REVIEW doi: 10.1111/sji.

12329
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Clinical Role of Human Leukocyte Antigen in Health

and Disease
Y. M. Mosaad

Clinical Immunology Unit, Clinical Pathology
Department & Mansoura Research Center for
Cord Stem Cell (MARC_CSC), Mansoura Faculty
of Medicine, Mansoura University, Mansoura,
Egypt
Received 23 April 2015; Revised 2 June 2015;
Accepted in revised form 12 June 2015
Correspondence to: Dr. Y. M. Mosaad, Clinical
Immunology Unit, Clinical Pathology Department
& Mansoura Research Center for Cord Stem Cell
(MARC_CSC), Mansoura Faculty of Medicine,
Mansoura University, Mansoura 35111, Egypt.
E-mails: youssefmosaad@yahoo.com, youssef
mosaadam@mans.edu.eg
Abstract
Most of the genes in the major histocompatibility complex (MHC) region express
high polymorphism that is fundamental for their function. The most important
function of human leukocyte antigen (HLA) molecule is in the induction,
regulation of immune responses and the selection of the T cell repertoire. A
clinician’s attention is normally drawn to a system only when it malfunctions. The
HLA system is no exception in this regard, but in contrast to other systems, it also
arouses interest when it functions well – too well, in fact. Population studies
carried out over the last several decades have identified a long list of human diseases
that are significantly more common among individuals that carry particular HLA
alleles including inflammatory, autoimmune and malignant disorders. HLA-
disease association is the name of this phenomenon, and the mechanism underlying
is still a subject of hot debate. Social behaviours are affected by HLA genes and
preference for HLA disparate mates may provide ‘good genes’ for an individual’s
offspring. Also, certain HLA genes may be associated with shorter life and others
with longer lifespan, but the effects depend both on the genetic background and on
the environmental conditions. The following is a general overview of the
important functional aspects of HLA in health and diseases.

of one trans-membrane heavy chain with three extra-

Definition of MHC and HLA
The major histocompatibility complex (MHC) is a large gene
complex present in all jawed vertebrates with an integral role
in the immune system. The antigen-presenting molecules
encoded by the MHC class I and class II genes are cell-surface
glycoproteins that bind intracellular and extracellular
peptides, respectively [1]. The human MHC is located on
chromosome 6 and contains more than 200 genes [2]. The
human MHC-encoded glycoproteins are known as human
leukocyte antigen (HLA) and are specialized in presentation
of short peptides to T cells and play a key role in the body’s
immune defence [3] (Fig. 1).
MHC name is derived from its role in graft rejection
and tissue compatibility between donor–recipient pair.
MHC compatibility between individuals is responsible for
successful graft transplant. MHC is characterized by
extensive polymorphism which in one hand is obstacle
for finding matched pairs and in the other hand enables the
immune system to recognize any invading pathogen.
HLA class I and II
HLA class I proteins are expressed on the surface of all
nucleated cells but to varying degrees. They are comprised
cellular domains (a1–3) and b2-microglobulin (b2 m)
light chain. Overall, a class I molecule has an immuno-
globulin-like tertiary structure with the most extra-cellular
domains being the location of nearly all amino acid allelic
variability. The normal function of HLA class I proteins is
a presentation of peptides from expired or defective
intracellular proteins and peptides from invasive viruses
from within the cell to the T cell receptor (TCR) on CD8+
T cells (often cytotoxic) leading to immune mechanisms
which destroy the cell. HLA proteins also interact with
killer inhibitory receptors (KIR) expressed on the surface of
natural killer (NK) cells, often leading to inhibition of NK
cell activity [4–6] (Fig. 2).
HLA class II proteins have constitutive expression
limited to immune active cells, including B cells and other
antigen-presenting cells (APC). In addition, expression can
be upregulated on other cell types in an inflammatory
environment. Each HLA class II protein comprises an
alpha- and beta-chain both of which are encoded within the
MHC (e.g. HLA-DRA with HLA-DRB1). Each chain has
two extra-cellular domains and again, those most distal to
the cell membrane form a peptide-binding groove which
always carries a self- or non-self-protein-derived peptide
sourced from outside the cell by endocytosis. Class II

