Review

doi: 10.1111/iji.12088

HLA and disease: guilt by association

W. M. Howell

Summary
It is now over forty years since the first associations
between particular HLA antigens and disease susceptibility were described, and the identification of large
numbers HLA-associated diseases parallels our
increased understanding of the genetic complexity of
the HLA system and its extensive polymorphism.
However, surprisingly and frustratingly, clear identification of the underlying mechanisms resulting in a
causative role for HLA polymorphism in the molecular
immunopathogenesis of individual HLA-associated diseases remains the exception rather than the rule. This
review, while not intended to be a comprehensive catalogue of HLA-associated diseases, aims to revisit a
number of well known and more recently described
HLA-associated diseases as exemplars of our current
understanding of the underlying molecular mechanisms which may result in genetic disease predisposition. Such mechanisms may act as pointers for further
investigations in other HLA-associated diseases. The
clinical utility of specific HLA disease associations in
disease diagnosis/exclusion is also considered.

Introduction
It is now over forty years since the first associations
between particular HLA antigens and disease susceptibility were described. These associations involved both
malignant and autoimmune diseases including a crossreactive group of HLA-B antigens and Hodgkins disease (Amiel, 1967), HLA-A2 and acute lymphocytic
leukaemia (Walford et al., 1970) and the much more
well known and now classic association between
HLA-B27 and ankylosing spondylitis (Brewerton
et al., 1973); Schlosstein et al., 1973). In fact, the
identification of HLA-associated diseases parallels our

Department of Histocompatibility and Immunogenetics, NHS Blood

and Transplant, Newcastle upon Tyne, UK
Received 25 June 2013; accepted 10 August 2013
Correspondence: Dr W. Martin Howell, Department of Histocompatibility and Immunogenetics, NHS Blood and Transplant, Holland Drive,
Newcastle upon Tyne NE2 4 NQ, UK. Tel: +44-(0)191-202-4475; Fax:
+44-(0)-191-202-4564; E-mail: martin.howell@nhsbt.nhs.uk

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International Journal of Immunogenetics, 2014, 41, 112

increased understanding of the genetic complexity of

the HLA system and its extensive polymorphism. With
the passage of time, several hundred diseases have
now been reported to occur more frequently in individuals with particular HLA genotypes. These diseases
include a broad spectrum of immune-mediated diseases involving all major organ systems, certain malignancies, infectious diseases and more recently, adverse
reactions to particular drugs. Despite the longevity of
this area of immunogenetics research, clear identification of a causative role for HLA polymorphism in the
molecular immunopathogenesis of HLA-associated diseases remains the exception rather than the rule. There
are a number of underlying reasons for this. The first
requirement in any definitive study is to establish the
exact nature of any HLA genetic association was a
particular disease. This may sound self-evident, but
there are a number of confounding factors. Firstly,
there is strong linkage disequilibrium between several
of the HLA loci, and these loci are extremely polymorphic, with over 9000 HLA alleles now described (Robinson et al., 2013). Secondly, in addition to the
classical HLA loci, there are over 200 genes in the
human MHC, with possibly around 40 expressed
genes with some immune-related function, and many
of these occur on extended haplotypes including HLA.
Thirdly, many reported HLA and disease associations
remain unconfirmed and the early (and some more
recent) literature abounds with very small casecontrol
studies, which are known to be prone to selection bias
and false positive associations. Taken together, large
casecontrol studies in diverse ethnic groups are
required to establish primary HLA associations with a
given disease.
A priori, what mechanisms might underlie a clearly
established HLA association with a given disease? In
terms of the role of HLA molecules in peptide presentation to T cells, a causative role of HLA in terms of
presentation of a disease-triggering self-peptide, nonself-peptide or altered-self-peptide at the site of disease
is clearly an attractive hypothesis. Alternatively, HLA
may play a causative role via influence on the T-cell
repertoire, including Treg cells, resulting in potential
autoreactivity. Other aspects of HLA biology may
additionally or alternatively influence the disease process. Finally, the associated HLA polymorphism may
play no direct role, and the actual disease-predisposing

W. M. Howell

polymorphism may be in linkage disequilibrium with

the initially reported HLA association, which merely
acts as a marker. The HFE association with hereditary
haemochromatosis is a classic example, in which the
original association was reported to be with HLA-A
and B (Simon et al., 1975), prior to discovery of the
HFE gene (Feder et al., 1996). In addition, other
genetic polymorphisms may also contribute to disease
susceptibility, even when HLA polymorphisms play a
direct, significant role.
On the fortieth anniversary of the initial reports of
the HLA-B27 association with susceptibility to ankylosing spondylitis, this short review aims to revisit a
number of well known and more recently described
HLA-associated diseases and summarizes current
understanding of the underlying mechanisms by which
the HLA associations in question may mediate disease
susceptibility. This review is not intended to be
exhaustive. Rather, the diseases included are selected
as exemplars of our current understanding of the
underlying molecular mechanisms which may result in
genetic disease predisposition. The clinical utility of
the HLA disease associations highlighted in disease
diagnosis/exclusion is also indicated.

Diseases in which HLA polymorphism may be

causative by inuencing the repertoire of
natural or modied peptides presented at the
site of disease
Coeliac disease (CD) will be considered first as it is
still the only completely described example of an
HLA-associated disease in which the mechanism by
which HLA confers susceptibility to disease has been
revealed in exquisite detail.
Coeliac disease

CD is an immunologically mediated disease of the

small intestinal mucosa, characterized by flattening of
the small intestinal villi, increased numbers of intraepithelial lymphocytes and inflammatory cell infiltrates
in the lamina propria, resulting in gut damage and
nonspecific malabsorption of nutrients. The disease is
elicited by ingestion of gluten, a protein found in several cereals, principally wheat, but also barley and to
a lesser extent, oats. Successful treatment is avoidance
of dietary gluten. Long-standing evidence suggests a Tcell-mediated response to peptides derived from the
gliadin fraction of wheat gluten, leading to immunologically mediated intestinal injury in genetically susceptible individuals. The strength of this genetic
susceptibility is indicated by 80% disease concordance
in monozygotic twins and 11% concordance in dizygotic twins (Nistico et al., 2006), and HLA has long
been implicated as strongly associated with susceptibility to CD. Various studies in the late 1980s and early
1990s, including those under the auspices of the International Histocompatibility Workshops, lead to defini-

tion of the DQA1*05:01, DQB1*02:01 heterodimer,

encoded in cis or trans, as being the principal HLA
association (see Sollid & Lie, 2005). This is one of the
strongest HLA and disease associations described, with
a relative risk for disease >200. There is also a secondary association with DQA1*03, DQB1*03:02, along
with a number of other possible weaker associations.
A very elegant series of experiments by Sollid and
colleagues in Norway and Koning et al. in the Netherlands have been conducted over a number of years to
identify wheat gluten-derived peptides that might be
presented by DQ heterodimeric antigens encoded by
these alleles. These experiments are summarized in a
number of original papers and reviews, and details
will not be repeated here. In simplest essence, this
body of work has clearly demonstrated that the
DQ2.5 and DQ8 antigens encoded by the two principal disease-associated DQA/DQB allele combinations
do not present native peptides derived from the gliadin fraction of wheat gluten. Rather, they present
modified peptides arising from native gliadin-derived
peptides, which do not themselves elicit strong T-cell
responses. Both the DQ2.5 and DQ8 CD-associated
antigens preferentially bind peptides with negatively
charged amino acids at particular anchor residues.
Gluten peptides are, however, virtually devoid of negatively charged amino acids and therefore bind poorly
to DQ2.5 and DQ8. However, the tissue transglutaminase 2 (TG2) enzyme, released during tissue damage
in CD, can convert noncharged glutamine residues to
negatively charged glutamic acid, by a process known
as deamidation. This deamidation process generates
modified peptides with negative changes at appropriate
positions for binding to DQ2.5 and DQ8. As a result,
the gluten-specific CD4+ T-cell repertoire is substantially expanded, enhancing inflammation and development of disease (Tollefsen et al., 2006; Bergseng et al.,
2008; Tjon et al., 2010). TG2 is also the target for
IgA anti-endomysial antibodies in CD, and the presence of anti-TG2 antibodies is highly specific to CD
(Dieterich et al., 1997), underlining the critical role of
TG2 in the disease process.
While most cases of CD occur in individuals of
HLA-DQA1*05:01, DQB1*02:01 or DQA1*03,
DQB1*03:02 genotype, these genetic associations are
not of themselves sufficient to trigger disease. In addition, some form of gut tissue damage is required as a
trigger in these genetically susceptible individuals,
which initiates TG2 release, leading to deamidation of
gluten peptides and presentation by DQ2.5 or DQ8,
resulting in CD4+ T-cell responses, cytokine production, additional tissue damage, upregulation of DQ
expression, in a self-amplifying loop. As yet, these specific triggers remain incompletely understood. Furthermore, while HLA-DQ is clearly the main genetic
determinant of susceptibility to CD, additional gene
polymorphisms have also been shown to contribute to
susceptibility to CD, many of which may contribute to
enhanced T-cell reactivity (Hunt et al., 2008; Tjon

