Human

Leukocyte
Antigen
(HLA)
System

Dr.C.S.N.Vittal
Human leukocyte antigen
• The human leukocyte antigen (HLA) system or complex is a gene
complex encoding the major histocompatibility complex(MHC)
proteins in humans.
Human leukocyte antigen
• The human leukocyte antigen (HLA) system,
the major histocompatibility complex (MHC)
in humans, is controlled by genes located on
chromosome 6.
• It encodes cell surface molecules specialized
to present antigenic peptides to the T-cell
receptor (TCR) on T cells.
• MHC molecules that present antigen (Ag) are
divided into 2 main classes:
• Class I MHC molecules
• Class II MHC molecules
The human MHC on the short arm of chromosome 6

The HLA-DR, DP, and DQ regions consist of one or more A and B genes, respectively. TNF (tumor
necrosis factors); C' (complement genes).

• Yonsei Med J. 2007 Feb 28; 48(1): 11–23.

Class I MHC molecules
• The class I region contains the classical HLA-A, HLA-B, and HLA-
C genes that encode the heavy chains of class I molecules.
• Present as transmembrane glycoproteins on the surface of all
nucleated cells.
Class I MHC molecules
• The class I heavy chain has
three extracellular domains
(α1, α2, and α3), a
transmembrane region, and
an intracytoplasmic
domain.
• The α3 and β2m domains
together form
immunoglobulin constant
domain-like folds
• Six of these antigens are present on the tissue cell membranes of
each person, but there are about 150 different HLA antigens to
choose from, representing more than a trillion possible combinations.
• Consequently, it is virtually impossible for two persons, except in the
case of identical twins, to have the same six HLA antigens.
• Development of significant immunity against any of these antigens
can cause graft rejection.
• The HLA antigens occur on the white blood cells, as well as on the
tissue cells. Therefore, tissue typing for these antigens is done on the
membranes of lymphocytes that have been separated from the
person’s blood. The lymphocytes are mixed with appropriate antisera
and complement; after incubation, the cells are tested for mem-
brane damage, usually by testing the rate of transmembrane uptake
by the lymphocytic cells of a special dye.
• Some of the HLA antigens are not severely antigenic. Therefore, a
precise match of some antigens between donor and recipient is not
always essential to allow allograft acceptance. By obtaining the best
possible match between donor and recipient, the grafting procedure
has become far less hazardous.
• The best success has been with tissue-type matches between siblings
and between parent and child. The match in identical twins is exact,
so transplants between identical twins are almost never rejected
because of immune reactions.
The class II region
• Consists of a series of subregions, each containing A and B genes
encoding α and β chains, respectively
The class III region
• does not encode HLA molecules, but contains genes for complement
components (C2, C4, factor B), 21-hydroxylase, tumor necrosis factors
(TNFs ), and some others
HLA haplotypes
• HLA genes are closely linked and
the entire MHC is inherited as an
HLA haplotype in a Mendelian
fashion from each parent.
• Two siblings have a 25% chance of
being genotypically HLA identical, a
50% chance of being HLA
haploidentical (sharing one
haplotype), and a 25% chance that
they share no HLA haplotypes
Expression of HLA
• HLA class I molecules are expressed on the surface of almost all
nucleated cells.
• Class II molecules are expressed only on B lymphocytes, antigen-
presenting cells (monocytes, macrophages, and dendritic cells), and
activated T lymphocytes.
Methods of HLA typing
• Serological (microcytotoxicity test)
• Mixed lymphocyte reaction
• Molecular methods
• PCR
 Interpretation of an HLA Typing Report
HLA Phenotype
Individual 1 A1, A3; B5, B44; DR 4, DR 15
Individual 2 A1, A3; B7, B8

Common Alleles : A1, B8, DR 4

If the two individuals are related (siblings, parent-child), these three
shared alleles are most probably the common shared haplotype and thus
this is interpreted as :ONE HAPLOTYPE MATCH
If they are Unrelated, and there are 3 shared alleles, this is interpreted as :
THREE ANTIGHE MATCH or THREE NATIGEN MISMATCH
HLA & Clinical Significance
• In organ transplantation
• In transfusion therapy
• Disease association
• Disputed paternity
• In cancer prevention
• Anthropological studies
 HLA typing in Organ Transplantation
• HLA antigens expressed on the
surface of lymphocytes of the
recipients against those from
various donors
• HLA A, HLA B and HLA DR:
major transplantation antigens
• HLA typing is performed for
bone marrow, kidney,
pancreases and heart
transplants, etc.
• HLA typing provides evidence
of tissue compatibility
HLA typing in Organ Transplantation
HLA typing in Transfusion Therapy
• Repeated transfusions may lead to alloimmunization
( development of antibodies after exposure to non-
self antigens)
• Alloimmunization may lead to platelet refractoriness
which can be avoided by
• ABO compatibility testing
• HLA typing (screening for anti HLA antiboides

• Transfusion related Acute Lung Injury

• Donor HLA antibodies react against recipient antigens
HLA & Disease Association
Disease HLA Relative Risk
Ankylosing spondyloarthritis B 27 87.4%
Uveitis B 27 10
Multiple sclerosis DR 2 4.8
Graves-Basedow disease DR 3 3.7
Goodpasture syndrome DR 2 15.9
SLE DR 3 5.8
Myasthenia gravis DR 3 2.5
Pemphigus DR 4 14.4
Rheumatoid arthritis DR 4 4.2
Hashimato thyroidits DR 5 3.2
HLA & Disease Association
HLA and Disputed Paternity
• HLA antigens of mother, child and alleged father are compared
• When an HLA antigen of the child can not be attributed to the mother
or alleged father, then the latter is excluded as the father of the child
HLA & Cancer Prevention
• Gluten sensitive enteropathy is
associated with T Cell lymphoma
• HLA molecules play a protective
role, recognizing increases in
antigens that are not tolerated
because of the low levels in the
normal state.
• Abnormal cells might be targeted
for apoptosis which is thought to
mediate many cancers before
diagnosis
• Dr.C.S.N.Vittal