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284 HLA in Health and Disease
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proteins and bound peptides interact with CD4+ T cells
(often helper) and their receptors. The affinity with which
peptides are bound to HLA molecules will influence
allogenicity as presented to and recognized by TCR [4]
(Fig. 2).
The peptide-binding structure consists of a membrane-
distal groove formed by two antiparallel a-helices overlay-
ing an eight-strand b-sheet. In the case of HLA class I, the
groove corresponds to a contiguous amino acid sequence
formed by the N-terminal region of the single HLA-
encoded subunit, or heavy chain, while for HLA class II, it
is formed by the juxtaposition of the N-terminal regions of
two HLA-encoded a- and b-chains (Fig. 2). A significant
difference is that for HLA class I the peptide is confined by
binding groove interactions at both the N- and C-termini,
while for HLA class II, each end of the peptide can
overhang the binding groove [7].
The role of HLA molecules is to present peptides from
invasive organisms, and the genes of the MHC are the most
Y. M. Mosaad
Figure 1 Human MHC complex. The human
MHC is located on chromosome 6 at 6p21.3.
The class I gene complex contains three major
loci, B, C and A. The class II gene complex
contains at least three loci, DP, DQ and DR;
each of these loci codes for one alpha- and one
beta-chain polypeptide which associate
together to form the class II antigens.
Figure 2 Structure of human leukocyte
antigen (HLA) class I and II molecules. HLA
class I molecule is formed of a chain and b2-
microglobulin chain. HLA class II molecule is
formed of a and b chains. The peptide-binding
groove is formed by a1 and a2 domains in
HLA class I molecules and by a1 and b1
domains in HLA class II molecules.
polymorphic of the human genome (total HLA alleles
13023; HLA class I alleles 9749 and HLA class II alleles
3274) [8]. As of April 2015, there are over 3017 HLA-A,
2623 HLA-C, 3887 HLA-B, 1829 HLA-DRB1, 780 HLA-
DQB1 and 520 HLA-DPB1 alleles recognized by the
World Health Organization (WHO) Nomenclature Com-
mittee for Factors of the HLA System [8, 9]. Therefore, it is
likely that this extreme polymorphism has evolved as a
mechanism for coping with all of the different peptides
that will be encountered [10]. HLA molecule differs
slightly from each other in its amino acid sequence
(different HLA antigens) which causes different structure
in the peptide-binding cleft. The distal membrane domains
(a1, a2 in HLA class I and a1, b1 in HLA class II) present
a high degree of variability, whereas the proximal mem-
brane domains (a3 in HLA class I and a2, b2 in HLA class
II) as well as the trans-membrane and cytoplasmic domains
have limited or no polymorphism. This explained by the
fact that the vast majority of the nucleotide polymorphisms
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occur in exon 2 of the HLA class II genes and in exons 2
and 3 of the HLA class I genes.
Cells contain two different antigen-processing pathways
that serve to present peptides to T cells. HLA class I
molecules are loaded in the endoplasmic reticulum (ER)
with peptides derived from degradation of cytosolic
proteins by the proteasome, and these HLA class I/peptide
complexes are then surface expressed and presented to
CD8+ T cells (Fig. 3). HLA class II molecules exit the ER
in association with the invariant chain (Ii) which occupies
their peptide-binding groove. In the endocytic pathway,
proteolysis results in the degradation of the invariant chain,
leaving the residual class II-associated invariant chain
peptide (CLIP) in the binding groove. In a process
catalysed by HLA-DM (in humans), CLIP is replaced by
peptides derived by proteolysis from proteins resident or
internalized into the endocytic pathway. After surface
expression, these are presented to CD4+ T cells. Hence,
HLA class I generally serves as a reporter of intracellular
infection, while HLA class II senses the antigens present in
the extracellular milieu (Fig. 4) [11].
Cross-presentation is the presentation of peptides
derived from exogenous acquired antigens in association
with HLA class I in professional APC. Cross-priming is the
sensitization of CD8+ T cells by dendritic cells (DCs) to
such antigens. Cross-priming plays an important role
during priming of antitumour CD8+ T cells as well as
priming the CD8+ response to pathogens which do not
Figure 3 Human leukocyte antigen (HLA)
class I antigen-processing and presentation
pathway. Cytosolic and nuclear proteins are
degraded into peptides by proteasomes.
Selected peptides are then translocated
through the transporter for antigen
processing into the endoplasmic reticulum,
where they are loaded into newly synthesized
class I molecules. The HLA–peptide
complexes are exported by way of the Golgi
apparatus to the surface of the cell.
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 285
directly infect DCs. Although various cell types are able to
cross-present under certain conditions, DCs are the most
important cross-presenting cells in vivo [11, 12].
The superior ability of DC to cross-present is largely
attributed to their antigen-processing capacity. Endocytic
pathways in DC preserve and retain antigen epitopes via
low lysosomal proteolysis and expression of protease
inhibitors [13]. This aspect makes sense when one considers
that DC pick up antigen in the peripheral tissue and
migrate for several hours-days (12–24 h for dermal DC and
3 days for Langerhans cells) reaching the lymph nodes [14].
Thus, instead of being processed and degraded prema-
turely, retention of antigen would allow optimal cross-
presentation for subsequent recognition by lymph node
resident na€ıve CD8 T cells [15].
Linkage disequilibrium (LD) refers to the tendency for
two ‘alleles’ to be present on the same chromosome (positive
LD), or not to segregate together (negative LD). As a result,
specific alleles at two different loci are found together more
or less than expected by chance. LD is the non-independence,
at a population level, of the alleles carried at different
positions in the genome. In this case, the expected frequency
of a two-locus haplotype can be calculated as the probability
of the occurrence of two independent (or joint) events simply
by multiplying their gene frequencies. The same situation
may exist for more than two alleles. Its magnitude is
expressed as the delta (D) value and corresponds to the
difference between the expected and the observed haplotype
286 HLA in Health and Disease
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frequency. If there is no LD, D will be zero (or not
significantly different from zero), and if there is positive LD,
it will be a positive value [16].
In some cases, HLA genes are co-located on chromosome
6 such that they are inevitably inherited ‘en bloc’ and are
linked as are the HLA-DRB1 and DRB3-5 genes. For
example, the –DR15:01 allele is always found with the -
DRB5 gene. In some cases, there is conserved inheritance of
alleles on the same chromosome constituting a haplotype.
HLA genes and their protein allotypes can sometimes be
identified on commonly recognized haplotypes such as
HLA-A1, -B8, -Cw7, -DR17, -DR52 and -DQ2 [5].
HLA in health and disease
Despite the temptation to think of HLA as ‘transplantation
antigens’, HLA antigens are not present on tissues simply to
confound transplant surgeons. The most important function
of HLA molecule is in the induction, regulation of immune
responses and the selection of the T cell repertoire [10]. A
clinician’s attention is normally drawn to a system only when
it malfunctions. The HLA system is no exception in this
regard, but in contrast to other systems, it also arouses
interest when it functions well – too well, in fact [4]. The
following is a general overview of some of the important
functional aspects of HLA antigens in health and diseases.
HLA in health
HLA and immune response
The most important function of HLA molecule is in the
induction and regulation of immune responses. T cells
Y. M. Mosaad
Figure 4 Human leukocyte antigen (HLA)
class II antigen-processing and presentation
pathway. Antigens from extracellular sources
are processed by endolysosomal enzymes into
peptides. HLA class II is synthesized in the
endoplasmic reticulum lumen and forms a
complex with invariant chain (Ii). The Ii is
degraded, leaving a fragment, class
II-associated invariant chain peptide (CLIP),
in the class II binding groove. HLA-DM
mediates the release of CLIP and the loading of
appropriate peptides onto HLA class II
molecules. These complexes are then
transported to the cell surface for
presentation to CD4+ T cells.
recognize foreign antigen in combination with HLA
molecules. In an immune response, foreign antigen is
processed by and presented on the surface of a cell (e.g.
macrophage). The HLA molecule has a section, called its
antigen (or peptide)-binding cleft, in which it has these
antigens inserted. T cells interact with the foreign antigen/
HLA complex and are activated [17]. The TCR usually
reacts with foreign antigens in the form of peptides from
the foreign material bound to HLA. The foreign peptide
fills the groove of HLA, and the TCR lies above the two in
an approximately diagonal orientation [18]. This allows the
loops at the ends of the TCR-a and TCR-b beta strands to
contact both HLA and foreign peptide, with the Comple-
mentarity determining regions (CDR1 and CDR2)
sequences (which are encoded in the germ-line DNA for
Va and Vb, respectively) contacting mostly the alpha
helices of the HLA proteins themselves. However, the
CDR3 regions of TCR-a and TCR-b (which are encoded
by the random, non-germ-line sequences that are created
by gene rearrangement) make many contacts with the
foreign peptide [19].
Upon activation, the T cells multiply and by the
release of cytokines are able to set up an immune response
that will recognize and destroy cells with this same
foreign antigen/HLA complex, when next encountered.
The exact mode of action of HLA Class I and HLA Class
II antigens is different in this process. HLA Class I
molecules, by virtue of their presence on all nucleated
cells, present antigens that are peptides produced by
invading viruses. These are specifically presented to CD8
T cells, which will then act directly to kill the virally
infected cell. HLA Class II molecules have an intracellular
chaperone network which prevents endogenous peptide
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Y. M. Mosaad
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from being inserted into its antigen-binding cleft. They
instead bind antigens (peptides) which are derived from
outside of the cell (and have been engulfed). Such peptides
would be from a bacterial infection. The HLA Class II
molecule presents this ‘exogenous’ peptide to CD4 T cells
which then set up a generalized immune response. Thus,
it is apparent that HLA products are an integral part of
immunological health, and therefore, it is no surprise to
see a wide variety of areas of clinical and genetic
implications [17].
HLA and selection in thymus
T cells arise from circulating bone-marrow-derived pro-
genitors that home to the thymus. After T lineage
commitment and expansion, TCR gene rearrangement
ensues and gives rise to either cd or ab progenitors at the
CD4 and CD8 double-negative (DN) stage. A small
number of ab committed DN cells give rise to a large
number of CD4 and CD8 double-positive (DP) thymo-
cytes, and somatic recombination of TCR genes results in
a remarkably broad repertoire of distinct ab TCRs with
random specificity. The TCR affinity for self-peptide–HLA
determines a thymocyte’s fate from this point forward. DP
thymocytes expressing TCRs that do not bind self-
peptide–HLA complexes die by neglect. Those with a
low affinity for self-peptide–HLA complexes differentiate
to CD4 or CD8 single-positive (SP) thymocytes – so-called
positive selection. However, those with high-affinity TCR
for self-peptide–HLA complexes represent a potential
threat to the health of the animal, and various mechanisms
operate to ensure tolerance to self, including clonal
deletion, clonal diversion, receptor editing and anergy
[20].
Treg cells are a suppressive subpopulation of CD4 T
cells that resembles autoreactive T cells thymic deletion in
their requirement for high-affinity TCR signals and
engagement of CD28 costimulatory ligands. On the other
hand, it differs from CD4 T cells in the expression of the
forkhead family transcription factor (Foxp3) and in their
dependence on cc-dependent cytokines such as interleukin-
2 (IL-2) [21]. Thymic Treg development is achieved in
two stages. Initially, post-positive selected thymocytes
undergo TCR and CD28 dependent maturation into
a Foxp Tregs precursor population. A subsequent IL-
2-dependent step leads to the development of Foxp3-
expressing mature Tregs [22]. The developing
(Foxp3 CD25 ) CD4 thymocytes that receive TCR/
CD28 costimulatory signals differentiate into
Foxp3+CD25 or Foxp3 CD25+ precursors. Foxp3+
CD25 precursors represent the major developmental
pathway for Tregs. Most of the Foxp3+CD25 precursors
die because of insufficient IL -2, while IL-2-signalled
Foxp3+CD25 precursors differentiate into mature
Foxp3+CD25+ Tregs [21].
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HLA in Health and Disease 287
HLA-disease association
Population studies carried out over the last several decades
have identified a long list of human diseases that are
significantly more common among individuals that carry
particular HLA alleles. For example, HLA-B alleles (e.g.
HLA-B*2702, HLA-B*2705) are associated with ankylos-
ing spondylitis (AS), HLA-DQB1*0602 is associated with
narcolepsy, HLA-DRB1 alleles (e.g. DRB1*04:01,
DRB1*04:04, DRB1*04:05, DRB1*01:01 and a few
others) that code for a sequence motif in the DRb chain
called ‘shared epitope’ (SE) are associated with seropositive
rheumatoid arthritis (RA) [3].
The mechanism underlying HLA-disease association is
unclear; however, many hypotheses have been postulated
and generally fall into two categories: (1) Those that blame
‘mistaken identity’ in which an HLA allele appears to
associate with the disease, although the actual culprit
belongs to a different locus in the haplotype or associates
through linkage disequilibrium and (2) Those that impli-
cate immune reactivity to self-antigens due to aberrant T
cell repertoire selection, immune cross-reactivity with
foreign antigens or immune attack on ‘altered self’ antigens
[3, 19, 23, 24].
HLA haplotypes can indeed explain some misinterpreted
associations such as narcolepsy, where an apparent associa-
tion with HLA-DRB1*15 was later found to be actually
attributed to an HLA-DQ allele in the haplotype, HLA-
DQB1*0602, which is in close LD with the hypocretin
receptor 2 (HCRTR2) gene [25]. Linkage disequilibrium has
been implicated in hereditary hemochromatosis (HH),
where an apparent association with HLA-A alleles was later
determined to be actually due to two point mutations in a
non-classical class I HLA gene, HFE, that are found in LD
with HLA-A3 and HLA-A29 alleles [26]. However, both
haplotype-based association and LD merely direct the blame
at another gene and do not provide testable hypotheses to
explain the pathogenic mechanism of HLA molecules in
disease aetiology [3].
The three other hypotheses listed in the second category
above implicate, in one way or another, antigen presenta-
tion by HLA molecules. They postulate that the basis of
HLA-disease association is an immune response to putative
self- or foreign antigens either in their native or modified
form. However, presentation of specific antigens as a
mechanism of HLA-disease association is difficult to
reconcile with a considerable body of scientific data [3].
First, the cause-effect fidelity between HLA alleles and
particular diseases is often challenged. For example, HLA-
DRB1*0401, the best known for its association with RA,
associates with type 1 diabetes (T1D) as well [27]. Thus, an
individual HLA allele can promiscuously associate with
distinct diseases that do not share pathogenesis, target
tissues or putative antigens. Second, allele-associated
diseases can demonstrate species non-specificity such as
288 HLA in Health and Disease
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HLA-DRB1*0401, which associates with human RA,
confers susceptibility to inflammatory arthritis in mice as
well [28]. Such ‘trans-species susceptibility’ is difficult to
reconcile with HLA-restricted antigen presentation. Third,
significant HLA allele-based associations have been
observed in conditions that do not involve antigen
recognition or any immune-based pathogenesis [29].
Finally, antigen presentation-based hypotheses cannot
easily explain allele-dose impact on disease severity or
offer a plausible explanation for allele-dose effects on
concordance rates in monozygotic twins [30]. Thus, HLA-
restricted antigen presentation, a common thread in most
of the prevailing hypotheses addressing HLA-disease
association, appears to be inharmonious with many
observations concerning the biology, epidemiology and
evolution of HLA molecules [3].
Seeking better answers to the question of HLA-disease
association, de Almeida and Holoshitz [31] have recently
put forward a heterodox, MHC Cusp theory at the focus of
this theory is a polymorphic region on HLA molecules
whose tri-dimensional cusp-like shape appears to have been
preserved in the entire MHC family. The theory proposes
that the MHC codes for allele-specific ligands in the cusp
region, which interact with non-HLA receptors and
activate various pathways. Aberrations in those pathways
could cause HLA-associated diseases.
One of the most conspicuous features in the HLA fold is
a prominent cusp-shaped prominence in the a2 domain of
class I HLA molecules, and its tri-dimensionally equivalent
b1 domain in class II HLA molecules. The cusp in both
molecules involves allele-diversity regions. Similarly,
shaped structures have been preserved in the entire MHC
gene product family, irrespective of whether or not they
can present antigens [32]. Importantly, cusp regions in
several HLA molecules have been found to act as ligands
that perform non-antigen presentation functions. For
example, ligands for NK cell receptors have been identified
in the cusp region of both classical and non-classical (HLA-
E) class I HLA molecules [33]. Thus, the cusp region,
whose peculiar tri-dimensional shape has been carefully
conserved through MHC evolution independent of antigen
presentation, is a hub for signal transduction ligands that
interact with a variety of non-HLA receptors and activate
important biologic functions. In class II and classical class I
HLA molecules, the cusp contains allelic hypervariable
regions. As discussed above, antigen presentation per se
cannot explain HLA-disease association. The MHC Cusp
theory proposes that HLA molecules may promote diseases
due to their allele-specific biologic effects independent of
antigen presentation function of HLA. Therefore, the
blame cannot be applied exclusively to the antigen
presentation function of HLA molecules [3].
Large meta-analysis studies and systematic reviews have
shown that at best no more than half of original
associations can be consistently replicated. This lack of
Y. M. Mosaad
consistency is a widely recognized limitation of the
association studies. The explanation for why the results
of HLA associations vary between cohorts includes
mistakes in genotyping [deviation from Hardy–Weinberg
equilibrium (HWE) in controls is usually an indication of
problems with typing rather than selection, admixture,
non-random mating or other reasons for violation of
HWE], poor control selection, design problems including
the statistical power issue (negative results due to lack of
statistical power should be distinguished from truly
negative results), publication bias, disease misclassification
or misclassification bias, excessive type I errors, post hoc and
subgroup analysis, unjustified multiple comparisons, fail-
ure to consider the mode of inheritance in a genetic disease,
failure to account for the LD structure of the gene (only
haplotype-tagging markers will show the association, other
markers within the same gene may fail to show an
association) and likelihood that the gene studied account
for a small proportion of the variability in risk and true
variability among different populations in allele frequen-
cies [16].
Deficiency of HLA molecules
HLA class I deficiency is a rare disease with remarkable
clinical and biological heterogeneity. The spectrum of
possible manifestations extends from the complete absence
of symptoms to life-threatening disease conditions. It is
usually diagnosed when HLA class I serological typing is
unsuccessful; flowcytometric studies then reveal a severe
reduction in the cell-surface expression of HLA class I
molecules (90–99% reduction compared to normal cells).
Isolated HLA class I deficiency, also termed ‘type I bare
lymphocyte syndrome’ (type I BLS), is not usually life-
threatening, in contrast to the more severe HLA class II
deficiency (type II BLS) and combined HLA class I and II
deficiencies. The symptoms present in the majority of the
patients are rather unexpected, considering the role of HLA
class I molecules in the presentation of viral peptides to
cytotoxic T lymphocytes (CTL) [34].
In most cases to date, this low expression is due to a
homozygous inactivating mutation in one of the two
subunits of the transporter associated with antigen
processing (TAP), critically involved in the peptide loading
of HLA class I molecules. TAP deficiency has been
molecularly characterized by a point mutation leading to
a premature stop codon, with or without frame-shift, and
thus to a truncated and non-functional protein. The
asymptomatic TAP-deficient siblings have a mutation in
the gene region encoding the ATP-binding cassette that
destroys the activity of TAP2, although interactions with
TAP1 and tapasin should be preserved [34, 35].
Several subtypes of HLA class I deficiency have been
described. Symptomatic TAP deficiency occurs when the
patients have a very large reduction in the cell-surface
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expression levels of HLA class I molecules. They display
recurrent bacterial infections of the respiratory tract and
about half of them also have granulomatous skin lesions.
Their HLA genotype is homozygous, and their parents are
usually first cousins [34, 36]. The absence of severe viral
infections despite the defective presentation of viral
antigens to CD8+ T cells may be explained, at least in
part, by different factors: (1) normal humoral response, (2)
presence of significant, although frequently reduced,
numbers of TCR-ab+ CD8+ T cells, (3) recognition by
certain TCR-ab+ CD8+ T cells of TAP-independent viral
antigens, (4) expansion of TCR-cd+ T cells and finally (5)
presence of NK cells [34, 37].
Atypical HLA class I deficiencies are characterized by
less severe reduction in surface expression of HLA class I
molecules (approximately tenfold). It is called atypical due
to absence of clinical symptoms, and if present, it will be
transient or moderate. It includes very heterogeneous
group due to the heterogeneous molecular defects that are
present in this type. Patients with atypical HLA class I
deficiency will have a homozygous HLA genotype and
evidence of a TAP2 deficiency. Thus, TAP deficiencies may
lead to variably severe reductions in the surface levels of
HLA class I molecules [34, 36].
Combined HLA class I and II deficiency where a
significant reduction in the surface expression of HLA class
I molecules is associated with a lack of expression of HLA
class II molecules. As in type II BLS, the resulting absence
of humoral and cellular immune responses produces
extreme susceptibility to viral, bacterial and parasitic
infections early in life. The reduced expression of HLA class
I molecules seems to be a direct consequence of the
mutations of the regulatory factor X (RFX) complex,
which regulates the transcription of HLA class II genes.
Indeed, the promoters of the genes of the heavy chains of
HLA class I molecules and of b2 m contain binding motifs
for several subunits of the RFX complex. These transcrip-
tion factors thus may also play a role in the transactivation
of the genes of HLA class I molecules [34, 38, 39].
Although patient history and clinical picture may
strongly suggest HLA class I deficiency, diagnosis needs to
be confirmed by serological HLA typing (but not by
molecular HLA typing because this would not identify the
disease) and/or by flow cytometry (staining of PBMC by a
pan-anti-HLA class-I antibody such as W6/32). Cells from
parents and siblings should be included, to identify other
affected family members. The degree to which surface
expression of HLA class I molecules is reduced may already
give some indications about the possible origin of the
defect. HLA genotyping of the patient and his family
should be performed. If the patient’s HLA genotype is
homozygous, the deficiency is likely to be linked to
chromosome 6 and may thus be a TAP or a tapasin
deficiency whose transmission is recessive and autosomal. If
not, a transcriptional and conditional defect could be
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 289
envisaged and confirmed by activation of T cells (Phyto-
hemagglutinin ‘PHA’, IL-2, allogeneic feeder cells) and
further stimulation with inflammatory cytokines, which
should then strongly upregulate HLA class I molecules [34,
40].
Abnormalities of genes linked to the HLA
A large group of diseases involve genes in the HLA region
that are linked to (or associated with) specific class I and
class II alleles or combinations of alleles (haplotypes). In
