Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases
Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases
0 G. Bodis V. Toth Institut fu ̈r Medizinische Diagnostik GmbH, Bioscientia Labor Ingelheim , Ingelheim Am Rhein , Germany
1 A. Schwarting ACURA Center for Rheumatic Diseases , Bad Kreuznach , Germany
2 G. Bodis V. Toth A. Schwarting (&) Division of Rheumatology and Clinical Immunology, University Hospital , Mainz , Germany
Since the discovery of HLA 60 years ago, it has contributed to the understanding of the immune system as well as of the pathogenesis of several diseases. Aside from its essential role in determining donor-recipient immune compatibility in organ transplantation, HLA genotyping is meanwhile performed routinely as part of the diagnostic work-up of certain autoimmune diseases. Considering the ability of HLA to influence thymic selection as well as peripheral anergy of T cells, its role in the pathogenesis of autoimmunity is understandable. The aim of this paper is to provide a brief overview of the role and current clinical relevance of HLA-B27 in spondyloarthritis and HLA-B51 in Behc¸et's disease as well as HLA-DQ2/DQ8 in celiac disease and HLA-DRB1 in rheumatoid arthritis and to discuss possible future implications.
Autoimmunity; Behc¸et's disease; Celiac disease; Genotyping; Human leucocyte antigen; MHC class I; MHC class II; Shared epitopes; Spondylarthritis; Rheumatoid arthritis
The human leukocyte antigen (HLA) system,
which corresponds to the major
histocompatibility complex (MHC) in humans, plays a
pivotal role in the antigen presentation of
intracellular and extracellular peptides and the
regulation of innate and adaptive immune
responses. The aim of this paper is to provide a
brief overview of the role and current clinical
relevance of HLA-B27 in spondyloarthritis and
HLA-B51 in Behc¸et’s disease as well as
HLADQ2/DQ8 in celiac disease and HLA-DRB1 in
rheumatoid arthritis and to discuss possible
future implications. This article is based on
previously conducted studies and does not
contain any studies with human participants or
animals performed by any of the authors.
MHC CLASS I: HLA-B27
AND SPONDYLOARTHRITIS (SPA)
The clinical entities of the spondyloarthritis
(SpA) group are inflammatory diseases with
distinctive axial and/or peripheral joint
involvement, enthesitis, and frequently
accompanied by inflammatory eye disease,
especially anterior uveitis. SpA belongs to the
most common rheumatic diseases with a
prevalence of 0.4–1.3% in the US with similar
prevalence in Europe and lower rates in African
and Asian populations [
]. It also poses a
major burden both socially and economically
due to work disability occurring in 18.5–21% of
SpA patients [
One of the common denominators among
distinct entities of the SpA family is the
frequent association with MHC class I molecules,
particularly with HLA-B27, which has obtained
significance in the routine diagnostic work-up
in the last decades. HLA-B27 belongs to the
MHC class I molecules. Its main function is the
presentation of intracellular peptides to
CD8positive T lymphocytes. These MHC class
I-restricted T cells possess cytotoxic or regulatory
function, their activation leading accordingly
either to tolerance, when the presented peptides
are recognized as ‘‘self’’, to activation of
cellmediated immunity in case ‘‘non-self’’ antigens
are presented or to a maladaptive autoimmune
response if the ‘‘self’’ antigen is misrecognized.
The prevalence of HLA-B27 shows a pronounced
north–south gradient in the normal population:
it is lowest in the equatorial region (* 0%) and
highest in northern countries (30–40%). This
geographical difference may be attributable to
HLA-B27 carriers being more susceptible to
malaria and also showing a more severe disease
course. This susceptibility might have led to the
negative selection of HLA-B27-positive
individuals in areas endemic for malaria [
population of Papua New Guinea and Eskimos seem to
have the highest prevalence of HLA-B27, with
] and 25–50% [
8, 9, 10
Among Caucasians, the prevalence is 6–10%. The
prevalence is lower in Chinese (2–8%) [
Arab (2–5%) [
], African-American (2–4%) [
and Japanese (0.4%) [
] populations. In the
natives of South America, equatorial and
southern Africa, and the Aboriginal people of Australia,
HLA-B27 is virtually absent [
prevalence of SpA corresponds to the distribution of
HLA-B27 alleles in various populations.