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HLA and disease

et al., 2010). To date, at least 40 genomic regions containing 64 candidate genes for CD susceptibility have
been identified, although these loci are thought to contribute only a small proportion of the genetic heritability of the disease (Abadie et al., 2011).
In the clinical histocompatibility & immunogenetics
(H&I) laboratory, HLA typing can play a role in the
diagnosis of certain patients with suspected CD.
Recent Guidelines from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition
(Husby et al., 2012) state that not all children with
symptoms of CD and high levels of IgA antibodies to
TG2 require a diagnostic biopsy the traditional gold
standard for diagnosis. Testing for HLA-DQ2 and
DQ8 is recommended. If positive, there is no need to
perform a diagnostic biopsy, so avoiding potential
complications of a gut biopsy. DQ2 and DQ8 typing
should also be performed on asymptomatic children
with other possible indicators of CD. If results are
negative for DQ2 and DQ8, then a diagnosis of CD is
virtually excluded. In adult patients, HLA DQ2/DQ8
typing may also have some albeit more limited
diagnostic utility. In the United Kingdom, while
National Institute for Health and Clinical Excellence
Guidelines do not recommend HLA typing in the diagnosis of CD in adult patients, its high negative predictive value may be of use to GI specialists in certain
clinical situations (NICE Clinical Guideline 86, 2009).
Other guidelines indicate that HLA typing should be
performed after duodenal biopsies are suggestive of
CD. In the absence of DQ2/DQ8 and/or CD-specific
antibodies, other causes of enteropathy should be
investigated (Bai et al., 2013).
Rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most important autoimmune disorders, with a worldwide prevalence of approximately 0.51% (Silman & Pearson,
2002). RA is characterized by chronic inflammation of
the synovial joints, with small joints of the hands and
feet most commonly affected. RA pathogenesis is multifactorial, with both genetic and environmental risk
factors (including smoking and diet) playing important
roles. The genetic contribution to RA susceptibility is
estimated to be 5060% (Seldin et al., 1999; MacGregor et al., 2000). Immunological responses are important in joint destruction and systemic disease involving
other organs, with T-cell responses playing a role in
disease initiation and progression. With regard to
genetic factors, multiple genes are likely to be involved
in RA susceptibility. However, HLA-DRB1 is the
principal locus contributing to disease susceptibility,
contributing an estimated 3050% of overall susceptibility to RA (Bowes & Barton, 2008; Imboden, 2009).
It is now well known that several DRB1 alleles contribute to RA susceptibility, principally DRB1*04:01,
04:04, 04:05 and to a lesser extent, 01:01 and 14:02.
These alleles share and encode a conserved amino acid

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sequence at positions 7074 of the third hypervariable

region of the expressed DRb1 chain (QKRAA,
QRRAA or RRRAA). This sequence is often termed
the shared epitope (SE), hence the shared epitope
hypothesis for HLA-mediated RA susceptibility (Gregersen et al., 1987; Ollier & Thomson, 1992).
The SE is situated in the a helix wall of the peptide
binding groove of the expressed DR molecule, and it
has therefore been postulated that the SE is directly
involved in the pathogenesis of RA by mediating the
binding and presentation of an arthritogenic peptide
to T cells (Gregersen et al., 1987). However, no specific arthritogenic antigen or peptides have been
clearly identified. Nevertheless, a number of clues are
now emerging. RA patients can be classified according to whether they are positive or negative for anticitrullinated peptide antibodies (ACPA). ACPA are
antibodies directed against citrullinated proteins. Citrullination is the post-translational modification of
proteins resulting from enzymatic conversion of positively charged arginine into neutral citrulline. Citrullination can occur under inflammatory conditions in the
joint and while ACPA are highly specific to RA,
ACPA+ and ACPA RA may represent two distinct
forms of the disease. Intriguingly, it has been reported
that the association between DRB1 SE alleles only
applies to ACPA+ RA (Huizinga et al., 2005). Fibrin,
vimentin, fibronectin and a-enolase can be citrullinated
in the joint (Van Beers et al., 2012), suggesting that
one or more of these proteins may be candidate arthritogens when citrullinated, and there is an emerging
evidence that the DRB1 SE may mediate susceptibility
to RA by presentation of citrullinated peptides to T
cells in the joint. In SE genetically susceptible individuals, a loss of tolerance to citrullinated peptides may
occur because T cells in the joints and periphery are
presented with HLA plus peptide complexes to which
they have not been tolerized in the thymus (RuyssenWitrand et al., 2012). T cells from ACPA+ RA
patients recognize citrullinated vimentin peptides
restricted by HLA-DR4 in vitro, and similar findings
have been made in HLA-DR4 transgenic mice (Feitsma & van der Voort, 2010). In addition, SE alleles
have been shown to predispose to the development of
antibodies against citrullinated vimentin (but not
fibrinogen) (Verpoort et al., 2007), perhaps via T cells
responding to citrullinated peptides providing help to
B cells to produce ACPA. Further support for the citrullination hypothesis comes from a study showing
that arthritis can be induced in SE transgenic mice
with citrullinated fibrinogen (Hill et al., 2008). Therefore, in RA, there is a body of evidence suggesting that
HLA mediates a disease promoting effect via presentation of a post-translationally modified disease-triggering peptide, not unlike the disease promoting
mechanism in CD, but as yet, this is much less clearly
defined and understood.
Notwithstanding the above, over the years, a number of other models have been proposed with regard

W. M. Howell

to HLA and RA susceptibility. For example, bacterial

heat shock proteins (HSPs) may bind to the SE, thus
triggering T-cell responses against self-HSPs such as
HSP-70 (Auger & Roudier, 2005). It has also been
proposed that the SE acts as a ligand for cell surface
calreticulin and activates innate immune signalling
(Ling et al., 2010). Older studies suggested that the
DR SE sequence is itself an autogenic peptide that is
presented to T cells by another HLA class II molecule,
for example HLA-DQB1*03:02, found in linkage disequilibrium with DRB1*04 alleles (Nepom, 1998). An
RA-prone T-cell repertoire is then shaped by
DQB1*03:02 presentation of SE peptides in the thymus.
As in other HLA-associated diseases, while HLA is
clearly the biggest single contributor to genetic susceptibility to RA, other loci are additionally involved. For
example, the Welcome Trust Case Control Consortium has carried out a genome wide association study
(GWAS) which identified 49 SNPs showing putative
associations with RA. Of these 3 SNPs mapping to
chromosomes, 10p15, 12q13 and 22q13 were confirmed as RA associated in an extended validation
study (Barton et al., 2008). Associations with polymorphisms in a number of candidate genes have also
been reported (see reviews by Bax et al., 2011; Ruyssen-Witrand et al., 2012).
In the H&I laboratory, HLA typing does not play a
significant role in RA diagnosis. Approximately 70%
of caucasoid RA patients carry at least one DRB1*04
SE alleles, compared with a population prevalence of
approximately 35%. Accordingly, the relative risk of
disease is too low to be of diagnostic value. However,
genotyping for SE alleles may be helpful in identifying
poor prognosis patients in early synovitis. These
patients may benefit more aggressive forms of therapy
(Wagner et al., 1997). Other early studies also suggested that determining SE status may be helpful more
generally in selecting treatment options (ODell et al.,
1998). Other immune polymorphisms, such as CCR5
promoter SNPs, may also predispose to severe erosive
disease (Han et al., 2012).
Insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus or type 1 diabetes (IDDM1) is a chronic T-cell-mediated autoimmune disease, leading to destruction of insulinproducing b cells within pancreatic islets. Autoantibody-producing B cells also play a role in this destructive process. IDDM1 is a common condition in
Europe and the United States, with a prevalence that
is still increasing. Disease management currently
requires lifelong therapy. While children are most visibly affected, approximately half of patients are diagnosed in adulthood. There is a strong genetic
component to IDDM1 susceptibility, with HLA class
II genes estimated to contribute 45% of the overall
genetic susceptibility to disease (Dib & Gomes, 2009).