some of these diseases, the responsible genes are unrelated
to the class I and class II genes (e.g. Narcolepsy), but in
other diseases, the class I, II and III genes are involved [4].
Narcolepsy
Narcolepsy is a neurological disorder characterized by
excessive daytime sleepiness, cataplexy, hypnagogic hallu-
cinations, sleep paralysis and disturbed nocturnal sleep
patterns. This disease is secondary to the specific loss of
hypothalamic hypocretin (orexin)-producing neurons in the
lateral hypothalamus [41, 42].
To act, hypocretins must bind to receptors, one of which
is rendered non-functional by a mutation carried by
patients with narcolepsy. The mutation apparently arose
in a common ancestor of these patients, in the HCRTR2
gene located in the vicinity of the HLA-DQB1*0602 and
DQA1*0102 alleles. As the mutation occurred relatively
recently, there has not been enough time for it to be
separated from the two HLA-DQ alleles by crossing over in
the patients with the most severe cases of narcolepsy. The
three genes therefore appear together at frequencies higher
than would be expected from random combinations of their
frequencies in the population, a situation referred to as LD
[4].
While nearly all narcoleptic patients express
DQB1*0602, expression of DQB1*0602 is not limited to
narcoleptic individuals between 12% and 38% of the
general population are carriers of this allele [43]. In
contrast, the closely related DQB1*0601 allele, which
differs at only nine residues, protects against developing
narcolepsy, suggesting that peptide-binding differences
between these two alleles determine whether they predis-
pose to or protect against narcolepsy [44]. The significant
association with DQB1*0602 strongly suggests an inter-
action between a specific T cell receptor subtype leading to
the destruction of hypocretin-producing neurons. An
autoimmune basis for the hypocretin cell loss in narcolepsy
has long been suspected due to its strong genetic
association with selected HLA alleles. HLA encodes
multiple subtypes of HLA class I and II proteins that
present foreign peptides to T cells during infections,
thereby triggering immune responses via TCR activation.
In autoimmunity, self-peptides are believed to be
290 HLA in Health and Disease
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mistakenly perceived as foreign, thus leading to tissue
destruction, which often occurs in context of specific HLA
alleles [45].
Among autoimmune diseases, narcolepsy is uniquely
positioned to demonstrate molecular mimicry in humans.
First, narcolepsy occurs nearly exclusively in individuals
with DQB1*0602. Second, a specific association with the
TCR-a locus also confers an increased risk, indicating a
crucial role for specific J segments of TCR-a in the
‘immunological synapse’ of narcolepsy. Finally, studies
have shown increased rates of narcoleptic onset in children
following exposure to influenza A H1N1 infections and
selected H1N1 vaccine preparations. These findings
strongly suggest that some T cells that can be activated
by H1N1 epitopes that lead to the destruction of
hypocretin-producing neurons. A parsimonious explana-
tion could involve mimicry between H1N1 and a peptide
contained in hypocretin cells [41, 42, 45].
Hemochromatosis
Iron-overload disorders owing to genetic mis-regulation of
iron acquisition are referred to as HH. The most prevalent
genetic iron-overload disorder in Caucasians is caused by
mutations in the HFE gene, an atypical HLA class I
molecule. The HFE gene was first identified in 1996 as an
MHC class I-like gene in which homozygosity for a missense
mutation that results in cysteine-to-tyrosine substitution at
amino acid 282 of human HFE protein (C282Y) was found
in vast majority of patients with HH [46, 47].
The protein encoded by the HFE gene is a non-classical
HLA class I-like protein which contains a signal sequence,
peptide-binding extracellular domains, a trans-membrane
region and a small cytoplasmic portion. Within the a-2
and a-3 extracellular domains are the four cysteine residues
that form disulphide bridges representing one of the most
conserved structural features of HLA class I molecules.
HFE interacts with b2 m, and this association enables
efficient transport of HFE to the cell surface where it
interacts with Transferrin receptor 1 (TfR1). C282Y
mutation disrupts the disulphide bridges in the extracel-
lular domains of the HFE protein, thereby preventing the
association of HFE with b2 m and TfR1. The lack of HFE
interaction with TfR1 increases the affinity of TfR1 for the
transferrin-bound iron, thereby modulating iron absorp-
tion. In contrast to the C282Y mutation, mutant H63D
HFE formed stable complexes with TfR1 being in line
with the clinical data that H63D HFE mutations margin-
ally affect iron absorption and rarely lead to HH [47].
HLA and infectious diseases
For an efficient immune response to a pathogen to occur,
HLA molecules must bind peptides derived from microbial
proteins and the T cell repertoire must include clones that
Y. M. Mosaad
can be activated by such HLA-bound peptides. Non-
fulfilment of either of these requirements may render a
person carrying a particular combination of HLA alleles
more susceptible to a particular infectious disease than one
who has a different combination of alleles [4, 48].
Malaria
The best example of this resistance is the association of
specific HLA class I and class II alleles with protection
against severe malaria in sub-Saharan Africa. In the
Gambia, infection with Plasmodium falciparum, which
causes malaria, is extremely common, although the
mortality rate among children with malarial anaemia or
cerebral malaria is low. Both complications are believed to
be the consequence of a failure to clear the parasites from
the blood, leading to increase haemolysis and blockage of
cerebral blood vessels by parasitized erythrocytes. HLA
typing of the relevant population revealed the presence of
the HLA-B*53 allele at a frequency of approximately 25%
among healthy people or children with mild malaria (the
allele is rare in non-African populations). By contrast, the
frequency of HLA-B*53 among patients with severe
malaria was approximately 15%. The comparison suggests
that possession of the HLA-B*53 allele reduces the risk of
death from severe malaria by approximately 40%. Pre-
sumably, the HLA-B53 molecules bind very efficiently
certain peptides produced by processing the malarial
circumsporozoite protein and present them to CD8+ T
cells, whose progeny attack the liver-stage parasites. Such
cytotoxic T cells have indeed been found in patients with
malaria, and circumsporozoite peptides have been eluted
from the HLA-B*53 molecules of these patients. Protec-
tion against severe malarial anaemia is also afforded by
possession of the class II HLA-DRB1*1302/DQB1*0501
haplotype. In other sub-Saharan populations, different
HLA class I and class II alleles are involved in the resistance
to severe malaria [4, 48–50].
The absence of a strong or clear association between
HLA and P. falciparum malaria may, in fact, result from a
unique biology which renders HLA less relevant. The
parasite spends most of its biomass not as freely circulating
sporozoites and merozoites, but as intra-erythrocytic ring
forms, trophozoites and schizonts. Despite their intracel-
lular development, remarkable immune evasion is
achieved. The erythrocyte is arguably appealing not only
for its nutritive iron and protein content, but also for its
lack of continued HLA expression after enucleation [51],
thereby unable to process and present immunologic
signature units for adaptive immune recognition [52].
HIV/AIDS
Human immunodeficiency virus and acquired immune
deficiency syndrome (HIV/AIDS) is one of only a few
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infectious diseases showing a clear-cut and consistent HLA
association. The primary influence of HLA loci on the HIV
disease relative to all other single human genetic variants
has now been confirmed by several genomewide association
studies (GWAS). The GWAS data supported numerous
genetic epidemiological studies reported previously, which
had implicated many HLA alleles in various aspects of HIV
disease. Thus, all the available evidence points to HLA as
the most significant locus in differential control of HIV
across humans [53].
HIV infection typically manifests with an acute viral
syndrome, followed by a period of immune control with
relatively low viral loads and stable CD4+ cell counts. After
this asymptomatic period of usually 8–10 years, viral loads
increase, CD4+ T cell counts drop and AIDS-defining
opportunistic infections or malignancies occur in untreated
patients. There are, however, some patients who display a
superior HIV control. These ‘elite controllers’ or ‘long-
term non-progressors’ have low viral loads and remain
asymptomatic even for decades before the onset of AIDS
[54].
The primary function of HLA molecules is to present
foreign antigens to elicit T cell responses, so the number of
distinct HLA allotypes expressed on the cell surface is
directly related to the range of foreign antigens the host
can present to T cells. Thus, individuals who are hetero-
zygous at the HLA locus will be able to present a broader
repertoire of antigenic peptides to T cells as compared to
homozygotes, thereby exerting greater pressure on the
pathogen to escape the CTL responses that may in turn
affect pathogen fitness. Under this model, it would be
expected that HLA homozygous individuals would pro-
gress more rapidly to AIDS than HLA heterozygous
individuals after HIV infection. Indeed, a highly signifi-
cant association of HLA class I homozygosity with rapid
progression to AIDS in both Caucasians and African
Americans was demonstrated and the three class I loci
contributed independently to the association, and the effect
was most pronounced in individuals who were homozygous
at two or three loci [53].
Overall, the data suggest that a broader range of HIV-1
peptides are recognized by HLA heterozygous individuals
resulting in more efficient-specific CTL responses against
the pathogen. It may also take the virus a longer time to
accumulate escape mutations in HLA heterozygous indi-
viduals relative to homozygous individuals. An alternative
interpretation of the data is based on a model of frequency-
dependent selection (or rare allele advantage), which argues
that HIV adapts to HLA alleles that are common in the
population. These alleles are most likely to be observed in
HLA homozygotes. HLA heterozygous individuals on the
other hand are more likely to carry rare alleles (in
combination with common alleles), to which the virus
has not adapted as well, and therefore, individuals with
these alleles are better able to contain the virus [53].
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 291
Kaslow et al. [55] assessed the role of HLA class I alleles
in HIV infection and found that HLA-B27 and B57 were
strongly associated with slow progression to AIDS.
Importantly, several independent studies have confirmed
this finding, including a recent study [56] that included
more than 2700 patients with HIV infection. It is
important to note, however, that HLA-B27 and B57 are
not unique in their association with HIV control, but are
rather extremes in an continuous spectrum of ‘protective’ to
‘hazardous’ HLA class I alleles. HLA-B27 is associated with
low viral load and long-term non-progression in HIV
infection as well as spontaneous clearance of hepatitis C
virus (HCV) infection. Recent studies linked protection by
HLA-B27 in HIV and HCV infection to virological
mechanisms such as complicated pathways of viral escape
from immunodominant HLA-B27-restricted virus-specific
CD8+ T cell epitopes. These virological mechanisms may
help to explain why CD8+ T cell responses targeting
certain HIV and HCV-specific epitopes contribute to
protection. However, they cannot explain why largely the
same HLA class I alleles, including HLA-B27 and HLA-
B57, are protective in unrelated viral infections [54].
Therefore, there must be additionally immunological
mechanisms that contribute to the protective effect of these
HLA alleles in HIV and HCV infection. Several immuno-
logical mechanisms have been suggested contributing to
protection by HLA-B27 including: CD8+ T cell polyfunc-
tionality (indicated by simultaneous production of multi-
ple antiviral cytokines) and functional avidity (the
sensitivity of CD8+ T cells to antigenic stimulation),
thymic selection of CD8+ T cell precursors (HLA class I
alleles that bind few self-peptides are associated with a
greater CD8+ T cell precursor repertoire and broader cross-
reactivity of CD8+ T cells, finally leading to superior viral
control), specific T cell receptor repertoires and clonotypes
(the selection of TCR clonotypes impacts antiviral efficacy
and the capacity to cross-recognize viral variants and in
HCV, limited TCR diversity has been linked to the
evolution of viral escape mutations), efficient antigen
processing (the amount of peptide produced by the
antigen-processing machinery (APM) correlated with the
magnitude and frequency of HIV-specific CD8+ T cell
responses) and evasion from Treg suppression (Tregs are
thought to suppress HIV and HCV-specific CD8+ T cells)
and thus contribute to CD8+ T cell exhaustion and failure.
It has been demonstrated, however, that HIV-specific
CD8+ T cells restricted by the protective HLA alleles B27
and B57 are not suppressed by Tregs [54, 57, 58].
Moreover, recent study by Elahi and Horton [58]
provided novel insights into the role of Tregs in chronic
viral infection. This study showed that HIV-specific CD8+
T cells restricted by protective HLA-B*27/B*57 alleles are
much more resistant to Treg-mediated suppression than
CD8+ T cells restricted by non-protective HLA alleles.
This resistance to Treg suppression was because CD8+ T
292 HLA in Health and Disease
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cells restricted by protective HLA alleles upregulated low
levels of T cell immunoglobulin Mucin Protein-3 (Tim-3)
when they encountered their antigen. Thus, Tregs were not
able to suppress proliferation of these HIV-specific CD8+
CTLs through Tim-3:Galactin-9 interactions. In contrast,
HIV-specific CD8+ CTLs restricted by non-protective
alleles upregulated high levels of Tim-3 when they
encountered their antigen and were subsequently sup-
pressed by Tregs. The lack of suppression of B*27/B*57-
restricted CTL allows them to continue to proliferate and
kill infected targets during chronic infection, which may
account for delayed disease progression in persons with
protective alleles [58].
HCV
HLA associations with respect to hepatitis B virus and
HCV infection susceptibility, protection, disease severity,
interferon treatment response and response to vaccination
have been intensively investigated across the global
populations [59]. The associations between HLA Class I
antigens and the outcome of HCV infection are extensively
investigated in different ethnic populations, and the
reported associations showed ethnic and geographical
differences sometimes with contradictory results [60]. In
the same time, there is a striking concordance between
several of the HLA alleles associated with clearance in both
HIV and HCV infection including, in particular, HLA-
B*27. Other associations with HLA-B*57 and HLA-B*08
DR3 are less consistent and may relate to differences in
viral sequences in certain subpopulations [61].
Both HLA-B*57 and HLA-B*27 have been identified as
protective in terms of both HIV and HCV infection. The
mechanisms for this joint efficacy could be manifold. First,
it is possible that both HLA alleles could be in LD with
other genes in the MHC which are more directly
responsible for their effects. Second, it is possible that
both HLA molecules select for epitopes that may have an
influence on viral fitness. Third, it is possible that such
associations are simply related to the prevalence of a
particular gene in a population because it is likely that in
any given population there will be less exposure to and
consequently less selection against, rare alleles, particularly
in populations where the prevalence of the condition has
increased recently. It is worth noting that there are also
striking differences between HIV and HCV in HLA types
associated with protection [61].
HLA and cancer
The theoretical model, which explains the manner through
which there is unrestrained growth of cells that are
different from those of the tissue from which they
originate, is based on the modification of surface molecules
that determine the recognition of self-cells by the immune
Y. M. Mosaad
system. Tumour cells do not respond to the regulatory
stimuli that normally limit tissue proliferation. Carcino-
gens and oncogenic viruses activate genes that destabilize
cell proliferation and repair. As a result, some cell-surface
antigens are lost and others are expressed. At the end of this
process, the tumour may no longer be recognized by the
immune system [62]. Structural and functional changes in
HLA, loss of expression of tumour antigens, lack of
co-stimulatory molecules and production of immunosup-
pressive cytokines are some of the possible mechanisms that
cause tumour cells to escape immune surveillance [63].
In humans, tumours alterations in the surface expression
and/or function of HLA class I antigens are frequently
found and equip neoplastic cells with mechanisms to escape
immune control. The aberrant expression of HLA class I
molecules can be caused by structural alterations or
dysregulations of genes encoding the classical HLA class
I antigens and/or components of the HLA class I APM. The
dysregulation of APM components could occur at the
epigenetic, transcriptional or post-transcriptional level.
Interestingly, none of the HLA class I and II alleles have
been demonstrated to be associated with an increased
incidence per se of any cancer. However, individual alleles
are known to be overrepresented in certain cancers or
correlate with survival, prognosis, higher tumour staging,
grading, disease progression and failure to CD8+ T cell-
based immunotherapies [64–66].
HLA-A*02 allele is associated with poor prognosis in
different cancers such as ovarian, prostate, melanoma and
lung cancer [66]. In the same time, in advanced ovarian
cancer, HLA-A2 is a negative clinical prognostic factor [67]
and it is phenotype overrepresented in both ovarian and
prostate cancer in Swedish patients compared to the normal
population [68]. At the genetic level, it is possible to
consider a linkage of HLA-A*2 allele to putative onco- or
tumour suppressor genes and could explain the increased
potential for oncogenic transformation of cells and thus an
increased mortality in these patients. At the epigenetic
level, it is speculated that a specific HLA-A2 microRNA
(miR181a) downregulate the HLA antigen expression in
the HLA-A2 patients. During the initial oncogenesis, the
transformed cells may upregulate transcription of the MHC
genes which serve to absorb and engage the pool of
miRNA. Potentially, this may prevent translation of HLA
antigen message which impedes expression of HLA antigen
and immune recognition. Moreover, normal regulatory
functions of the miRNA are also compromised as the
‘decoy’ transformed cells absorb and engage the available
pool of miRNA [66, 69].
Downregulation or complete loss of HLA class I gene
expression has been reported in a variety of human solid and
haematopoietic malignancies such as melanoma, colorectal,
breast, lung and cervical carcinoma, and these changes were
ranged from 3.4% to 60% depending on the tumour
subtype analysed. In addition, loss of heterozygosity at the
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HLA loci is a frequent event in some tumour entities-like
colorectal carcinoma and melanoma, but not in others, like
renal cell carcinoma and could therefore contribute to the
downregulation of HLA class I antigens in selected tumour
types [64]. The molecular mechanisms leading to defects in
the HLA class I antigen presentation pathway have been
well characterized upon viral infections. The human
cytomegalovirus (HCMV) represents one suitable model
for viral interference with the HLA class I antigen
presentation pathway. For example, HCMV encodes at
least four proteins that impair the antigen-processing
pathway at different steps from proteasomal degradation
to peptide transport, formation of the trimeric HLA class I
HC/b2 m/peptide complex to its transport to the cell
surface [64]. Furthermore, many other viruses also interfere
with the HLA class I APM [70].
These deviations include the complete absence or
downregulation of HLA class I expression or of HLA class
I allo-specificities in frequent association to an impairment
of a single or various members of the antigen-processing
and antigen-presenting machinery. In most cases, it seems
that the HLA class I abnormalities result from a deregu-
lation rather than a structural defect suggesting an
intervention at the epigenetic, transcriptional and or
post-transcriptional level [71]. This observation increases
even more the importance of studying the crosstalk
between the tumour cells and the microenvironment [72].
HLA-G, -E and -F are important regulators of the
immune system, and their role in tumour immunology is
attracting a steadily growing interest. The upregulation of
HLA-G, -E and -F following interferon-c stimulation
suggests that non-classical HLA class I molecules may be
involved in negative feedback responses to potentially
harmful pro-inflammatory responses. Inflammation is also
one of the hallmarks of cancer. While inflammatory
responses are required to eliminate cancer cells, they also
trigger strong immuno-regulatory mechanisms that limit
the recognition of malignant cells by the immune system,
hence favouring tumour progression. Thus, tumour results
in the recruitment strongly immunosuppressive cells such
as Tregs, myeloid-derived suppressor cells and tumour-
infiltrating macrophages [72]. Non-classical HLA class I
molecules constitute another means whereby malignant
cells escape immuno-surveillance. Indeed, these molecules
inhibit the activity of the immune system by binding to
inhibitory receptors expressed by effector cells, hence
suppressing their functions or inducing their apoptotic
demise [73, 74]. Thus, the molecules might become an
important target for anticancer immunotherapy. Interfer-
ing with the functions of non-classical HLA class I
molecules might robustly boost the antineoplastic poten-
tial of cytotoxic effectors while antagonizing the activity of
intrinsically immunosuppressive cells. The specific mech-
anisms whereby these molecules control excessive inflam-
mation are currently under investigation for therapeutic
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 293
purposes, not only in the context of anticancer immuno-
therapy [72].
HLA and transfusion
The HLA class I antigens are carried in high concentration
by leucocytes and platelets, but only in trace amounts on
erythrocytes. Each transfusion of either platelets or leuco-
cytes therefore carries a risk of immunizing the patient.
Patients, with an intact immune system, who require
multiple transfusions of whole blood, platelets or leucocyte
concentrates, will therefore usually develop antibodies to
HLA antigens. Anti-HLA antibodies may lead to two
problems. Firstly, these patients become refractory to
platelet transfusions, which they destroy rapidly, and
secondly, non-haemolytic transfusion reactions may occur
in response to HLA antigen [10].
In the circulation, platelets have the greatest amount of
circulating HLA class I molecules and most of these HLA
molecules are adsorbed on the platelets. The majority of
HLA antigens on the platelet surface are composed
primarily of heavy chains; therefore, they have the ability
to dissociate from the platelet especially with storage.
When platelets are transfused into an allogeneic recipient,
the host is thus exposed to a huge dose of potentially
altered donor HLA class I molecules. The donor HLA
molecules (whether still associated with the platelet or not)
eventually circulate through the spleen and are either
phagocytosed (e.g. the platelet-associated class I) or taken
up by pinocytosis (soluble class I) by cells (e.g. macro-
phages) of the reticuloendothelial system. These initial
uptake mechanisms allow for recipient splenic macrophag-
es and DCs to potentially act as APC that stimulate the
host’s adaptive immune system and the eventual produc-
tion of IgG antidonor antibodies [75].
During the era of donor-specific transfusion, patients
were given blood from their prospective transplant donors,
typically three reduced volume transfusions during a period
of 1–2 months. Under these protocols, many patients were
transfused with blood from HLA-typed donors who had a
variable degree of HLA match such as HLA-DR-matched
transfusions, partially or totally HLA-matched donor
transfusions. As expected, when more HLA antigens were
matched, there was an independent association with a
significantly decreased risk of sensitization [76, 77].
Patients receiving blood transfusion in the first five
years on the waiting list of transplantation is associated
with a fivefold higher risk of death and an 11% reduction
in the likelihood of ever receiving a transplant. In the same
time, after transplantation, the presence of preformed HLA
antibodies is associated with an increased risk of early and
late graft loss. Also, the pre-existing donor-specific HLA
antibodies identified by Luminex at the time of transplan-
tation are associated with a higher incidence of antibody-
mediated rejection and inferior graft survival [78–81].
294 HLA in Health and Disease Y. M. Mosaad
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HLA and end-stage renal disease