A potential genetic susceptibility to
ankylosing spondylitis (AS) was first recognized in
] and the strong link to HLA-B27 was
discovered in 1973 by two research groups
]. AS is a radiographic axial SpA primarily
with spinal and sacroiliac joint involvement,
which is characterized by enthesitis with
chronic inflammation, which subsequently
results in fibrosis and ossification of the
involved sites. HLA-B27 has the strongest
association with AS among disease entities of the
SpA group, especially in Caucasians, with
88–96% of patients being positive [
Asian AS patients carry HLA-B27 less frequently.
Among African Americans, HLA-B27 is present
in 50% of patients with AS [
]. Thirty to eighty
percent of patients with reactive arthritis (ReA)
and 20–35% of patients with psoriatic arthritis
are HLA-B27 positive [
Ethnic differences seem to exist regarding
disease susceptibility conferred by HLA-B27.
The relative risk of developing SpA in HLA-B27
positive individuals is increased 20-100-fold in
the Caucasian population [
24, 25, 26
a study carried out on the Indonesian
population found no increased relative risk among
HLA-B27 positive subjects [
]. Ten to 30
percent of HLA-B27-positive first-degree relatives of
HLA-B27-positive AS patients also develop the
The risk of HLA-B27-positive individuals to
develop ReA is 5–10 times greater than that of the
general population [
]. The role of gene dosage
is inconclusive. On one hand, higher relative risk
of developing AS in HLA-B27 homozygotes was
observed in Finnish AS patients. Interestingly,
homozygous patients showed a less severe
disease course [
]. On the other hand, an earlier
study carried out in the Netherlands and a more
recent study in Korea found no significant
difference between homozygous and heterozygous
Structure and Subtypes
Similar to other MHC class I molecules,
HLAB27 is a heterotrimer derived from a heavy
chain encoded by the HLA genes, a
b2-microglobulin light chain and the presented
peptide. HLA-B27 differs from other HLA-B
molecules on possessing a free cysteine at
residue 67 (Cys67) allowing the molecule to create
stable homodimers without b2-microglobulin
due to the formation of disulfide bonds [
HLA-B27 shows a marked genotypic and
phenotypic polymorphism with at least 132 alleles
and 105 subtypes. Non-synonymous nucleotide
substitutions affecting the antigen-binding cleft
can lead to differences in antigen presentation
and ultimately in disease association [
Furthermore, the frequency of HLA-B27
subtypes varies among different ethnic groups
as well. One of the benefits of genetic HLA-B27
testing is that the different subtypes can be
determined more reliably and reproducibly, all
of which have different levels of associations
with disease [
]. The B*27:05 subtype is the
most common in Caucasians, other subtypes
evolved from this ancestral type by gene
conversion, reciprocal combination, and point
mutation. It is, however, probably not linked to
SpA in the African population. B*27:02 shows a
strong association in the Mediterranean
population, while B*27:04 is a common subtype in
Asian SpA patients [
]. A recent meta-analysis
composed of 8993 AS patients and 19,254
healthy controls confirmed the significant
association of B*27:02 and B*27:04 with AS.
B*27:03, *27:06, and *27:09 are considered to be
protective subtypes, although SpA cases in
patients carrying these subtypes have been
reported. B*27:03 and B*27:06 are common in
Southeast Asia, while *27:09 is frequently found
in Sardinia and Italy. Some rare subtypes also
seem to contribute to the risk of SpA, including
B*27:01, B*27:07, B*27:08, B*27:10, B*27:13,
B*27:14, B*27:15, B*27:19, and B*27:25.
Changes of the primary structure of the HLA-B27
protein may explain the different levels of
disease associations, especially the variations
affecting the antigen-binding cleft and as a
consequence possibly the peptide specificity.
There has been a difference of two amino acids
observed between the F pockets of the peptide
binding groove of B*27:06 and B*27:04, as well
as a difference of one amino acid between
B*27:09 and B*27:05. These minor changes of
the amino acid sequences result in significantly
different risk profiles [
37, 38, 39, 40, 41
Contribution to Disease
Despite intensive research in the last decades,
the pathomechanism of SpA and the
contribution of HLA-B27 to disease still remains unclear,
as neither one of the existing hypotheses can
fully describe and explain the underlying
It is, however, more than likely that the
pathomechanism is more sophisticated than a
single—not yet identified—self-antigen. While
the molecular mimicry and arthritogenic
peptides hypothesis presents a model compatible
with classic autoimmunity, the unfolded
protein response hypothesis as well as the cell
surface HLA-B27 homodimers hypothesis rather
support the autoinflammatory aspects of SpA.