In European caucasoid populations, over 95% of

IDDM1 patients are of DR3 or DR4 genotype and of
these 60% are heterozygotes for DR3/4 (Dib &
Gomes, 2009). However, extensive studies have long
indicated that HLA-DQ alleles are largely responsible
for this IDDM1 susceptibility, with multiple alleles
correlating with both susceptibility and resistance to
disease. DQB1*03:02 is the predominant susceptibility
allele (RR = 8), with risk also conferred by alleles
including DQB1*02:01 (RR = 4) and DQB1*03:03
(RR = 4). There is also heterozygote synergy, with
DQB1*03:02/02:01 conferring a RR of ca 20 (see
review by Nepom, 2000). DQB1*06:02 is the strongest protective allele. Predisposing and protecting alleles
are distinguished by the amino acid present at position
57 of the DQb chain of the expressed DQB1 molecule,
with alleles encoding aspartic acid (Asp) at position 57
associated with resistance to IDDM1 and alleles
encoding neutral amino acids at this position [such as
alanine (Ala) or serine (Ser)] conferring susceptibility
(Todd et al., 1987; Dorman & Bunker, 2000; Jones
et al., 2006). Position 57 is believed to be a critical
residue in peptide binding pocket P9, forming a salt
bridge with arginine (Arg) at position 52 of the DQa
chain, stabilizing the expressed DQ heterodimer (Todd
et al., 1987; review by Nepom, 2000). The presence
or absence of Asp at position 57 could therefore affect
the stability of the DQ molecule and the repertoire of
peptides which can be bound and presented to T cells,
resulting in non-Asp57 DQ molecules having greater
potential for binding and presenting peptides from certain autoantigens, leading to an autoreactive T-cell
response. Other HLA alleles and haplotypes may modulate these DQ-associated disease susceptibility/resistance genotypes.
Despite these well-described and long-standing
HLA-DQ associations with IDDM1 susceptibility/
resistance and an attractive molecular model to underpin the association, identification of potential b cell
autoantigen-derived peptides or modified peptides has
been problematic. It is probable that several antigens/
peptides are involved, particularly as the autoimmune
response develops. Peptide bound to HLA class II molecules is conventionally identified via biochemical
analysis of eluates. However, this is difficult for islet
cells, as antigens responsible for the autoimmune reaction are not presented directly, but only after transfer
to an antigen-presenting cell and the number of class
II bearing islet cells is limited. An alternative way of
approaching this is to use a computational approach
to identify binding motifs for IDDM1-associated
HLA-DQ molecules (e.g. DQA1*03:01/DQB1*03:02)
and use this to predict the b-cell peptidome and
hence potential target autoantigens. This approach has
been shown to have some strengths and some weaknesses (Chang & Unanue, 2009), but to date, a clear
molecular basis for the HLA-DQ associations with
IDDM1 remains elusive. However, more conventional
approaches are now providing some clues. For exam-

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HLA and disease

ple, it has been shown that a single insulin epitope

(InsB13-21) can bind to a and b cis- and trans-heterodimers encoded by the DQ2/DQ8 heterozygous genotype, resulting in a proinflammatory T-cell response.
Conversely insulin peptide (InsB6-14) binding to a and
b heterodimers encoded by the protective DQ6 molecule resulted in an anti-inflammatory response (Eerligh
et al., 2011). Similar studies have investigated T-cell
reactivity to peptides derived from the zinc transporter
8 (ZnT8) protein, which is a major target of autoantibodies in IDDM1. These experiments showed that
ZnT8 may also be a major target of disease-associated
autoreactive T cells in IDDM1 (Dang et al., 2011).
Intriguingly, and of relevance to other autoimmune
diseases, a pathway for presentation of free peptides
or denatured proteins has recently been described,
resulting in unique peptideMHC complexes, which
select for nonconventional CD4+ T cells. In the autoimmune diabetic NOD mouse model, a distinct set of
such T cells has been identified, which does not recognize processed insulin peptide presented by antigenpresenting cells. Rather, these T cells reacted strongly
to the presentation of a soluble insulin peptide. This
T-cell subset was not deleted in the thymus was abundant in the periphery and caused diabetes. Thus, selfreactive T cells that escape thymus selection can
become pathogenic in the target organ where high
concentrations of antigen and/or differences in intracellular processing lead to presentation of peptides
bound in different registers from those found in the
thymus (Mohan & Unanue, 2013).
A number of GWAS scans to identify additional loci
conferring susceptibility to IDDM1 have been performed (e.g. Concannon et al., 2009). All such studies
consistently find that the strongest linkage occurs
between the HLA complex and IDDM1. Over 40
additional non-HLA polymorphisms have been shown
to be associated with IDDM1 (see review by Nokoff
& Rewers, 2013), all with minor effects on disease
susceptibility compared with HLA-DQ. First and foremost among these is the region surrounding the insulin
gene at 11p15.5 (Concannon et al., 2009).
HLA-DQ typing is of little general utility in the
diagnosis of IDDM1. However, it has been proposed
that typing for multiple additional susceptibility loci in
children with high risk HLA genotypes and from
IDDM1 affected families may be useful in identification of neonates with sufficient risk of IDDM1 to be
considered for early intervention (Winkler et al.,
2012).
CD, RA and IDDM1 are but three examples of diseases in which HLA polymorphism may have a direct
causal effect on disease susceptibility via the role this
polymorphism plays in influencing the repertoire of
peptides (extraneous, self-peptide or modified self-peptide) presented to T cells at the site of disease,
although in the cases considered, our understanding of
the molecular mechanisms involved is more or less
well developed. It is thought that similar immunopath-

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ological mechanisms may underpin the HLA associations seen in other diseases of an autoimmune nature,
for example multiple sclerosis. However, in other diseases, alternative mechanisms may also play a role in
mediating disease susceptibility.

Ankylosing spondylitis: a strong HLA

association and complex immunobiology
Ankylosing spondylitis (AS) is a chronic, inflammatory
disease that primarily involves the axial skeleton and
sacroiliac joints, although peripheral joints and uvea
and tendon insertions may also be affected. AS is a
male predominant disease, unlike most autoimmune
diseases. The genetic heritability of disease is extremely high, with estimates exceeding 90% (Brown
et al., 1997). Heritability of radiological disease severity and age of onset are also high (Thomas & Brown,
2010). A strong association between HLA-B27 and AS
was described very early on (Brewerton et al., 1973;
Schlosstein et al., 1973), and this is, in fact, the
strongest HLA class I association with any autoimmune disease and indeed one of the strongest HLA
and disease associations described. The contribution of
HLA-B27 to overall genetic susceptibility to AS has
been estimated to be 20% (Brown et al., 1998). In
general, the prevalence of AS is proportional to the
frequency of B27 in the population. Over 96% of AS
patients are positive for HLA-B27.
The HLA-B27 family is made up of a large number of closely related alleles, differing in only a small
number of positions that encode amino acid variants
in the a1 and a2 domains comprising the peptide-presenting groove of the expressed HLA-B27 molecule.
Most of the relatively common HLA-B27 alleles,
namely B*27:02, B*27:04, B*27:05 and B*27:07,
have been shown to be associated with AS, although
two alleles, B*27:06 (common in south-east Asian
populations) and B*27:09 (found in Sardinia and
southern Italy) may be exceptions (see review by DiazPena et al., 2012). Associations with other alleles are
unclear, due to the small numbers available for study.
Despite the long-standing and well-described association between particular HLA-B27 alleles and AS, the
mechanism by which HLA-B27 predisposes to disease
remains both frustratingly and surprisingly elusive.
However, studies of transgenic rodents have long indicated that HLA-B27 is directly involved in disease pathogenesis, rather than acting as a linked marker for
another, disease-associated gene (Hammer et al.,
1990). As HLA class I molecules act to present peptide
antigens to CD8 T cells, an arthritogenic peptide
model for disease immunopathogenesis is clearly attractive, but HLA-B27 may also possess other immunobiological properties, unrelated to peptide presentation.
Molecular similarities among AS-associated alleles
and key differences with less strongly associated or
nonassociated alleles can be used to predict differences
in HLA-B27 peptide-presenting grooves and pockets