Kidney failure is traditionally regarded as the most serious
outcome of chronic kidney disease, and symptoms are
usually caused by complications of reduced kidney func-
tion. When symptoms are severe, they can be treated only
by dialysis and transplantation; kidney failure treated in
this way is known as end-stage renal disease (ESRD). The
role of the HLA system in the pathophysiology of ESRD is
intriguing, but not completely resolved. Numerous asso-
ciations and non-associations of HLA with ESRD have been
reported in the medical literature, but with controversial
results in Table 1 [82–93].
The HLA-B8, DR3 haplotype is remarkable for its
association with a number of autoimmune diseases such as
lupus, Type 1 diabetes mellitus and IgA deficiency [94].
The extended HLA-B8, DR3 haplotype (8.1 AH) is highly
conserved [95] and in LD with the tumour necrosis factor
(TNF*2) promoter allele which leads to a genetically high
setting of TNF-a [96, 97] and C4AQ0, which leads to
defect in opsonization and clearance of immune complexes
[98]. Studies in healthy individuals have revealed an altered
balance of cytokines produced in carriers of the haplotype
such as an impaired production of IL-2, IL-5, IL-12 and
INF-c after a mitogen stimulus [99]. The immune response
is thus skewed towards Th2 cytokine production and the
humoral response, although IL-5 production is also
depressed [100]. Furthermore, both an increased produc-
tion of autoantibodies [101] and an increased blood
lymphocyte spontaneous apoptosis are observed resulting
in low levels of circulating lymphocytes [102].
HLA and Transplantation
In addition to situations in which a malfunction of the
HLA system occurs, problems can arise when it functions
too well. This is the case when one attempts to transplant
tissues or organs between genetically disparate individuals
of the same or different species (allografts and xenografts,
respectively). The T cell receptors of the recipient’s
lymphocytes recognize either the donor’s (allogeneic)
HLA molecules on APC of the graft (a process known as
direct presentation) or the donor’s HLA molecules on APC
of the recipient (a process known as indirect presentation).
During indirect presentation, the peptides are generated by
the degradation of the allogeneic HLA molecules released
from the graft [4, 103].
Haematopoietic stem cell transplant
The HLA system is the primary immunologic barrier to
successful stem cell transplant. Therefore, the clinical
outcomes of haematopoietic stem cell transplant (HSCT)
are dependent on optimizing the histocompatibility
matching between the patient and the donor. The HLA
antigens are effective stimulators and targets of graft versus
host disease (GVHD) and graft rejection. HLAs possess
outstanding ability to elicit an immune response either by