The unfolded protein response hypothesis is
based on the ability of HLA-B27 heavy chains to
form stable homodimers owing to the free thiol
groups of Cys67 [
]. These complexes are
retained in the endoplasmic reticulum in the
absence of b2-microglobulin, misfold, and
accumulate in the endoplasmic reticulum,
leading to stress response and inflammation
]. The protective B*27:06 and B*27:09
subtypes are less prone to misfolding than subtypes
associated with disease risk. While this
observation might seem to support this hypothesis, it
is undermined by the fact that the
disease-associated B*27:07 subtype has been shown to
fold equally efficiently [
b2-microglobulin-free HLA-B27 heavy chain
homodimers can also be found on the cell
membrane, where they can also interact with
CD4-positive T lymphocytes, NK cells, and
myelomonocytic cells that express
killer-immunoglobulin-like receptors (KIR) and
leukocyte immunglobulin-like receptors (LILR).
b2microglobulin can also be released from
HLAB27 molecules on the cell surface and be
deposited in synovial tissue, suggesting a
possible role in the pathogenesis of SpA [
The molecular mimicry and arthritogenic
peptides hypothesis proposes that owing to the
properties of the antigen-binding cleft HLA-B27
can present certain microbial peptides similar to
self-antigens. The immune response triggered
by the displayed microbial peptides causes
HLAB27 restricted CD8-positive T-lymphocytes to
cross-react with these arthritogenic peptides,
triggering chronic inflammation [
several such microbial peptides have been
identified. The nitrogenase enzyme of Klebsiella
pneumoniae shares a sequence of six consecutive
amino acids with HLA-B27 [
]. Another K.
pneumoniae protein, the pullulanase enzyme
and certain outer surface proteins of Yersinia
enterocolitica and pseudotuberculosis, Shigella
flexneri and Salmonella typhimurium also possess
sequences homologous with HLA-B27 [
A recent study aiming to identify such
arthritogenic peptides assessed the peptide repertoire
of eight frequent HLA-B27 subtypes
(HLAB*27:02-09). They identified more than 7500
endogenous peptides presented by these B27
subtypes. However, most peptides that are
presented by the risk subtypes could also bind to
B*27:06 and B*27:09, which are considered to
be protective. This significant overlap of
presented peptides between the subtypes leads the
authors to the conclusion that the different risk
profiles among subtypes may be due to
quantitative changes affecting antigen sensitivity of
autoreactive T cells and most likely not to
qualitative changes of the HLA-B27 peptide
repertoire . Additionally, several studies
proposed a link between the interaction of
HLAB27 with the intestinal microbiome and the
pathogenesis of related diseases. HLA-B27 may
affect the composition of the gut flora. Indeed,
dysbiotic changes have been described in
patients with SpA. HLA-B27 transgenic rats had
increased proportions of Prevotellaceae and loss
of Rikenellaceae in the intestinal flora. If these
HLA-B27 transgenic animals were kept in a
germ-free environment, they did not develop
arthritis. Recolonization of the gut with
Bacteroides vulgatus resulted in inflammatory
]. However, introducing Lactobacillus
and fusiform bacteria to the gut of germ-free
animals had shown no such effect. These
observations suggest that the modulation of the
complex interplay between the immune system
and microbiome can influence (and in some
cases prevent) disease manifestation in this
animal model. These changes might be
connected with the unfolded protein response: the
endoplasmic reticulum stress response could
lead to intestinal inflammation, impaired
barrier function, and loss of oral tolerance. The
resulting increased translocation of microbial
antigens could on one hand induce
extraintestinal inflammation and on the other hand
prime autoreactive T-lymphocytes [
52, 53, 54
However, a significant role of microbial
antigens or arthritogenic peptides in the
pathogenesis of SpA has not been unequivocally
HLA-B27 determination has obtained clinical
significance in the past decades in the routine
diagnostic work-up of SpA due to its strong
genetic association with disease. HLA-B27
determination has a sensitivity of 83–96%,
specificity of 90–96%, and a likelihood ratio of
9.0 for AS in Caucasians with inflammatory
back pain [
]. HLA-B27 positivity is part of the
Assessment of Spondyloarthritis International
Society (ASAS) classification criteria for axial
and peripheral SpA as well as the Amor Criteria
for diagnosis of SpA [
]. Current German
guidelines also recommend HLA-B27
determination in case of clinical suspicion of SpA.