W. M. Howell

and peptide repertoires that might be presented by ASassociated B27 subtypes. The arthritogenic peptide
hypothesis proposes that the structure of the peptidepresenting molecule encoded by disease-associated
HLA-B27 alleles enables presentation of disease-triggering microbial peptides that exhibit molecular mimicry with specific arthritogenic self-peptides. This
would allow HLA-B27 restricted cross-reactive cytotoxic T-cell responses to be directed against self-peptide as well as foreign microbial peptides, resulting in
chronic inflammation. A considerable body of research
has been directed towards identification of triggering
microbial and self-peptides that show B27 allele-specific molecular mimicry (e.g. Ziegler et al., 2009), but
definitive proof for any individual peptides or antigens
remains lacking.
The HLA-B27 molecule has a number of unusual
properties compared with other HLA class I molecules, and one or more of these properties may also
play a role in predisposition to AS. For example, the
HLA-B27 heavy chain has a tendency to misfold in
the endoplasmic reticulum, prior to conjugation with
b2 microglobulin (b2 m) and its cargo peptide. Misfolded heavy chains can accumulate in the endoplasmic reticulum, causing stress, cytokine production by
macrophages and resultant inflammation (Colbert
et al., 2009). Evidence for this misfolding hypothesis
in AS susceptibility is conflicting: HLA-B2706 and
2709 (not associated with AS) fold more efficiently
than 2702, 2704 and 2705 (AS associated). Conversely, B2707 (associated with AS in populations in
which it is found) folds as efficiently as B2706 and
2709 (Galocha & de Castro, 2008). In addition, formation of disulphide bonds between cysteine at position 67 within the B pocket of peptide binding groove
of two separate B27 heavy chains creates heavy chain
homodimers without involvement of b2 m. Such heavy
chain homodimers can be expressed on the cell surface
where they can bind with immunoregulatory receptors
on other cells, including killer immunoglobulin-like
receptors (KIRs) and leucocyte immunoglobulin-like
receptors (LILRs). Ligation with these receptors can
promote survival of NK- and T-cell-expressing KIRs,
so modulating cytokine production (Kollnberger &
Bowness, 2009). LILR binding is also involved in regulation of the immune response (Thomas et al., 2010).
Accordingly, binding of cell surface B27 heavy chain
homodimers may play a role in the pathogenesis of
AS. Finally, it has also been suggested that the release
of b2 m from a subpopulation of cell surfaceexpressed HLA-B27 molecules leads to b2 m deposition within the synovia and to the initiation of an
inflammatory process, culminating in destructive
spondyloarthropathy (Uchanska-Ziegler & Ziegler,
2003).
None of the above hypotheses as yet satisfactorily or completely explain the mechanism by which
particular HLA-B27 alleles predispose to AS. There is
likely some interdependency of the multiple molecular

properties of HLA-B27 in disease predisposition, but

peptide binding remains a favoured cornerstone of all
the biological properties of HLA-B27 which may contribute to disease predisposition (Marcilla & L

opez de
Castro, 2008).
A number of studies have suggested that other polymorphisms in the MHC may also influence AS susceptibility (Reveille, 2006), but linkage disequilibrium in
the MHC complicates such studies. With regard to
HLA, additional class I alleles have been variably
reported to be associated with AS, as have a number
of class II alleles, but little replication has been
reported. However, one recent study has confirmed an
association between HLA-DPA1*01:03 and AS in
HLA-B27 positive populations (Diaz-Pe~
na et al.,
2013). A number of non-MHC genes may also contribute to genetic susceptibility to RA, as revealed by
candidate gene and GWAS scans (e.g. TASC et al.,
2010; Wellcome Trust Case Control Consortium
et al., 2007; Brown, 2010; Thomas & Brown, 2010;
Reveille, 2012). These genes include those involved in
antigen processing (ERAP1) and cytokines such as
those involved in the IL-17/IL-23 pathway (Reveille,
2012). The individual contributions of polymorphisms
of these genes are small in comparison with the
genetic load attributable to HLA-B27.
HLA-B27 typing is performed in a large number of
laboratories worldwide, as an aid to the diagnosis of
AS, as 96% of AS patients are HLA-B27 positive, as
opposed to a 57% prevalence of HLA-B27 in caucasoid populations. While the presence of HLA-B27 is
not diagnostic (since only a few per cent of HLA-B27
positive individuals will develop AS), patient positivity
for HLA-B27 can be a useful confirmatory marker.
Equally and perhaps more importantly its absence
virtually excludes a diagnosis of AS. In addition,
HLA-B27 typing may play a useful role in the diagnosis of other diseases which show significant, but less
strong associations with HLA-B27, for example
Reiters disease.

HLA and drug hypersensitivity

In addition to HLA associations with immune-mediated and autoimmune diseases such as those described
above, HLA associations with a number of severe and
even fatal drug hypersensitive reactions have also been
described. These include HLA-B*57:01 and abacavir
hypersensitivity, HLA-B*15:02 and A*31:01 and carbamazepine and HLA-B*58:01 and allopurinol hypersensitivity. However, a considerable number of other
HLA and adverse drug reactions have now been
reported, which are reviewed elsewhere (e.g. Pompeu
et al., 2012; Profaizer & Eckels, 2012; Illing et al.,
2013). The exact mechanism by which HLA polymorphism can mediate such hypersensitive reactions to
small molecule drugs seemed paradoxical at first, but
a clear picture is now emerging, at least with respect
to HLA-B*57:01 and abacavir hypersensitivity.

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International Journal of Immunogenetics, 2014, 41, 112

HLA and disease

HLA-B*57:01 and abacavir hypersensitivity

Abacavir is an antiretroviral drug used to treat HIV-1

infection. Although abacavir is a proven and costeffective antiviral therapy in both adults and children,
potentially life-threatening adverse reactions can occur
in 68% of patients taking the drug. This hypersensitivity reaction is a multiorgan process. Work in two
independent laboratories showed that this hypersensitivity reaction was seen in patients carrying HLAB*57:01 (Hetherington et al., 2002; Mallal et al.,
2002). With a RR of >500, this is one of the strongest
HLA associations with any condition.
The adverse drug reaction is driven by activation
of specific CD8 T cells capable of recognizing abacavir in some way when presented by HLA-B*57:01. It
was originally thought that as abacavir is too small a
molecule to be immunogenic in its own right, it
could act as a hapten by modifying certain host selfproteins, resulting in CD8 T-cell recognition of the
resulting hapten/self-peptide complex as a novel antigen. However, recent experiments have indicated that
a quite different molecular mechanism underlies the
B*57:01 association with abacavir hypersensitivity.
McCluskey and colleagues have performed elegant
experiments showing that abacavir binds noncovalently to HLA-B*57:01, lying across the bottom of
the antigen-binding cleft and reaching into the Fpocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLAB*57:01, changing the shape and the chemistry of
the antigen-binding cleft, such that the repertoire of
endogenous peptides that can bind to HLA-B*57:01
is changed. Immunological self is therefore altered,
and the altered peptide repertoire presented by HLAB*57:01 plus abacavir drives a polyclonal T-cell
response which results in manifestation of abacavir
hypersensitivity reactions (Illing et al., 2012, 2013).
This mechanism may also be a model for other such
drug hypersensitivities involving small molecules.
HLA-B*57:01, like many other HLA alleles, is not
found at comparable frequencies among all ethnic
populations, occurring at a frequency of only 34%
in caucasoid populations and at much lower frequencies in Africans and Asians (Meyer et al., 2007).
However, despite this low population frequency, the
very strong association between HLA-B*57:01 and
abacavir hypersensitivity is of clinical utility. International AIDS Society Guidelines recommend HLAB*57:01 typing of HIV-1 positive patients prior to
initiation of therapies including abacavir and categorically recommend that HLA-B*57:01 individuals
should not receive abacavir (Hammer et al., 2008).
Additionally, both the EMA and U.S. Food and Drug
Administration have made the same recommendations
(U.S. FDA Panel on Antiretroviral Guidelines for
Adults & Adolescents, 2009; European Public Assessment Report, 2010).