Table 1 HLA association with end-stage renal disease..

Sample tested
Population patient/control HLA susceptibility OR HLA protection OR References

Kuwaiti 334/191 HLA-B8 2.62 HLA-28, B18, DR11 0.42, 0.32, [82]
0.44
Caucasian 177/106 HLA-B35, B8/DR3 – HLA-B27, B40, DR13 – [89]
European 1620/1211 HLA-B35, DR5 1.5, 1.74 HLA-B7, B8, DR2, DR3 0.65, 0.64, [85]
0.45, 0.67
African 250/4506 HLA-DR3, -DR5 2.2, HLA-DR7 0.53 [90]
Americans 1.6
and whites
Iranian 26/51 HLA-A11, A33, B49 – Non – [92]
Braziliana 105/160 HLA-A78, DR11 30.3, 18.8 HLA-B14 29.9 [91]
Iraqi 200/110 HLA-A2 in Arab 3.6 Non – [93]
HLA-B35 in Kurdish 3.9
Egyptiana 37/100 HLA-B27, A11, B13, B12 3.7, 2.7, 2.9 Non – [86]
Egyptian 207/250 HLA-A2, B8, – Non – [87]
DRB1*3, DRB1*11
Saudia 235/60 HLA–DQB1 *03 3.7 HLA Cw2 0.46 [88]
Turkish 587/2643 HLA-B58 – HLA-A11, 23, 24, 26, – [84]
29, 30, 32, 66, 68, 69;
HLA-B7, 57; HLA-DRB1*11
Venezuela 188/202 B38, B51, 2.42, 2.55, 2.57, 3.75 HLA-A9, B12, B17, B40, 0.25, 0.16, [83]
B53, B62 B48 0.15, 0.19, 0.08

OR, odds ratio.

a
Relative risk.