However, screening of the general population is
not recommended, as a positive result merely
indicates genetic susceptibility. Accordingly,
only a minority of HLA-B27 carriers will develop
a disease of the SpA spectrum. Generally, testing
for HLA-B27 should not be repeated, although
in case of serological typing cross-reactivity
with other HLA-B molecules as well as
falsenegative results were reported [
The data provided by the Recognising and
Diagnosing Ankylosing Spondylitis Reliably
(RADAR) study has lead to the development of a
strategy for primary care physicians when to
refer patients with early onset (\45 years)
chronic back pain to rheumatologic evaluation:
the selection could be based on either HLA-B27
positivity, inflammatory back pain, or
sacroiliitis on MRI. The authors concluded that a
referral strategy based on these three criteria can
lead to the diagnosis of axial SpA in 35% of
In addition to being a pivotal part of the
diagnostic work-up, a prognostic value has been
attributed to HLA-B27 as well. In patients with
AS HLA-B27, positivity is associated with earlier
disease onset, higher disease activity, risk of
peripheral joint involvement, symmetric
sacroiliitis, severity of MRI findings in
sacroiliitis, and positive family history [
60, 61, 62, 63
although there have been conflicting reports
]. Undiagnosed patients with early
inflammatory back pain—especially in case of
non-radiologic axial SpA—benefit from the
combination of MRI of the sacroiliac joints and
HLA-B27 determination. Severe sacroiliitis in
HLA-B27-positive patients is highly specific for
the development of AS. Patients with mild or no
sacroiliitis on MRI have a low risk of developing
AS regardless of the HLA-B27 status [
NSAID use and higher need for biologicals has
been observed in HLA-B27-positive patients
with AS [
]. On the other hand, TNF-alpha
inhibitors show a greater therapeutic effect in
HLA-B27-positive patients with AS [
Psoriatic arthritis (PsA), a further entity of
the SpA group, is a multifaceted chronic
inflammatory joint disease, which is associated
with cutaneous psoriasis in the majority of
patients. It generally manifests as an
asymmetrical oligoarthritis, although polyarticular as
well as axial forms also commonly occur. In
patients with PsA, HLA-B27 is associated with
axial manifestation and possibly also with distal
phalangeal joint involvement, and this
association seems to be independent of psoriasis [
However, PsA is not associated with HLA-Cw6,
which is present in 10–60% of patients with
], although earlier studies using
serologic methods described a possible
connection. Interestingly, 61% of PsA patients with
symmetric sacroiliitis carried HLA-B*27:05, as
opposed to 9.8% of patients with asymmetric
sacroiliitis, where the haplotype
HLA-B*08:01C*07:01 was more prevalent.
Patients possessing B*27:05 and especially
the B*27:05-C*01:02 haplotype had a higher
risk of dactylitis. The B*27:05 and C*01:02
alleles were associated with enthesitis in PsA.
Patients with a synovial-predominant
pattern carried the B*08:01-C*07:01 haplotype
more frequently, which predisposes to joint
deformity. The B*27:05-C*02:02,
B*37:01C*06:02 and B*08:01-C*07:01 haplotypes are
associated with a more severe disease course
]. Therefore, the different MHC class I alleles
play a role in determining whether the patients
with PsA develop asymmetrical or symmetrical
sacroiliitis as well as enthesitis and dactylitis.
Uveitis is strongly linked to HLA-B27 as well.
Conversely, the presence of an isolated
HLAB27-positive uveitis confers a high risk for
developing SpA [
]. HLA B27 positivity
correlates with worse prognosis and more severe
disease course in ReA compared to B27-negative
]. Therefore, the diagnostic role of
HLA B27 is mostly to support the clinical
suspicion of SpA in addition to providing
In addition to SpA, HLA-B27 has also been
linked to other disease entities. Although
rheumatoid arthritis is not associated with
HLAB27 in itself, an elevated risk of atlanto-axial
subluxation has been described in carriers [
HLA-B27 is also considered to have a
protective role in several viral diseases such as HIV,
hepatitis C, influenza, Epstein–Barr virus,
herpes simplex virus and Puumala hantavirus
infection, although it increases the risk of
contracting malaria [
76, 77, 78, 5
]. Interestingly, a
recent study reported the HLA-B27 molecule
sharing a homology of four consecutive amino
acids with an immunodominant peptide of E1
glycoprotein of Chikungunya virus. This leads
the authors to the conclusion that HLA-B27
positivity might also play a role in persistent
arthralgia following Chikungunya infection; its
importance, however, remains to be seen .