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International Journal of Immunogenetics, 2014, 41, 112

HLA-B*15:02 and A*31:01 and carbamazepine

hypersensitivity

The widely used anti-epileptic and mood modifying

drug carbamazepine (CBZ) is responsible for a wide
range of cutaneous adverse drug reactions, including
hypersensitivity syndrome, maculopapular exanthema,
StevensJohnson syndrome (SJS) and toxic epidermal
necrolysis (TEN). SJS and TEN are considered lesser
and more severe manifestations of the same skin
disease, with clear CD8 T-cell involvement. Carbamazepine hypersensitivity is strongly associated with
HLA-B*15:02 in Asian populations, but the closely
related B*15:01 is not associated (Chung et al., 2004;
Locharernkul et al., 2008; Mehta et al., 2009). This
association like that between HLA-B*57:01 and
abacavir hypersensitivity is incredibly strong (RR
>1000) and seems one of the few factors required for
disease manifestation in these populations. Again, elegant experiments in the laboratory of McCluskey have
shown that CBZ binds noncovalently to HLAB*15:02. Purification of HLA-B*15:02-peptide complexes shows that binding of CBZ causes a shift in
bound peptide repertoire, with a change in preferred
amino acid side-chain selection, with an increase in
hydrophobicity at several positions and a preference
for smaller residues at P4 and P6 (Illing et al., 2012).
The magnitude of the CBZ-induced shift is smaller
than that observed for abacavir, probably due to the
nature of CBZ binding to HLA-B*15:02. This relatively small shift in peptide repertoire may explain the
restricted T-cell receptor usage in T cells reactive in
HLA-B*15:02-expressing patients with CBZ-induced
SJS (Illing et al., 2012). Therefore, although there are
some differences in T-cell reactivity patterns in abacavir hypersensitivity in HLA-B*57:01-expressing HIV
patients and carbamazepine hypersensitivity in HLAB*15:02 patients, these findings may suggest a more
general model for HLA associations with hypersensitivity reactions to small molecule drugs (Illing et al.,
2012, 2013). However, recent experiments have suggested that generation of immunogenic HLA complexes may also occur at the cell surface, involving not
only CBZ but its metabolite CBZ-10,11-epoxide (Wei
et al., 2012), supporting the concept that the mechanisms underlying CBZ hypersensitivity may be more
complex than those for abacavir.
Additional studies have revealed an association
between HLA-A*31:01 and CBZ-induced cutaneous
adverse drug reactions in both Japanese and caucasoid
populations (McCormack et al., 2011; Ozeki et al.,
2011). HLA-B*15:02 and A*31:01 show many
sequence dissimilarities, but share two of three residues probably involved in CBZ binding. Nevertheless,
other differences suggest that CBZ binding by these
two HLA molecules may differ significantly (Illing
et al., 2013).
Due to the strength of the association between
HLA-B*15:02 and CBZ hypersensitivity, it is unsur-

W. M. Howell

prising that a number of health bodies have made recommendations regarding prospective HLA-B*15:02
typing of patients of Asian origin prior to CBZ therapy, for example the Medicines and Healthcare Regulatory Authority in the UK and the Netherlands
College ter Beoordeling van Genesmiddelen Medicines
Evaluation Board (MEB Summary of Product Characteristics, 2008; MHRA Drug Safety Update, 2008).
HLA-B*58:01 and allopurinol hypersensitivity

Allopurinol is an enzyme inhibitor used to block uric

acid production in the treatment of gout, but it can
also be used in any situation where excess uric acid
production can occur, for example, during some forms
of chemotherapy. However, adverse drug reactions
can be relatively frequent. Such hypersensitivity reactions have been shown to occur in individuals expressing HLA-B*58:01, but not the closely related B*58:02
(Kaniwa et al., 2008; Tassaneeyakul et al., 2009). In
fact, some involvement of the HLA system in allopurinol-induced adverse reactions had already been suspected, due to evidence showing restricted
presentation of the drug or one of its metabolites
(Zanni et al., 1998). The exact mechanism underlying
the strong association between HLA-B*58:01 and
allopurinol hypersensitivity (RR >800. Kaniwa et al.,
2008; Tassaneeyakul et al., 2009) is less well understood than in the cases of HLA-B*57:01 and abacavir
and B*15:02 and carbamazepine hypersensitivities.
However, allopurinol may bind in the HLA-B*58:01encoded antigen-binding cleft and alter the repertoire
of peptides bound and presented to CD8 T cells as in
the examples discussed above. Alternatively, allopurinol may bind to HLA-B*58:01 in a different manner,
for example, outside of the peptide binding cleft in a
manner which can still influence T-cell recognition,
including via direct TcR contact. Finally, it has been
proposed that small molecules such as allopurinol may
bind to multiple sites on the HLA molecule, including
both polymorphic and conserved sites (Pompeu et al.,
2012).
Despite the strength of the HLA-B*58:01 association with allopurinol hypersensitivity, at present neither the US FDA nor the EMA has made any formal
recommendations regarding prospective HLA-B*58:01
typing. However, this has been recommended by the
Clinical Pharmacogenetics Implementation Consortium
(Hershfield et al., 2013).

Role of HLA in other disease processes

Pathogen exposure is believed to be the main historical
selective pressure maintaining HLA polymorphism in
populations. Accordingly, it is unsurprising that particular HLA polymorphisms have been shown to be associated with susceptibility to resistance and progression
of a number of viral and microbial infectious diseases,
including HIV/AIDS, Hepatitis B and C, Dengue fever,

leprosy, tuberculosis, malaria and helminth infections

(e.g. see review by Blackwell et al., 2009; Stephens,
2010). HLA associations with HIV and progression to
AIDS are the most extensively studied virally associated disease, due in part to the prevalence and disease
burden of HIV/AIDS. Of all genetic factors studied, a
number of HLA class I alleles have been shown to
exhibit the strongest associations with the natural history of HIV-1 infection, underscoring the critical role
of CD8 T cells in the control of viral infection. In
summary, a number of alleles/allele groups have been
identified as playing a protective role (HLA-B*27,
B*57, B*58:01), while other alleles (B*35, B*53) act
as susceptibility factors. Heterozygosity for class I loci
is also more generally associated with a protective role
(e.g. see review by Kaur & Mehra, 2009). While the
role of HLA in modulating the progression of HIVassociated disease will not be considered in more
detail in this short review (the reader is directed elsewhere, e.g. Kaur & Mehra, 2009; Martin & Carrington, 2013; Limou & Zagury, 2013), it is important to
note that HLAviral peptide interactions are the major
factors modulating durable control of HIV infection,
via viral peptide presentation to CD8 T cells (International HIV Controllers Study et al., 2010). However,
a body of genetic and functional data also indicates a
function for HLA in natural killer cell-mediated innate
immunity by interacting with KIR (see review by Martin & Carrington, 2013). A considerable number of
GWAS in HIV/AIDS have now been performed, which
underline the central role of HLA class I polymorphism in HIV-1 progression, along with a clear role
for a chemokine coreceptor deletion (CCR5), reported
much earlier in candidate gene studies (see review by
Limou & Zagury, 2013).
Genetic variants that are associated with resistance
to a particular infection or are associated with less
severe clinical disease provide powerful information
that can be used for vaccine design. In the case of
HLA, definition of protective HLA allelic associations
may permit identification of HLA-restricted pathogen
peptide epitopes than can be used for vaccine design,
such that natural resistance can be replicated by
immunization to create a potent CD8 T-cell response
against the viral antigen in question. This process has
been termed reverse immunogenetics, but thus far
translation into effective vaccine development has been
relatively disappointing, probably reflective of the
complexity and dynamic nature of hostpathogen
immune responses (Blackwell et al., 2009). However,
a number of vaccine trials are underway, and the H&I
laboratory can play a critical role in appropriate HLA
typing of patients to identify those patients in which
particular vaccines require trialling.
In addition to all the diseases discussed above, in
which there is clear a priori evidence for the central
role of T-cell-mediated immune processes, there are
some other HLA-associated diseases in which an
immune component would seem paradoxical at first

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International Journal of Immunogenetics, 2014, 41, 112

HLA and disease

sight. First and foremost among these diseases is the

narcolepsy/cataplexy complex. Narcolepsy is a neurological disorder, characterized by excessive daytime
sleepiness, hypnagogic hallucinations, sleep paralysis
and disturbed sleep patterns. A very strong association
with HLA-DQB1*06:02 is well established, such that
DQB1*06:02 negativity virtually excludes a diagnosis
of narcolepsy, so avoiding treatment with inappropriate drugs. There is now much clearer evidence for an
autoimmune basis for this disease, in which loss of
hypocretin-producing neurons in the hypothalamus
takes place, possibly via an autoimmune process
involving presentation of hypocretin-associated peptides to T cells via the DQB1*06:02 molecule. However, the exact molecular mechanisms involved remain
to be elucidated. In addition, GWAS studies have provided evidence for additional immune system and
other polymorphisms in susceptibility to narcolepsy
(Shimada et al., 2010; Faraco et al., 2013; Mahlios
et al., 2013).

