stands for Human Leukocyte Antigens and is the Human Major H i s t o
c o m p a t i b i l i t y Complex ( MHC ).
IMPORTANCE OF HLA
The first evidence for the existence for Human Leukocyte Antigens (HLA)
in man was obtained in the year 1954 by Jean Dausset in France who observed
that patients whose sera contained Leukoagglutinins had
received a large number
of blood transfusions than those lacking such antibodies. He named them
MAC. Rose Pyne et al.4 in USA and Jon van Rood et al in Holland showed
simultaneously and in independent studies that pregnancy per se provided
an effective stimulus for induction of leukocyte isoantibodies since
the mother raises antibodies to the antigens that the foetus has inherited
from the father. Sera obtained from such pregnant women provided the
most efficient source of HLA reagents.
The concept that the MHC contains Immune Response Genes and HLA is an
MHC was formulated in the year 1969 by Devitt and Benacerrof. HLA genes
are located on the short arm of Human Chromosome 6 ( 6 p 21.3 ) and
the most polymorphic genetic complex known so far in the human genomes.
These polymorphic genes encode a variety of cell surface molecules called
This system plays major role in the regulation of immune system that is
self / non-self recognition. In more modern times, the HLA system is extremely
important for organ and bone marrow transplantation. HLA genes signi.cantly
patients involved in transplantation. Clinically, HLA typing is of greatest
importance in organ transplantation, where the determination of the donor
and recipient tissue typing of HLA loci is done to ensure the best outcome
the risk of graft rejection. This is particularly important in bone marrow
transplantation where the graft itself has immune activity. The goal in
the transplantation is to accurately match HLA antigen variability of
the donor and patient to achieve the highest clinical success.
GENES AND ALLELES ARE IN HLA
HLA region is divided into two classes on the basis of their function
viz. Class I which encompasses the HLA A,B and C and Class II which includes
the HLA DR, DQ and DP. Each person can have 6 class I and II molecules,
respectively, three from each parent. About 1400 alleles are known to
be existing at class I and II loci.
TYPING HLA ANTIGENS
The polymorphism of HLA molecule is determined by serology, cellular and
molecular methods. However, serology and molecular techniques are widely
used. As far as accuracy is concerned molecular typing is the best and
reproducible. Recently, DNA based molecular typing has largely replaced
serology typing in most parts of the world. Because molecular methods
allow identification of alleles which are not determined by serology and
compromised by low expression of HLA molecules in some patients. O.ate
anti HLA sera of required speci.cities are not available due
to non-availability of multiparous women who are the source of HLA sera.
Hence, all antigen speci.cities are not available all the time to meet
USES OF HLA TYPING
A. Immunological Donor Selection for :
1. Solid organ transplantation viz. kidney, liver and heart.
2. Bone marrow transplantation.
3. Blood component therapy.
B. Clinical Aids in the:
1. Diagnosis of diseases (spondylosis, diabetes mellitus etc.).
2. Prediction of risk for disease development in families.
3. Possible prognosis of certain diseases.
4. Paternity testing .
Over the past several years, molecular techniques to determine HLA type
have largely displaced the original serological methods. This has led
to greater powers of discrimination of tissue types (HLA alleles) and
the discovery of hundreds of previously undescribed alleles. Serological
methods are based on an antibody reaction against an epitope on the
HLA molecules and therefore this technique has limited powers of resolution
due to the inconsistent performance and limited target . In general, molecular
techniques allow better discrimination. The field of molecular biology
has shown that
HLA antigens are more complex than we had initially thought. If we take
this into account we need to alter conventional antigen counting. Molecular
matching must be developed for the following reasons:
1. There is extensive evidence showing that the serological response to
allograft ranges far wider than the narrower speci.cities recognized today
for HLA matching. Many antibodies against the broad specificities are
probably directed against epitopes which are just as immunologic as those
directed to the specific cities.
2. The concept of single mismatch between 2 HLA specificities is no longer
tenable. Obviously, many incompatibilities exist among the speci.cities.
LOWERING IN PATIENTS WITH DIABETES
`Cholesterol lowering statin therapy can produce substantial
reductions in the risk of heart attacks, of strokes, and of revascularisations
in people with diabetes'
Although plasma LDL cholesterol concentrations among people with
and without diabetes are generally similar, individuals with diabetes
are at raised risk of cardiovascular disease. Limited evidence
on the effects of cholesterol-lowering therapy mean that most
patients with diabetes do not receive this treatment. The Heart
Protective Study Collaborative Group investigated whether statin
treatment is bene.cial compared with placebo among patients with
diabetes. For statin-treated patients signi.cant
reductions were seen for major coronary events, strokes, and revascularisation,
even if manifest coronary disease was not present. The investigators
suggest that statin therapy should be considered routinely for
patients with diabetes at high risk of major vascular events,
irrespective of initial cholesterol concentration. In a Commentary,
Lars Lindholm asks whether this approach should be taken one step
further, and all patients with type 2 diabetes should be given
a statin, irrespective of cholesterol concentration.
Lancet, 2003; 2000, 2005.