Recent genome-wide associated studies
performed in large groups of patients pinpointed
the association of several non-B27 HLA as well
as non-HLA genes with SpA [
Nevertheless, routine genetic testing of non-B27 HLA as
part of the diagnostic work-up of SpA is likely
MHC CLASS I: HLA-B51
AND ADAMANTIADES-BEHC¸ ET’S
Behc¸et’s disease (BD) belongs to the group of
variable vessel vasculitides according to the
2012 Revised International Chapel Hill
Consensus Conference Nomenclature of
Vasculitides, characterized by inflammatory eye disease
(uveitis), oral and genital ulcers. Similarly to
SpA, BD also shows a marked geographical
distribution with Mediterranean and Asian
populations being most affected, hence the name
‘‘Silk Road disease’’. The prevalence of BD is
17–42/10,000 in Turkey, 2.1–420/100,000 in
Asian and North African populations and
0.3–7.5/100,000 in Western Europe and the
United States [
83, 84, 85
Patients with BD often carry an MHC class I
molecule, HLA-B51 [
], especially those of
Turkish or Asian origin, whereas the association
in Caucasian patients is weaker. In a recent
meta-analysis, the prevalence of HLA-B51 in BD
patients ranged between 50% and 72% [
compared to 10–15% in healthy controls in
Further genetic and environmental factors
are likely to play an additional role in the
pathogenesis of BD. A change of BD phenotype,
in particular a decrease in HLA-B51 frequency,
has recently been reported in Japanese patients,
Structure and Subtypes
HLA-B51 is one of two distinct split-antigens of
the HLA-B5 serotype and is primarily associated
with BD risk, although some case reports have also
found a possible link with the second
split-antigen, HLA-B52 [
]. Several HLA-B51 subtypes
have been described, of which especially B*51:01,
B*51:02(01), B*51:08, B*51:09, and B*51:22 seem
to be associated with BD risk [
Contribution to Disease
The role of HLA-B51 in the pathogenesis of BD
is not fully understood. Selective binding of
certain peptides and the activation of
CD8positive T-lymphocytes and NK cells due to
interactions of the HLA-B51-heterotrimer and
T-cell receptors as well as killer
immunoglobulin-like receptors are likely to be implicated.
Gamma-delta T cells also play a role in the
pathogenesis of BD. Furthermore, active BD was
associated with significant in vivo activation of
Vd1 and Vd2 gamma-delta T-cells, while an
overproportional activation of Vd1
gammadelta T-cells has been seen exclusively in
HLAB51 positive patients [
]. Additionally, a
possible role of HLA-B51 in neutrophile
hyperfunction in BD has been described. The
spontaneous activation of HLA-B51-positive
neutrophils leads to perivascular tissue injury
and promotes a Th1 immune response [
These findings suggest that HLA-B51 is involved
in the activation of CD8-positive T-cells,
gamma-delta T-cells, NK-cells, and neutrophils.
As for the clinical significance, HLA typing is
not part of the International Criteria for Behc¸et
disease, however, the testing is available in
several medical laboratories. The estimated
sensitivity is 51% and the specificity 71% [
is important to understand the limitations and
the diagnostic conclusiveness of both positive
and negative results. It is not meant to diagnose
BD, but rather support the diagnosis. The
screening of high-risk populations is not
recommended, as the majority of HLA-B51 carriers
do not develop BD. Conversely, BD can not be
excluded in the absence of HLA-B51.