Conclusions
Over 40 years of study have led to a vastly increased
understanding of the genetic complexity of the human
MHC and the genes of the HLA system, along with the
discovery of other interrelated immune response gene
families such as KIR and LILR. This has been paralleled by demonstration that a wide range of autoimmune, and other diseases occur more frequently in
individuals with particular HLA genotypes. The same
applies to a number of diseases in which an immune
component is at first sight less obvious. The first phase
of these studies was directed towards identification of
the exact disease-predisposing allele(s) for each specific
disease, against the backdrop of genetic complexity of
the HLA system, linkage disequilibrium between loci
and the extensive polymorphism of these loci. The second phase of research, directed towards elucidating the
precise molecular mechanisms by which HLA mediates
susceptibility to each of this myriad of diseases has
proved much more complex. However, this review has
sought to highlight those cases where good progress
has been made in molecular dissection of the role HLA
plays in the disease-triggering process. Perhaps unsurprisingly, most success has been achieved in those
diseases where the HLA molecule acts to present nonself-peptide, aberrantly expressed self-peptide and
particularly altered-self-peptide or altered-non-selfpeptides to CD4 or CD8 T cells. The role of posttranslationally modified peptides has perhaps been the
most intriguing finding in several diseases. More recent
findings in HLA-associated hypersensitivity to small
drug molecules has highlighted a related, but distinct
mechanism by which such drug molecules can bind to
the peptide-presenting groove of particular HLA molecules, thus modifying the repertoire of self-peptides that
can be presented, leading to a loss of self-tolerance. It is
plausible that similar processes may be at work in other

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International Journal of Immunogenetics, 2014, 41, 112

HLA-related conditions. Finally, there may be unexpected idiosyncracies in the immunobiology of certain
expressed HLA molecules, unrelated to peptide presentation, which may a role in the initiation of particular
HLA-associated diseases. Leaving aside the diagnostic
utility of individual HLA and disease associations, it
seems certain that research in this field will continue
for many years to come and may yet reveal further surprises in our understanding of the ways in which HLA
polymorphism can predispose to disease.

Acknowledgements
With thanks to Phil Evans, who first introduced me to
HLA and disease associations and with whom I have
spent many hours of enjoyable and productive discussions.

References
Abadie, V., Sollid, L.M., Barreiro, L.B. & Jabri, B. (2011)
Integration of genetic and immunological insights into a model
of celiac disease pathogenesis. Annual Review of Immunology,
29, 493.
Amiel, J.L. (1967) Study of the leukocyte phenotypes in
Hodgkins disease. In: Histocompatibility Testing, 1967 (ed.
E.S. Curtoni, P.L. Mattiuz & M.R. Tosi), pp. 79.
Munksgaard, A/S, Copenhagen, Denmark.
Auger, I. & Roudier, J. (2005) Interaction between HSP73 and
HLA-DRB1*0401: implications for the development of
rheumatoid arthritis. Immunology Research, 31, 261.
Australo-Anglo-American Spondyloarthritis Consortium (TASC),
Reveille, J.D., Sims, A.M., Danoy, P., Evans, D.M., Leo, P.
et al. (2010) Genome-wide association study of ankylosing
spondylitis identifies non-MHC susceptibility loci. Nature
Genetics, 42, 123.
Bai, J., Fried, M., Corazza, G.R., Schuppan, D., Farthing,
M.J.G., Catassi, C. et al. (2013) World Gastroenterology
Organisation Global Guidelines on celiac disease. Journal of
Clinical Gastroenterology, 47, 121.
Barton, A., Thomson, W., Ke, X., Eyre, S., Hinks, A., Bowes, J.
et al. (2008) Rheumatoid arthritis susceptibility loci at
chromosomes 10p15, 12q13 and 22q13. Nature Genetics, 40,
1156.
Bax, M., van Heemst, J., Huizinga, T.W.J. & Toes, R.E.M.
(2011) Genetics of rheumatoid arthritis: what have we
learned? Immunogenetics, 63, 459.
Bergseng, E., Sidney, J., Sette, A. & Sollid, L.M. (2008) Analysis
of the binding of gluten T-cell epitopes to various human
leukocyte antigen class II molecules. Human Immunology, 69,
94.
Blackwell, J.M., Jamieson, S.E. & Burgner, D. (2009) HLA and
infectious diseases. Clinical Microbiology Reviews, 22, 370.
Bowes, J. & Barton, A. (2008) Recent advances in genetics of RA
susceptibility. Rheumatology, 47, 399.
Brewerton, D.A., Hart, F.D., Nicholls, A., Caffrey, M., James,
D.C. & Sturrock, R.D. (1973) Ankylosing spondylitis and HLA 27. Lancet, 1, 904.
Brown, M.A. (2010) Genetics of ankylosing spondylitis. Current
Opinion in Rheumatology, 22, 126.
Brown, M.A., Kennedy, L.G., MacGregor, A.J., Darke, C.,
Duncan, E., Shatford, J.L. et al. (1997) Susceptibility to
ankylosing spondylitis in twins: the role of genes, HLA, and
the environment. Arthritis & Rheumatism, 40, 1823.

10

W. M. Howell

Brown, M.A., Pile, K.D., Kennedy, G., Campbell, D., Andrew,

L., March, R. et al. (1998) A genome-wide screen for
susceptibility loci in ankylosing spondylitis. Arthritis &
Rheumatism, 41, 588.
Chang, K.Y. & Unanue, E.R. (2009) Prediction of HLA-DQB8 b
cell peptidome using a computational program and its
relationship to autoreactive T cells. International Immunology,
6, 705.
Chung, W.H., Hung, S.I., Hong, H.S., Hsih, M.S., Yang, L.C.,
Ho, H.C. et al. (2004) Medical genetics: a marker for StevensJohnson syndrome. Nature, 428, 486.
Coeliac Disease NICE Clinical Guideline 86 (2009) National
Institute for Health and Clinical Excellence.
Colbert, R.A., DeLay, M.L., Layh-Schmitt, G. & Sowders, D.P.
(2009) HLA-B27 misfolding and spondyloarthropathies. Prion,
3, 15.
Concannon, P., Chen, W.-M., Julier, C., Morahan, G., Akolkar,
B., Elrich, H.A. et al. (2009) Genome-wide scan for linkage to
type 1 diabetes in 2,496 multiplex families from the Type 1
Diabetes Genetics Consortium. Diabetes, 58, 1018.
Dang, M., Rockell, J., Wagner, R., Wenzlau, J.M., Yu, L.,
Hutton, J.C. et al. (2011) Human Type 1 Diabetes is
associated with T cell autoimmunity to zinc Transporter 8.
The Journal of Immunology, 186, 6056.
Diaz-Pena, R., L

opez-V
azquez, A. & L

opez-Larrea, C. (2012)
Old and new HLA associations with ankylosing spondylitis.
Tissue Antigens 80, 205.
Diaz-Pe~
na, R., Castro-Santos, P., Aransay, A.M., Brges-Armas,
J., Pimentel-Santos, F.M. & L

opez-Larrea, C. (2013) Genetic
study confirms association of HLA-DPA1*01:03 subtype with
ankylosing spondylitis in HLA-B27-positive populations.
Human Immunology, 74, 764.
Dib, S.A. & Gomes, M.B. (2009) Etiopathogenesis of type 1
diabetes mellitus: prognostic factors for the evolution of
residual beta cell function. Diabetology & Metabolic
Syndrome, 1, 1.
Dieterich, W., Ehnis, T., Bauer, M., Donner, P., Volta, U.,
Riecken, E.O. et al. (1997) Identification of tissue
transglutaminase as the autoantigen of celiac disease. Nature
Medicine, 7, 797.
Dorman, J.S. & Bunker, C.H. (2000) HLA-DQ locus of the
human leukocyte antigen complex and type 1 diabetes mellitus:
a HuGE review. Epidemiologic Reviews, 22, 218.
Eerligh, P., van Lummel, M., Zaldumbide, A., Moustaskas, A.K.,
Duinkerken, G., Bondinas, G. et al. (2011) Functional
consequences of HLA-DQ8 homozygosity versus
heterozygosity for islet autoimmunity in type 1 diabetes.
Genes and Immunity, 12, 415.
European Public Assessment Report (EPAR) for ziagen (Abacavir)
(2010) http://www.ema.europa.eu/ema/index.jsp?curl=pages/
medicines/human/medicines/000252/human_med_001179.
jsp&murl=menus/medicines/medicines.
jsp&mid=WC0b01ac058001d125 [Accessed on 10 June 2013].
Faraco, J., Lin, L., Kornum, B.R., Kenny, E.E., Trynka, G.,
Einen, M. et al. (2013) ImmunoChip study implicates antigen
presentation to T cells in narcolepsy. PloS Genetics, 9,
e1003270. doi:10. 1371/journal.pgen.1003270. Epub 2013
Feb 14.
Feder, J.N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy,
D.A., Basava, A. et al. (1996) A novel MHC class I-like gene
is mutated in patients with hereditary haemochromatosis.
Nature Genetics, 13, 399.
Feitsma, A.L. & van der Voort, E.l. (2010) Identification of
citrullinated vimentin peptides as T cell epitopes in HLA-DR4positive patients with rheumatoid arthritis. Arthritis &
Rheumatism, 62, 117.
Galocha, B. & de Castro, J.A. (2008) Folding of HLA-B27
subtypes is determined by the global effect of polymorphic