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Y. M. Mosaad
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presentation of variable peptides or by recognition of
polymorphic fragments of foreign HLA molecules. In the
future, evaluation before HSCT is likely to comprise a
more detailed genetic analysis of patient and donor, but
currently the standard is HLA typing at A, B, C, DRB1
and DQB1 genetic loci [104, 105].
After 1998, when better HLA typing methods replaced
DNA fingerprinting, serology and low-resolution methods
used for final donor matching the overall survival of
transplant patients have improved greatly. Most studies
now agree that HLA-DQB1 does not need to be considered
in a well-matched donor, but there is evidence that there
may be additive effects of a DQB1 mismatch, if a mismatch
at another locus is present. In certain circumstances (and
particularly if more than one donor is available), typing for
the HLA-DPB1 locus should be performed and the degree
and type of matching considered in donor selection
[105–108].
Petersdorf [9] summarized the rich history of studies
investigating the importance of HLA matching in HSCT
either unrelated donor transplantation or cord blood
transplantation. In unrelated donor HSCT, there are five
major concepts regarding the role of donor HLA mis-
matching and GVHD: (1) type and match at high
resolution, (2) consider HLA-DP especially if HLA-A, C,
B, DR, DQ-matched donors are available, (3) when
matched donors are not available, limit the total number
of HLA mismatches, (4) when selecting among HLA-
mismatched donors, distinguish allele from antigen mis-
matches and (5) consider KIR ligands, KIR alleles, and KIR
haplotypes. In cord blood transplantation, there is strong
evidence that fewer mismatches are associated with overall
improved outcome and that HLA-associated effects are
influenced by the cell dose of the cord blood unit (s). Like
unrelated donor HSCT, there is emerging evidence that
matching the cord blood unit for HLA-C will lower post-
transplant complications [105, 106].
HLA sequence polymorphisms that are recognized by
antibodies (serologic method) are termed antigens, whereas
those that can be identified only by DNA-based typing
methods are termed alleles [109]. Any given HLA antigen
may be encoded by a family of HLA alleles with similar
nucleotide sequences. Transplant donor and recipient pairs
with different HLA antigens always have different alleles
(antigen mismatched), and pairs with the same allele
always have the same antigen (matched). Some donors and
recipients with the same HLA antigen have different alleles
(allele mismatched). With few exceptions, HLA allele
mismatches are characterized by amino acid substitutions
in the regions of the HLA molecule that bind peptides for
presentation to T cells, whereas HLA antigen mismatches
are characterized by amino acid substitutions relevant to
both peptide binding and contact with T cells [110].
There are conflicting data concerning the value of
selecting an allelic mismatch over an antigenic mismatch.
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 295
Petersdorf et al. [111] did not find any apparent difference
between allele and antigen mismatches with respect to the
number of deaths from transplants, suggesting that donors
with a single HLA allele of antigen mismatch may be used
for HSCT when a fully matched unrelated donor is not
available for patients with severe diseases not permitting
time for a lengthy search. There were no significant
differences in survival depending on whether the mismatch
was allelic or antigenic were reported by Lee et al. [112],
except for antigenic mismatch at HLA-C. However,
Flomenberg et al. [113] found that antigenic mismatch
was associated with higher mortality compared to allelic
mismatch. They indicated that selection of donors with
high-resolution mismatches over those with low-resolution
mismatches may lower the rate of post-transplant compli-
cations [114].
While the role of donor-specific antibodies (DSA) in
solid organ transplantation is well established, their
importance in HSCT is only now becoming clear. A
review of the literature reporting on HLA immunization in
HSCT provides ample circumstantial evidence that DSA
are associated with a twofold to tenfold increase of graft
failure of HLA-mismatched HSCT, irrespective the type of
the graft or the patient conditioning. HSCT with HLA-
mismatched donors is for many patients the only curative
option. Relapse of malignancy, GVHD and post-transplant
infections still poses considerable hurdles for transplant
success. The contribution HLA antibodies to transplant
outcome have been a relatively neglected focus until
recently. However, not all HLA antibodies can cause graft
failure which may depend on antigens involved, titre or
other, as yet unravelled, functional antibody potentials. A
higher number of stem cells may overcome rejection in the
case of low strength antibodies, but it is impossible to give
more specific recommendations. Even less can be concluded
from approaches to reduce DSA. It seems reasonable to aim
for a negative or low titre DSA at the moment of HSC
administration and to inhibit antibody-mediated cell
destruction machinery by blocking the macrophage.
Although the role of DSA in graft failure is becoming
acknowledged, non-DSA antibodies may also be a con-
founder in the search for a broader repertoire of allo-
antibodies affecting transplant outcome. It is obvious that
progress calls for registration and collaboration to resolve
confusion around test results. For this aim, the assessment
of HLA antibodies should be included in HSCT manage-
ment protocols [115].
Renal transplantation
Although the impact of HLA compatibility has been
recognized for two decades, the advances in immunosup-
pression protocols are such that rejection episodes are
managed more efficiently, thus minimizing the importance
of HLA matching. A study based on the United Network
296 HLA in Health and Disease
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for Organ Sharing (UNOS) data reported that the impact
of HLA compatibility had greatly diminished [116].
Consequently, some allocation programs have gradually
toned down the role of HLA matching from the algorithms
used for prioritizations on the waiting list. The lower
importance of HLA matching was also favoured in the early
years of the 21st century with the advent of the microarray-
based Luminex technology for detecting DSA, thus
allowing organ allocation around well characterized HLA
specificities [117].
However, the results of Opelz and Dohler [118] on a
large study cohort (135,970 kidney transplants) clearly
showed that the significance of HLA matching on graft
survival rate has not lost its importance, and this is obvious
when comparing the decades 1985–1994 and 1995–2004.
Even when analysing the last five years of the study period
separately (2000–2004), a significant correlation of graft
survival with HLA matching was disclosed [118]. An
analysis of the Scientific Registry of Transplant Recipients
(SRTR) database (1988–2007) consisting of >15,000 re-
transplant candidates revealed the negative effect of poor
HLA matching on graft survival after the first transplan-
tation and was associated with a significant increase in the
development of anti-HLA antibodies measured by panel
reactive antibody (PRA) proportional to increasing HLA
mismatches. Only 10% of patients with zero HLA-A and
HLA-B mismatches became newly sensitized after graft
loss compared to 37% (>30% PRA) in transplants with a
greater extent of HLA mismatches [119].
In addition to the classical HLA-A, HLA-B and HLA-
DR antigens, the role of HLA-C and HLA-DQ antigens in
terms of graft survival or sensitization is now documented
[120, 121]. Analysis of the immunogenicity of incompat-
ible HLA-A, HLA-B antigens in terms of the numbers of
amino acid residue mismatches (epitopes mismatches) is
associated with better transplant outcome than conven-
tional matching based on HLA typing by serology [122].
Although anti-DP antibodies are frequently detected in
sensitized patients, their impact on transplant outcome is
still not clear and needs to be further evaluated [117]. In
the context of kidney transplantation from live donors,
donor age and HLA matching have recently been shown to
be independent donor-related risk factors associated with
both decreased patient and graft survival [123].
HLA and drug sensitivity
Allergic drug reactions occur when a drug, usually a low
molecular weight molecule, has the ability to stimulate an
immune response [124]. Several alternative mechanisms of
immune recognition have been proposed to explain HLA-
associated drug hypersensitivity. These mechanisms
include the hapten (or pro-hapten) concept, which states
that drugs and their metabolites are too small to be
immunogenic on their own, but act as haptens to modify
Y. M. Mosaad
certain self-proteins in the host that lead to immune
recognition of the resulting hapten: self-peptide complexes
as de novo antigens [125]. The superantigen interaction
concept states that drugs may bridge TCR and HLA
molecules without binding directly to peptide antigen
[126]. The p-i concept (short for pharmacological interac-
tion with immune receptors) states that drugs can induce
the formation of HLA:drug complexes that can activate T
cell immune responses directly without requiring a specific
peptide ligand [127]. Recently, several groups reported
data suggested that these commonly considered mecha-
nisms mentioned above may not apply in the case of
abacavir. Instead, abacavir seems to alter the peptide
repertoire presented by HLA-B*57:01 by occupying sites
within the antigen-binding cleft [128, 129]. The poly-
morphic residues implicated in drug interactions suggest
that different drugs may bind HLA molecules or other
elements of the trimolecular complex (HLA, peptide and
TCR) in alternative binding modes [130].
Because most drugs are low molecular weight chemi-
cals, in theory too small to be able to stimulate the
immune system, it has long been assumed that the drug or
a reactive metabolite must first bind covalently to a
macromolecule such as a protein, forming a multivalent
conjugate that is processed and presented by the immune
system to T cells [131]. Probably, the clearest example of
drug haptenation is that which occurs with penicillin,
which is chemically reactive and undergoes stable covalent
binding to proteins or peptides, resulting in the creation of
an immunogenic self-protein [124].
The drug or a reactive product reacts with a self-protein
or peptide which results in formation of a novel drug
conjugate or adduct. This undergoes antigen processing to
generate a small, but novel HLA ligand that is loaded onto
the HLA and transported to the cell surface, where it can
interact with antigen-specific T cells. This process requires
a metabolically active APC and time. Once generated, the
HLA drug–peptide complex is stable and ligand removal
requires peptide exchange or peptide stripping from the
HLA groove [124, 132].
However, not all drugs seem to be capable of interacting
covalently with proteins, and some immune reactions to
drugs occur without antigen processing. This has led to the
pharmacological interaction or p-i hypothesis, whereby
some chemically inert drugs are able to bind non-
covalently to antigen-presenting structures such as the
TCR or HLA and cause stimulation directly of an immune
response, as is the case with sulfamethoxazole [133]. Most
drugs have been designed to fit into protein pockets in
receptors and enzymes. The drug interaction with the
receptor is highly specific such that small changes in drug
structure can affect reactivity. T cell activation can occur
rapidly, before metabolism and processing of the drug
could occur. However, the reactions that occur are the same
as those induced by a drug-modified peptide antigen,
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because the immune response once activated proceeds in a
fixed way. The hypothesis could explain why reactions can
sometimes occur without known previous sensitization
[124].
The role of the HLA in drug allergy has received
particular attention with regard to certain drugs and ethnic
groups. The drug hypersensitivity syndrome caused by
abacavir is strongly associated with HLA-B*5701, and key
structures in the peptide-binding cleft of HLA-B*5701
have been identified that permit non-covalent interactions
with this drug [134–136]. This binding may also occur in
so-called empty, non-peptide bearing MHC class I mole-
cules. The binding of abacavir to the F pocket of HLA-
B*5701 alters the spectrum of self-peptides that can be
presented by this MHC class I molecule. This results in the
display of a novel peptide repertoire that appears foreign to
the immune system. Memory T cell responses in abacavir-
hypersensitive donors are directed against a self-peptide
that requires abacavir to efficiently bind to HLA-B*5701.
The situation is then analogous to alloreactions with the
development of a severe cytotoxic response through the
activation of cross-reactive effector memory cytotoxic T
cells. The rapidity of onset of the reaction and its intensity
may depend upon differences in TCR avidity [124, 137].
HLA and pregnancy problems
Cases of recurrent abortions, pre-eclampsia or babies born
with haemolytic diseases of the newborn raise a question
‘Why did your mother reject you?’ Although, after looking
at the complexity of the maternal-foetal immune interac-
tion and the cases of successful pregnancies, with surprise
and admiration the question now becomes ‘Why didn’t
your mother reject you?’ The cells from the placenta are the
only part of the foetus that interacts directly with the
mother’s uterine cells, and therefore, the maternal immune
system is able to evade immune rejection. The foetus itself
has no direct contact with maternal cells. Moreover, the
foetus per se is known to express paternal HLA antigens and
is rejected as allograft if removed from its cocoon of
trophoblast and transplanted to the thigh muscle or kidney
capsule of the mother. A number of mechanisms have been
proposed to account for the immune-privileged state of the
decidua. The different hypothesis can be summarized in
five main ideas: (1) a mechanical barrier effect of the
trophoblast, (2) suppression of the maternal immune
system during pregnancy, (3) the absence of HLA class I
molecules in the trophoblast, (4) cytokine shift and more
recently and (5) local immune suppression mediated by the
Fas/FasL system [138].
The discovery that foetal cells are devoid of the highly
polymorphic HLA class Ia molecules, except for a low
expression of HLA-C, is believed to play a dominant role
for the induction of tolerance to the semi-allogenic foetus
[139]. Interestingly, the foetal-derived tissue in placenta
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 297
does express the less polymorphic HLA class Ib molecules,
HLA-E, HLA-F and HLA-G, which has led to increased
interest in the immunological role of these three proteins
during pregnancy [140].
For many years, the term ‘foetal allograft’ has been
widely used for description of foetal immunological status
during pregnancy. In such an approach, immunological
acceptance describing maternal reaction directed towards
foetal antigens is understood as the state of recipient’s
tolerance to an engrafted organ. Consequently, immuno-
pathological recognition of foetal antigens that occurs in
recurrent pregnancy loss (RPL) or recurrent miscarriage
(RM) and possibly pre-eclampsia (PE) should be viewed as
graft rejection-like alloimmune reaction. However, there
are still some doubts concerning this approach, as some
proofs speak against it. For example, absence of expression
of classical HLA antigens on the surface of trophoblast,
foetal survival is not affected by the HLA-sharing between
partners and no impact on the pregnancy outcome for the
blocking anti-HLA. Recurrent pregnancy loss is thought to
be due to increased activity of the innate immune system
(especially NK cells) and organ specific auto-immunity as
indicated by a higher prevalence of autoantibodies and its
association with particular maternal class II HLA geno-
types especially HLA-DR [141].
Lack of classical HLA antigens on trophoblast has been
postulated as an argument against the hypothesis that
foetal rejection is akin to allograft rejection. However,
downregulation of HLA-G molecules and increased expres-
sion of classical HLA antigens were documented in RPL
and PE pregnancies. The sparse presence of anti-HLA
antibodies in RPL patients resulted probably from the
failure to carry gestation long enough to produce response.
They could originate from recognition of classical HLA
antigens expressed on small remnants of trophoblast and
foetal membranes exposed to maternal effector cells
‘cleaning up’ uterine cavity post-delivery. Anti-HLA
antibodies are not able to affect adversely the next
pregnancy with the same partner, as classical HLA targets
are hidden, and trophoblast exposed to maternal immune
recognition is protected by HLA-G [141, 142].
HLA-G has many immune regulatory functions in
pregnancy. First, HLA-G interact with the inhibitory
receptors, immunoglobulin-like transcript-2 and -4 (ILT-2
and ILT-4) expressed by a wide variety of immune cells
especially monocytes, macrophages and DCs. The binding
affinity of these receptors for HLA-G is higher than for
other HLA class I molecules. In the same time, these
receptors compete with CD8 in binding HLA-G, which
could prevent activation of cytotoxic CD8+ T cells, thereby
contributing to the induction of tolerance. Furthermore,
HLA-G has been shown to upregulate both ILT-2 and ILT-
4, along with the killer-cell immunoglobulin-like recep-
tor-2DL4 (KIR2DL4), on the surface of both APC, NK
cells and CD4+ T cells without preceding antigenic
298 HLA in Health and Disease Y. M. Mosaad
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co-stimulation. This provides an interesting possibility Table 2 HLA association with recurrent pregnancy loss..
that these receptors function at the materno-foetal interface
Sample tested
by raising the threshold of the maternal immune system Population patient/control HLA susceptibility OR References
activation, thereby serving to induce tolerance [140, 143,
144]. Egyptian 108/120 HLA-E*0101 1.7 [149]
The HLA-E protein is one of the most extensively Homozygous 2.02
0101/0101
studied HLA class Ib antigens and the least polymorphic
Indian 120/120 HLA-E*0101 1.48 [148]
one compared to other HLA class I molecules. In the Homozygous 1.94
human population, there have been reported just ten alleles 0101/0101
encoding three different peptides. Only two of these alleles, New Zealand 45/17 No association – [150]a
namely HLA-E*0101 and HLA-E*0103, are widely dis- Caucasians/ 78/52 No association, 1.85 [153]
Germany but
tributed (around 50% each). The proteins encoded by these
in women
alleles differ from each other in one amino acid at position with ≥5
107. In HLA-E*0101, it is arginine, and in HLA-E*0103, RPLs: Trend for
it is glycine. The difference between these proteins E*0101 and
manifests itself in surface expression levels, affinities to E*0102
Japanese 30/38 No association – [151]
leader peptides and thermal stabilities of their complexes.
Danish 82/150 No association – [152]
The HLA-E molecule is a ligand for CD94/NKG2
receptors on NK cells and TCR on NK-CTL, so it plays OR, odds ratio.
a double role in both innate and adaptive immunity [145,
a
The samples tested were placental and decidual biopsy, all other studies
were EDTA blood.
146].
Several studies have focused on the distribution of
these two alleles in women experiencing RPL (Table 2) T1D, a multifactorial disease with a strong genetic
[147–152]. Expression of HLA-E at the feto-maternal component, is caused by the autoimmune destruction of
interface may be implicated in the successful pregnancy pancreatic b cells. The major T1D susceptibility locus
because of its ability to downregulate maternal immune maps to the class II loci HLA-DRB1 and HLA-DQB1 on
response. In the decidua, the area of the interface where chromosome 6p21 [154]. The highest risk DR/DQ hapl-
feto-maternal interaction occurs, CD56-positive NK cells otypes for T1D are DR3-DQA1*0501-DQB1*0201 (DR3)
are the dominant type of lymphocytes and express CD94: and DR4-DQA1*0301-DQB1*0302 (DR4), and these
NKG2A complex, suggesting that HLA-E protein on the alleles account for 30–50% of genetic T1D risk [155].
trophoblasts can be recognized by the maternal immune The association of specific HLA-DQB1 alleles and geno-
cells. Thus, the expression of HLA-E might play a role in types with T1D susceptibility/protection depends on the
preventing the foetus from being attacked by maternal ethnicity and racial background of each population. For
immune system. Evidence showing lower expression of example, in Caucasians, T1D is positively associated with
HLA-ER (0101), and its lower stability may impair its DQB1*0201 and DQB1*0302 while in Japanese, it is
capability to downregulate NK cells and hence may be associated with DQB1*0401 and DQB1*0303 [156].
associated with RPL [146–148]. Although HLA-DR3/4 genotype confers extremely high
risk, there is a spectrum of risk associated with HLA-DR/
DQ genotypes – from increased, to neutral, to protective.
HLA and autoimmune diseases
For instance, the HLA-DQA1*0102, DQB1*0602 haplo-
Strong association between the HLA region and autoim- type confers dominant protection from T1D, even in the
mune disease (AID) has been established for over 50 years. presence of islet autoantibodies. However, while the
Association of components of the HLA class II-encoded incidence of T1D is increasing, the percentage of patients
HLA-DRB1-DQA1-DQB1 haplotype has been detected carrying the high-risk HLA-DR3/4 genotype is decreasing.
with several AIDs including RA, T1D and Graves’ disease These temporal changes in HLA genotypes suggest
(GD). Molecules encoded by this region play a key role in increased environmental pressure with higher disease
exogenous antigen presentation to CD4+ Th cells, indi- progression rate in individuals with lower-risk HLA
cating the importance of this pathway in AID initiation genotypes and/or contribution of other non-HLA class II
and progression. Association of the HLA class I region, alleles or non-HLA-related alleles to T1D risk [154].
independent of known HLA class II effects, has now been A stronger association with the DQB1 locus alone was
detected for several AIDs, including strong association of reported when an allele-encoding aspartic acid (Asp) at
HLA-B with T1D and HLA-C with multiple sclerosis (MS) position b57 of DQB1 was found to be associated with
and GD. These results provide further evidence of a resistance to T1D, while an allele encoding a neutral
possible role for bacterial or viral infection and CD8+ residue, such as alanine (Ala) or serine (Ser) at position b57
T cells in AID onset [153]. conferred susceptibility. This molecule forms a critical