A possible prognostic value has been
attributed to HLA-B51: HLA-B51 carriers have been
shown to have a higher risk of genital ulcers as
well as ocular or skin involvement. Male
patients are more likely to be HLA-B51 positive
]. Certain subtypes may be associated with
different risk profiles, for example Turkish
HLAB*51:03-positive patients are at a higher risk of
neurological involvement, and HLA-B*51:09
may lower the risk of developing
papulopustular lesions [
The testing of additional BD susceptibility
HLA alleles, such as HLA-A03, A26, B15, 27, 57
], is currently not considered to be
clinically or diagnostically relevant due to their low
MHC CLASS II: HLA-DQ2/DQ8
AND CELIAC DISEASE (CD)
Celiac disease (CD) is one of the most common
organ-specific autoimmune diseases with a
prevalence of 1% that primarily affects the small
intestines following gluten exposure [
]. It has
strong links to both genetic and environmental
factors, the latter being gluten exposure. As for
the genetic factors, a strong association exists
with MHC class II alleles, HLA-DQ2, and DQ8. A
link with non-MHC genes has also been
described in genome-wide association studies
Subtypes and Contribution to Disease
Ninety percent of Caucasian patients with CD
express HLA-DQ2.5cis encoded by
HLADQA1*0501-DQB1*0201 or DQ2.5trans on
DQB1*0301/DQA1*0201DQB1*0202 haplotypes. Five percent of these
patients carry HLA-DQ8 with the
HLADQA1*0301-DQB1*0302 haplotype. Patients
negative for these HLA molecules mostly
possess HLA-DQA1*0201-DQB1*0202 haplotypes
]. HLA-DQ2.2 carriers have an
inconsequential risk of developing CD. In
contrast, approximately 20–30% of the healthy
Caucasian population is HLA-DQ2 positive. A
gender-specific distribution of HLA alleles has
been described: female patients with celiac
disease are infrequently DQ2.5/DQ8-negative.
However, not all DQ2 carriers develop CD.
Non-HLA genes are likely to play an additional
role, as seen in identical twins, who show a
higher concordance rate (70%) than HLA
identical siblings. HLA-DQ2 or –DQ8 are necessary,
but not sufficient for the development of CD.
The estimated risk of DQ2/DQ8 carriers is
Zygosity is a strong determinant of gluten
peptide presentation and disease risk.
Additionally, homozygous patients have been
shown to have a more severe disease course.
Especially HLA-DQ2.5 homozygotes may
exhibit an augmented immune response following
infections of the gastrointestinal tract due to
elevated interferon gamma concentrations,
which has been shown to regulate HLA-DQ
expression indirectly [
Different haplotypes recognize different
ligands with different affinity, resulting in
different risk profiles. A comparison of
DQ2.5-ligands with DQ2.2-ligands revealed that DQ2.5
can present a broader spectrum of gliadin
peptides than DQ2.2. Gliadin peptides can
withstand gastrointestinal digestion, therefore,
DQ2-molecules can recognize these resistant
immunodominant epitopes and present them
to CD4-positive T-lymphocytes in the intestinal
mucosa. The affinity of DQ2 to gliadin peptides
is further increased by the tissue
transglutaminase enzyme, which deamidates glutamine
residues of gliadin peptides. The resulting
glutamic acid residues display an increased affinity
to DQ2 molecules [
]. The activation of
both the innate and adaptive immune system
leads to a humoral response against tissue
transglutaminase, as well as to TNF alpha and
interferon gamma secretion, which ultimately
result in tissue damage and disease
Additionally, possible links with infections
have been described. Due to a homology of an
amino acid sequence between the 54 kDa E1b
protein of human adenovirus type 12 and
gliadin, exposure to the virus may promote
autoimmunity in genetically susceptible
]. Hepatitis C, Giardia lamblia,
Campylobacter jejuni, Rotavirus and Enterovirus
have also been implicated as possible triggers of
CD. It has been postulated that HLA-DQ
molecules may also have an impact on the intestinal
microbiome. Patients with celiac disease have a
different composition of the intestinal
microbiome with decreased proportion of
Actinobacteria (especially Bifidobacterium genus)
and elevated proportion of Firmicutes,
Proteobacteria and Staphylococcus spp. [
There is a permanent interaction between
microbes and Th17, Treg, and B-lymphocytes.
HLA-DQ molecules are likely to influence this
interaction depending on the displayed ligands
and lead to either tolerance of certain microbial
strains or immune response against them. It is
therefore possible that the effect of HLA
molecules on the pathogenesis of celiac disease may
be to some extent due to the altered
Regarding the clinical and diagnostic relevance,
the testing of DQ2/DQ8 has an excellent
negative predictive value of 99%: a negative test
virtually excludes CD , while a positive test
merely indicates genetic susceptibility. An
advantage of HLA testing is that a gluten-free
diet is not necessary for optimal diagnostic
conclusiveness in marked contrast to
autoantibody testing and histology [
According to the European Society for
Pediatric Gastroenterology, Hepatology, and
Nutrition guidelines for the diagnosis of celiac
disease testing of HLA-DQ2/DQ8 should be
included in the diagnostic work-up of celiac
disease in children. Small-bowel biopsy may not
be necessary in the pediatric population in case
of symptomatic patients with significantly
elevated tTG and EMA antibody titers and
HLADQ2/DQ8 positivity [
A similar straightforward approach has been
suggested for all age groups with suspected CD.