residues and shows incomplete correspondence in ankylosing

spondylitis. Arthritis & Rheumatism, 58, 401.
Gregersen, P.K., Silver, J. & Winchester, R.J. (1987) The shared
epitope hypothesis. An approach to understanding the
molecular genetics of susceptibility to rheumatoid arthritis.
Arthritis & Rheumatism, 30, 1205.
Hammer, R.E., Maika, S.D., Richardson, J.A., Tang, J.P. &
Taurog, J.D. (1990) Spontaneous inflammatory disease in
transgenic rats expressing HLA-B27 and human beta 2 m: an
animal model of HLA-B27-associated human disorders. Cell,
63, 1099.
Hammer, S.M., Eron, J.J. Jr, Reiss, P., Schooley, R.T.,
Thompson, M.A., Walmsley, S. et al. (2008) International
AIDS society-USA panel. Antiretroviral treatment of adult
HIV infection: 2008 recommendations of the International
AIDS society-USA panel. The Journal of the American Medical
Association, 300, 555.
Han, S.W., Sa, K.H., Kim, S.I., Lee, S.I., Park, Y.W., Lee, S.S.
et al. (2012) CCR5 gene polymorphism is a genetic risk factor
for radiographic severity of rheumatoid arthritis. Tissue
Antigens, 80, 416.
Hershfield, M.S., Callaghan, J.T., Tasseneeyakul, W., Mushiroda,
T., Thorn, C.F., Klein, T.E. et al. (2013) Clinical
Pharmacogenetics Implementation Consortium guidelines for
human leukocyte antigen-B genotype and allopurinol dosing.
Clinical Pharmacology and Therapeutics, 93, 153.
Hetherington, S., Hughes, A.R., Mosteller, M., Shortino, D.,
Baker, K.L., Spreen, W. et al. (2002) Genetic variations in
HLA-B region and hypersensitivity reactions to abacavir.
Lancet, 359, 1121.
Hill, J.A., Bell, D.A., Brintnell, W., Yue, D., Wehrli, B., Jevnikar,
A.M. et al. (2008) Arthritis induced by posttranslationally
modified (citrullinated) fibrinogen in DR4-IE transgenic mice.
Journal of Experimental Medicine, 205, 979.
Huizinga, T.W., Amos, C.I., van der Helm-van Mil, A.H., Chen,
W., van Gaalen, F.A., Jawaheer, D. et al. (2005) Refining the
complex rheumatoid arthritis phenotype based on specificity of
the HLA-DRB1 shared epitope for antibodies to citrullinated
proteins. Arthritis & Rheumatism, 52, 3433.
Hunt, K.A., Zhernakova, A., Turner, G., Heap, G.A.R., Franke,
L., Bruinenberg, M. et al. (2008) Newly identified genetic risk
variants for celiac disease related to the immune response.
Nature Genetics, 40, 395.
Husby, S., Koletzko, S., Korponay-Szab

o, I.R., Mearin, M.L.,
Phillips, A., Shamir, R. et al. (2012) European Society for
Pediatric Gastroenterology, Hepatology, and Nutrition
guidelines for the diagnosis of coeliac disease. Journal of
Paediatric Gastroenterology Nutrition, 54, 572.
Illing, P.T., Vivian, J.P., Dudek, N.L., Kostenko, L., Chen, Z.,
Bharadwaj, M. et al. (2012) Immune self-reactivity
triggered by drug-modified HLA-peptide repertoire. Nature,
486, 554.
Illing, P.T., Vivian, J.P., Purcell, A.W., Rossjohn, J. &
McCluskey, J. (2013) Human leukocyte antigen-associated
drug hypersensitivity. Current Opinion in Immunology, 25,
81.
Imboden, J.B. (2009) The immunopathogenesis of rheumatoid
arthritis. Annual Review of Pathology, 4, 417.
International HIV Controllers Study, Pereyra, F., Jia, X.,
McLaren, P.J., Telenti, A., de Bakker, P.I. et al. (2010) The
major genetic determinants of HIV-1 control affect HLA class
I peptide presentation. Science, 10, 1551.
Jones, E.Y., Fugger, L., Strominger, J.L. & Siebold, C. (2006)
MHC class II proteins and disease: a structural perspective.
Nature Reviews Immunology, 6, 271.
Kaniwa, N., Saito, Y., Aihara, M., Matsunaga, K., Tohkin, K.,
Kurose, K. et al. (2008) HLA-B locus in Japanese patients
with anti-epileptics and allopurinol-related Stevens-Johnson

2013 John Wiley & Sons Ltd

International Journal of Immunogenetics, 2014, 41, 112

HLA and disease

syndrome and toxic epidermal necrolysis. Pharmacogenetics,

9, 1617.
Kaur, G. & Mehra, N. (2009) Genetic determinants of HIV-1
infection and progression to AIDS: immune response genes.
Tissue Antigens, 74, 373.
Kollnberger, S. & Bowness, P. (2009) The role of B27 heavy
chain dimer immune receptor interactions in spondyloarthritis.
Advances in Experimental Medicine and Biology, 649, 277.
Limou, S. & Zagury, J.-F. (2013) Immunogenetics: genome-wide
association of non-progressive HIV and viral load control:
HLA genes and beyond. Frontiers in Immunology, 118, 1.
Ling, S., Cheng, A., Pumpens, P., Michalak, M. & Holoshitz, J.
(2010) Identification of the rheumatoid arthritis shared epitope
binding site on calreticulin. PLoS ONE, 5, 1.
Locharernkul, C., Lopulumlert, J., Limotai, C., Korkij, W.,
Desudchit, T., Tongkobpetch, S. et al. (2008) Carbamazepine
and phenytoin induced Stevens-Johnson syndrome is
associated with HLA-B*1502 allele in Thai population.
Epilepsia, 49, 2087.
MacGregor, A.J., Snieder, H., Rigby, A.S., Koskenvuo, M.,
Kaprio, J., Aho, K. & Silman, A.J. (2000) Characterizing the
quantitative genetic contribution to rheumatoid arthritis using
data from twins. Arthritis & Rheumatism, 43, 30.
Mahlios, J., De la Herr
an-Arita, A. & Mignot, E. (2013) The
autoimmune basis of narcolepsy. Current Opinion in
Neurobiology May29. pii:S0959-4388(13)00102-5. doi: 10.
1016/j.conb.2013.04.013. [Epub ahead of print].
Mallal, S., Nolan, D., Witt, C., Masel, G., Martin, A.M., Moore,
C. et al. (2002) Association between presence of HLAB*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to
HIV-1 reverse-transcriptase inhibitor abacavir. Lancet, 359,
727.
Marcilla, M. & L

opez de Castro, J.A. (2008) Peptides: the
cornerstone of HLA-B27 biology and pathogenetic role in
spondyloarthritis. Tissue Antigens, 71, 495.
Martin, M.P. & Carrington, M. (2013) Immunogenetics of HIV
disease. Immunological Reviews, 254, 245.
McCormack, M., Alfirevic, A., Bourgeois, S., Farrell, J.J.,
Kasperaviciute, D., Carrington, M. et al. (2011) HLA-A*3101
and carbamazepine-induced hypersensitivity reactions in
Europeans. The New England Journal of Medicine, 364, 1134.
MEB Summary of Product Characteristics (2008) http://db.
cbg-meb.nl/veegactie/nlvert/carbamazepine-related- stevens2008.doc
Mehta, T.Y., Prajapati, L.M., Mittal, B., Joshi, C.G., Sheth, J.J.,
Patel, D.B. et al. (2009) Association of HLA-B*1502 allele
and carbamazepine-induced Stevens-Johnson syndrome among
Indians. Indian Journal of Dermatology, Venereology and
Leprology, 75, 579.
Meyer, D., Singe, R.M., Mack, S.J., Lancaster, A., Nelson, M.P.,
Erlich, H. et al. (2007) Single locus polymorphism of classical
HLA genes. In: Immunobiology of the Human MHC (ed. J.A.
Hansen), Proceedings of te 13th International
Histocompatibility Workshop and Conference, Vol., 1, pp.
653704. IHWG Press, Seattle, WA.
MHRA Drug Safety Update (2008) Vol 1, 5, http://www.mhra.
-gov.uk/Safetyinformation/DrugSafetyUpdate/CON084888
Mohan, J.F. & Unanue, E.R. (2013) A novel pathway of
presentation by class II-MHC molecules involving peptides or
denatured proteins important in autoimmunity. Molecular
Immunology, 55, 166.
Nepom, G.T. (1998) Major histocompatibility complex-directed
susceptibility to rheumatoid arthritis. Advances in
Immunology, 68, 315.
Nepom, G.T. (2000) HLA and type I diabetes. HLA in Health
and Disease, Chapter 15, pp. 231. Academic Press, London.
Nistico, L., Fangani, C., Coto, I., Percopo, S., Cotichini, R.,
Limongelli, M.G. et al. (2006) Concordance, disease

2013 John Wiley & Sons Ltd

International Journal of Immunogenetics, 2014, 41, 112

11

progression and heritability of coeliac disease in Italian twins.