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Y. M. Mosaad
..................................................................................................................................................................
residue in peptide-binding pocket nine (P9) of the DQB1-
binding pocket involved in antigen presentation and TCR
interaction. Its carboxylate group forms a salt bridge with
arginine (Arg) at position a57 of the DQA1 chain that
stabilizes the heterodimer between the DQA1 and DQB1
chains. The presence of Asp at this position could alter the
stability of the molecule and/or antigen-presenting reper-
toire, thus making the molecule more prone to binding
autoreactive antigens [153, 157].
The term ‘Shared Epitope’ (SE) most commonly refers to
a five amino acid sequence motif in residues 70–74 of the
DR chain coded by several HLA-DRB1 alleles that are
overrepresented among patients with RA. The SE motif
consists of three homologous amino acid sequence variants:
(1) QKRAA, the SE variant that is the most common motif
among Caucasian, is coded primarily by the HLA-
DRB1*0401 allele, (2) the second most common motif,
QRRAA, is coded by several alleles, among them HLA-
DRB1*0404, HLA-DRB1*0101 and HLA-DRB1*0405
and (3) the third motif, RRRAA, coded by allele HLA-
DRB1*1001, is the rarest. In addition to increasing RA
risk, SE-coding HLA-DRB1 alleles have been shown to
associate with more severe disease and to exhibit allele-dose
effect, that is patients with two SE-coding alleles tend to
experience more severe disease than patients with one
allele, who, in turn, have more severe RA than SE-negative
patients [158, 159].
The mechanism underlying the effect of the SE is
unclear, but it was postulated that the presentation of
arthritogenic self-peptides, molecular mimicry with for-
eign antigens or T cell repertoire selection are involved.
While these hypotheses are all plausible, they are difficult
to reconcile with the fact that data-supporting antigen-
specific responses as the primary event in RA are
inconclusive. Additionally, several other human diseases
have also been shown to be associated with SE-encoding
DRB1 alleles such as T1D, SLE and autoimmune hepatitis
[160].
An immense number of studies based on different
ethnicities have identified HLA class II associations with
SLE especially the haplotypes containing DR2 and/or DR3
alleles. The haplotypes containing DR2 and/or DR3 are
directly involved in disease pathogenesis, clinical presen-
tation, lupus nephritis and production and specificity of
autoantibodies. Studies in European populations identified
a potential association of the class II HLA-DRB1 alleles
HLA-DRB1*08:01, -*03:01 and -*15:01 with SLE. Two
of these alleles (HLA-DRB1*03:01 and -*15:01) have also
been identified in a recent study of the IMAGEN
consortium using high-density SNP typing across the
MHC and in other populations (Table 3) [161–174].
Multiple sclerosis is a chronic disabling disease of the
central nervous system that results from the effects of
unknown environmental risk factors acting in genetically
susceptible individuals [175]. Susceptibility to MS has
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 299
been linked mainly to the HLA-DRB1 locus, with the
HLA-DR15 haplotype (DRB1*1501-DQA1*0102-
DQB1*0602-DRB5*0101) dominating MS risk in Cauca-
sians. Although genes in the HLA-II region, particularly
DRB1*1501, DQA1*0102-DQB1*0602, are in tight LD,
GWAS and gene, candidate studies identified the
DRB1*15:01 allele as the primary risk factor in MS. Many
genetic and immune-functional studies have indicated
DRB1*15:01 as a primary risk factor in MS, while only
some functional studies suggested a disease-modifying role
for the DRB5*01 or DQB1*06 alleles [176].
Several non-mutually exclusive mechanisms have been
proposed to explain association of DR/DQ with AIDs: (1)
variation in binding groves of associated DR/DQ molecules
could lead to preferential presentation of only a specific
limited set of self-peptides or low affinity self-peptides may
allow autoreactive T cells to escape tolerance and enter the
periphery. This could affect thymic T cell education,
causing incomplete thymic tolerance and a Th and Treg
cell population that does not recognize all self-molecules,
(2) polymorphic residues of the TCR-exposed surfaces of
DR/DQ could select autoreactive T cells or fail to select a
good Treg population, (3) promiscuous restriction where
some TCRs will use a series of different restriction
elements to bind to and, therefore, interact with a wider
variety of different peptides, (4) preferential binding in
DR/DQ heterozygous subjects could be occurring through
epitope stealing by one HLA molecule over another which,
depending on TCR restriction of CD4+ Th cells, could
affect whether an immune response is mounted and (5)
presentation of endogenous antigens by HLA class II.
Although class II molecules traditionally present exoge-
nous antigens and class I present endogenous antigens, this
system is not absolute and presentation of endogenous
antigens by class II and exogenous antigens by class I can
be seen. This could alter how these antigens are presented
to the immune system and the response triggered. These
hypotheses suggest a series of potential mechanistic
pathways by which the HLA class II molecules could be
involved in disease onset by altering the Th and Treg cell
repertoire or through changes in how the antigen is
recognized in the periphery [153, 177–181].
Ankylosing spondylitis is a complex disease involving
multiple risk factors, both genetic and environmental. AS
patients are predominantly young men, and the disease is
characterized by inflammation and ankylosis, mainly at the
cartilage–bone interface and enthesis. HLA-B27 has been
known to be the major AS-susceptibility gene for more
than 40 years and is present in over 90% of AS patients.
There are about HLA-B*27 31 alleles with the B*2701,
B*2704 and B*2705 alleles are strongly associated with
susceptibility, and the B*2706 and B*2709 alleles are
associated with protection. The presence of amino acid Asp
or histidine (His) at position 116 is the only difference
between B*2705 and B*2709. There are three principle
300 HLA in Health and Disease Y. M. Mosaad
..................................................................................................................................................................

