLA-A34
antisera.
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