Gut, 55, 803.
Nokoff, N. & Rewers, M. (2013) Pathogenesis of type 1
diabetes: lessons from natural history studies of high-risk
individuals. Annals of the New York Academy of Sciences,
1281, 1.
ODell, J.R., Nepom, B.S., Haire, C., Gersuk, V.H., Gaur, L.,
Moore, G.F. et al. (1998) HLA-DRB1 typing in rheumatoid
arthritis: predicting response to specific treatments. Annals of
the Rheumatic Diseases, 57, 209.
Ollier, W. & Thomson, W. (1992) Population genetics of
rheumatoid arthritis. Rheumatic Diseases Clinics of North
America, 18, 741.
Ozeki, T., Mushiroda, T., Yowang, A., Takahashi, A., Kubo, M.,
Shirakata, Y. et al. (2011) Genome-wide association study
identifies HLA-A*3101 allele as a genetic risk factor for
carbamazepine-induced cutaneous adverse drug reactions in
Japanese population. Human Molecular Genetics, 20, 1034.
Pompeu, Y.A., Stewart, J.D., Mallal, S., Phillips, E., Peters, B. &
Ostrov, D.A. (2012) The structural basis of HLA-associated
drug hypersensitivity syndromes. Immunology Reviews, 250,
158.
Profaizer, T. & Eckels, D. (2012) HLA alleles and drug
hypersensitivity reactions. International Journal of
Immunogenetics, 39, 99.
Reveille, J.D. (2006) Major histocompatibility genes and
ankylosing spondylitis. Best Practice & Research Clinical
Rheumatology, 20, 601.
Reveille, J.D. (2012) Genetics of spondyloarthritis beyond the
MHC. Nature Reviews. Rheumatology, 8, 296.
Robinson, J., Halliwell, J.A., McWilliam, H., Lopez, R.,
Partham, P. & Marsh, S.G.E. (2013) The IMGT/HLA
database. Nucleic Acids Research, 41, D1222.
Ruyssen-Witrand, A., Constantin, A., Cambon-Thomsen, A. &
Thomsen, M. (2012) New insights into the genetics of
immune responses in rheumatoid arthritis. Tissue Antigens,
80, 105.
Schlosstein, L., Terasaki, P.I., Bluestone, R. & Pearson, C.M.
(1973) High association of an HL-A antigen, W27, with
ankylosing spondylitis. The New England Journal of
Medicine, 288, 704.
Seldin, M.F., Amos, C.I., Ward, R. & Gregersen, P.K. (1999)
The genetics revolution and the assault on rheumatoid
arthritis. Arthritis & Rheumatism, 42, 1071.
Shimada, M., Miyagawa, T., Kawashima, M., Tanaka, S.,
Honda, Y. & Tokunaga, K. (2010) An approach based on a
genome-wide association study reveals candidate loci for
narcolepsy. Human Genetics, 128, 433.
Silman, A.J. & Pearson, J.E. (2002) Epidemiology and genetics of
rheumatoid arthritis. Arthritis Research, 4, S265.
Simon, M., Pawlotsky, Y., Bourel, M., Fauchet, R. & Genetet, B.
(1975) H
emochromatose idiopathique: maladie associ
ee

a
lantig
ene tissulaire. La Nouvelle Presse M
edicale, 4, 1432.
Sollid, L.M. & Lie, B.A. (2005) Celiac disease genetics: current
concepts and practical applications. Clinical Gastroenterology
and Hepatology, 3, 843.
Stephens, H.A. (2010) HLA and other gene associations with
dengue disease severity. Current Topics in Microbiology and
Immunology, 338, 99.
Tassaneeyakul, W., Jantararoungtong, T., Chen, P., Lin, P.Y.,
Tiamkao, S., Khurnarkornsiri, U. et al. (2009) Strong
association between HLA-B*5801 and allopurinol-induced
Stevens-Johnson syndrome and toxic epidermal necrolysis in a
Thai population. Pharmacogenetics and Genomics, 19, 704.
Thomas, G.P. & Brown, M.A. (2010) Genetics and genomics of
ankylosing spondylitis. Immunological Reviews, 233, 162.
Thomas, R., Matthias, T. & Witte, T. (2010) Leukocyte
immunoglobulin-like receptors as new players in

12

W. M. Howell

autoimmunity. Clinical Reviews in Allergy and Immunology,

38, 159.
Tjon, M.-L., van Bergen, J. & Koning, F. (2010) Celiac disease:
how complicated can it get? Immunogenetics, 62, 641.
Todd, J.A., Bell, J.I. & McDevitt, H.O. (1987) HLA-DQ beta
gene contributes to susceptibility and resistance to insulindependent diabetes mellitus. Nature, 329, 599.
Tollefsen, S., Arentz-Hansen, H., Fleckenstein, B., Molberg, .,
R

aki, M., Kwok, W.W., Jung, G., Lundin, K.E.A. & Sollid,
L.M. (2006) HLA-DQ2 and DQ8 signatures of gluten T cell
epitopes in celiac disease. The Journal of Clinical
Investigation, 116, 2226.
Uchanska-Ziegler, B. & Ziegler, A. (2003) Ankylosing spondylitis:
a b2 m-deposition disease? Trends in Immunology, 24, 73.
U.S. FDA Panel on Antiretroviral Guidelines for Adults and
Adolescents (2009) Guidelines for the Use of Antiretroviral
Agents in HIV-1-Infected Adults and Adolescents. pp. 166.
January 10, 2011. Department of Health and Human Services,
Washington, WA.
Van Beers, J.J., Willemze, A., Stammen-Vogelzangs, J., Drijfhout,
J.W., Toes, R.E. & Pruijn, G.J. (2012) Anti-citrullinated
fibronectin antibodies in rheumatoid arthritis are associated
with HLA-DRB1 share epitope alleles. Arthritis Research &
Therapy, 14, R35.
Verpoort, K.N., Cheung, K., Ioan-Facsinay, A., van der Helmvan Mil, A.H., de Vries-Bouwstra, J.K., Allaart, C.F. et al.
(2007) Fine specificity of the anti-citrullinated protein
antibody response is influenced by the shared epitope alleles.
Arthritis & Rheumatism, 56, 3949.
Wagner, U., Kaltenhauser, S., Sauer, H., Arnold, S., Seidel, W.,
H
antzschel, H. et al. (1997) HLA markers and prediction of

clinical course and outcome in rheumatoid arthritis. Arthritis

& Rheumatism, 40, 341.
Walford, R.L., Finkelstein, S., Neerhout, R., Konrad, P. &
Shanbrom, E. (1970) Acute childhood leukaemia in relation to
the HL-A human transplantation genes. Nature, 31, 461.
Wei, C.-Y., Chung, W.-H., Huang, H.-W., Chen, Y.-T. & Hung,
S.I. (2012) Direct interaction between HLA-B and
carbamazepine activates T cells in patients with StevensJohnson syndrome. The Journal of Allergy and Clinical
Immunology, 129, 1562.
Wellcome Trust Case Control Consortium, Australo-AngloAmerican Spondylitis Consortium, Burton, P.R., Clayton,
D.G., Cardon, L.R., Craddock, N. et al. (2007) Association
scan of 14,500 nonsynonymous SNPs in four diseases
identifies autoimmunity variants. Nature Genetics 39, 1329.
Winkler, C., Krumsiek, J., Lempainen, J., Achenback, P.,
Grallert, H., Giannopoulou, E. et al. (2012) A strategy for
combining minor genetic susceptibility genes to improve
prediction of disease in type 1 diabetes. Genes and Immunity,
13, 549.
Zanni, M.P., von Greyerz, S., Schnyder, B., Brander, K.A.,
Frutig, K., Hari, Y. et al. (1998) HLA-restricted, processingand metabolism-independent pathway of drug recognition by
human b Lymphocytes. The Journal of Clinical
Investigation, 102, 1591.
Ziegler, A., Loll, B., Misselwitz, R. & Uchanska-Ziegler, B.
(2009) Implications of structural and thermodynamic studies
of HLA-B27 subtypes exhibiting differential association with
ankylosing spondylitis. Advances in Experimental Medicine
and Biology, 649, 177.

2013 John Wiley & Sons Ltd

International Journal of Immunogenetics, 2014, 41, 112