Table 3 HLA-DRB1 association with SLE..

Sample tested
Population patient/control HLA susceptibility OR References

American 80/213 DRB1*0301 2.3 [162, 163]

(Caucasian)
DRB1*1503 (African-American) –
Chinesea 53/78 DRB1*15, 10.7 [165]
DRB1*09/*15, DRB1*03/*15 7.7, 14.2
Mexican 81/99 DRB1*0301/DRB1*1501 2.97 [166]
Latin 747/1180 DR2 1.75 [167]
Americans DRB1*0301 2.14
Brazilian 55/308 No association – [173]
Taiwanese 105/855 DRB1*0301, DRB1*1501 2.01, 2.06 [168]
Portuguese 218/223 DRB1*03 3.0 [169]
Egyptian 65/150 DRB1*15 4.76 [164]
European 3701/12110 DRB1*0301 1.86 [172]
Japanese 656/911 DRB1*15:01 2.9 [170]
Japanese 459/524 DRB1*1501 2.17 [171]
Saudi 86/356 DRB1*15 1.45 [174]
Indian 53/110 DRB1*03 9.7 [175]

OR, odds ratio.

a
Relative risk.

features of HLA-B27 that are known to distinguish it from
other HLA class I molecules such as the peptide-binding
specificity, the tendency to misfold and the predilection for
forming heavy chain homodimers during cell-surface
recycling [177, 180, 182]. The current hypotheses linking
HLA-B27 to spondyloarthritis pathogenesis includes (1)
Arthritogenic peptides: self-peptides selected and pre-
sented by properly folded forms of HLA-B27 complexed
with b2 m have been hypothesized to be the target of
autoreactive CD8+ T cells and serve as an upstream
initiator of inflammation, (2) recognition of non-canonical
HLA-B27: naturally occurring cell-surface HLA-B27
dimers are hypothesized to be recognized by killer
immunoglobulin receptors (such as KIR3DL2) in the
leucocyte immunoglobulin-like receptor family (LILR) and
trigger inflammation and (3) HLA-B27 misfolding: the
formation of misfolded oligomers and BiP binding by
newly synthesized HLA-B27 heavy chains causes ER stress,
which has intrinsic effects on cellular function that are
hypothesized to promote development of spondyloarthritis.
HLA-B27 can exhibit all three of these behaviours in the
same cell and these concepts are not mutually exclusive
[182].
Several hypotheses have been suggested to explain how
variation in HLA class I genes could trigger autoimmunity.
HLA class I molecules play a role in presenting endogenous
antigens, including those derived from viruses and/or
bacteria, which have been proposed to be key environmen-
tal triggers for AID. Viral/bacterial antigens may trigger
AID through molecular mimicry and via acting as
superantigens. HLA class I molecules could also be
associated with AID due to their role in inhibiting NK
cell activity. Non-viral mechanisms have also been
proposed including: (1) protein misfolding causing specific
molecules to accumulate in the RER, where they are
degraded, potentially causing a pro-inflammatory unfolded
protein stress response or misfolded proteins themselves to
become autoantigenic, (2) conversion of HLA class I
molecules into peptides which could then be presented by
HLA class II molecules to the immune system and an
immune response mounted as has been proposed in AS
with B*27 and (3) peptide binding and presentation by
specific HLA molecules as suggested earlier for HLA class
II molecules with mechanisms including selection of
antigen-specific CD8+ T cells during thymic education,
and positive or negative selection of a strong CD8+ T
suppressor population [153, 179, 183–185].
Other HLA associations
HLA and longevity
Literature data suggest that human longevity may be
directly correlated with optimal functioning of the
immune system. Therefore, it is likely that one of the
genetic determinants of longevity resides in those poly-
morphisms for the immune system genes that regulate
immune responses. Accordingly, studies performed on
mice have suggested that the HLA, known to control a
variety of immune functions, is associated with the lifespan
of the strains. In the last 25 years, a fair number of cross-
sectional studies that searched for the role of HLA genes on
human longevity by comparing HLA antigen frequencies
between groups of young and elderly persons have been
published, but conflicting findings have been obtained. In
fact, the same HLA antigens are increased in some studies,

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Y. M. Mosaad
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decreased or unchanged in others. On the whole that could
lead to hypothesize that the observed age-related differ-
ences in the frequency of HLA antigens are due to bias.
This hypothesis is real for most studies owing to major
methodological problems. However, some studies that do
not meet these biases have shown an association between
longevity and some HLA-DR alleles or HLA-B8, DR3
haplotype, known to be involved in the antigen non-
specific control of immune response. Thus, HLA studies in
human may be interpreted to support suggestions derived
from the studies on congenic mice on HLA effects on
longevity. However, in mice, the association may be by
way of susceptibility to lymphomas whereas, in human
beings, the effect on longevity is likely, via infectious
disease susceptibility. Longevity is associated with positive
or negative selection of alleles (or haplotypes) that,
respectively, confer resistance or susceptibility to disease
(s), via peptide presentation or via antigen non-specific
control of the immune response [186].
HLA and social behaviour
Mate choice studies on rodents and other species usually
find preference for HLA dissimilarity in potential partners.
HLA-associated mate choice studies in humans are based
on three broadly different aspects: (1) odour preferences, (2)
facial preferences and (3) actual mate choice surveys. As in
animal studies, most odour-based studies demonstrate
disassortative preferences, although there is variation in the
strength and nature of the effects. In contrast, facial
attractiveness research indicates a preference for HLA-
similar individuals. Results concerning HLA in actual
couples show a bias towards similarity in one study,
dissimilarity in two studies and random distribution in
several other studies [187].
Most of the genes in the MHC region express extremely
high intrapopulational polymorphism. Such polymorphism
in virtually all vertebrates can hardly be interpreted as an
incidental phenomenon, and dozens of theories have
attempted to elucidate the evolutionary pressures that
have shaped it. First, the polymorphism is maintained by
heterozygote advantage. As HLA gene expression is co-
dominant, HLA heterozygotes express absolutely more
types of functional HLA proteins than homozygotes and
are thus able to present a broader spectrum of peptides.
Second, the HLA polymorphism is a result of frequency-
dependent selection in an evolutionary arms race between
pathogens and the vertebrate immune system. According
to this scenario, pathogens rapidly evolve the ability to
escape recognition of most common host genotypes, for
example by mutation that eliminates all peptides with
affinities to common variants of the host HLA genes.
Third, the maintenance of HLA polymorphism under
variable selection over time due to a varying degree of
pathogen presence. It shows that temporal variation in
Ó 2015 The Foundation for the Scandinavian Journal of Immunology
HLA in Health and Disease 301
resistance itself can maintain polymorphism even without
co-dominant-based heterozygote advantage. Finally, the
HLA polymorphism is maintained by sexual selection.
Individuals of one or both sexes prefer partners possessing a
relatively dissimilar HLA genotype to their own. Selection
of HLA dissimilar partners increases offspring heterozy-
gosity at the HLA and therefore can potentially increase
pathogen resistance in resulting progeny [187].
Conclusion
Most of the genes in the MHC region express high
polymorphism that is fundamental for their function. The
most important function of HLA molecule is in the
induction and regulation of immune responses. Many of
human diseases, such as autoimmune, inflammatory and
malignant, are significantly more common among indi-
viduals carrying particular HLA alleles. HLA-disease
association is the name of this phenomenon, and the
mechanism underlying is still a subject of hot debate.
Social behaviours are affected by HLA genes, and preference
for HLA disparate mates may provide ‘good genes’ for an
individual’s offspring. Also, certain HLA genes may be
associated with shorter life and others with longer lifespan,
but the effects depend both on the genetic background and
on the environmental conditions.
Acknowledgment
The author gratefully acknowledges Doctor Rania Shawky
Hassan, English Department, Mansoura Faculty of Arts for
the English language revision and check of the review. The
Author would like to acknowledge all colleagues at the
Mansoura research Center for Cord Stem Cell (MARC_
CSC).
Conflict of interest
The authors report no conflict of interests. The authors
alone are responsible for the content and writing of the
manuscript.
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