This so-called ‘‘four out of five rule’’ allows the
diagnosis of CD if four of the following five
criteria are met: typical symptoms, significant
elevation of CD antibodies, HLA-DQ2 or
HLADQ8, typical biopsy result, response to
glutenfree diet [
US Guidelines do not recommend HLA-DQ2/
8 testing in the routine diagnostic work-up of
CD, however, it may be useful in selected
clinical situations, such as a discrepancy between
histologic and serologic results [
HLA testing may also be useful to exclude CD
in high-risk individuals, such as first-degree
relatives of CD patients, patients with
autoimmune diabetes mellitus, selective IgA
deficiency, Down syndrome, Turner syndrome,
Williams syndrome, or autoimmune thyroiditis.
Testing could also be considered in case of
unexplained iron deficiency anemia or early
onset osteoporosis [
]. With the help of
HLA testing, the number of invasive diagnostic
procedures may be reduced in this high-risk
MHC CLASS II: HLA-DRB1, SHARED
AND RHEUMATOID ARTHRITIS (RA)
Rheumatoid arthritis (RA) is a common chronic
systemic autoimmune disease, which primarily
presents with a symmetrical polyarthritis and
has a prevalence of 0.5–1% worldwide [
Although the exact pathogenesis of RA remains
unclear, its complex association with MHC class
II molecules has been described [
contribution of HLA genes to susceptibility is
estimated to account for 50% of risk [
Remarkably, RA seems to be associated with
such HLA-DRB1 alleles, which share sequences
of five amino acids in position 70–74 of the
antigen-binding groove of HLA-DR-b-chains, as
described by the shared epitope hypothesis
]. The shared epitopes (for example
QKRAA, QRRAA, RKRAA, RRRAA) are present in
70–90% of Caucasian patients with seropositive
RA in contrast to the prevalence of 20–30% in
the general population and patients with
seronegative RA . The highest relative risk
of developing RA has been attributed to
HLADRB1*0401 and *0404, which can be detected
in 50–61% and 27–37% of seropositive patients,
respectively. DRB1*0404 may also be associated
with seronegative RA. The Latter population
also exhibits HLA-DRB1*0101 [
HLA-DRB1*0401/*0404 genotype is associated
with elevated risk of disease, earlier onset,
seropositivity, accelerated joint damage and the
presence of rheumatoid nodules . Ethnic
differences have been reported, the prevalence
of DRB-1 in African-American patients is lower
]. HLA-DRB1*0405 is the most
frequent allele in Asian RA patients [
HLA-DRB1*1402 is associated with RA in Native
American patients . A large European
meta-analysis has shown that HLA-DRB1*13:01
provides protection against anti-citrullinated
protein antibodies (ACPA)-positive disease but
not against ACPA-negative RA [
Homozygosity or compound heterozygosity
for HLA-DRB1 alleles containing one of the
shared epitope sequences is associated with
increased risk of developing RA. Patients
carrying two shared epitope-containing
HLADRB1*04 alleles—especially homozygosity for
HLA-DRB1*0401—have a higher risk of
extraarticular manifestations including
rheumatoid vasculitis [
Contribution to Disease
Several theories of the pathogenetic role of the
shared epitopes have been proposed such as
molecular mimicry, antigen presentation of
arthritogenic peptides, as well as a role in the
positive selection of specific autoreactive
T-lymphocytes in the thymus. However, the
exact mechanisms remain unclear.
Recent studies have shown that
polymorphisms in certain amino acid positions of MHC
molecules can better account for genetic
susceptibility than solely the shared epitope
hypothesis. Amino acids in positions 11, 13, 70,
71, and 74 of the DR-b chain show strong
independent correlation with relative risk.
Interestingly, only changes of the latter three
affect the shared epitope motif. Positions 70 and
71 have a significant role in presentation of
vimentin, alpha-enolase, and collagen as well as
in modulating the interaction with T-cell
]. Positions 67 and 86 may also
affect the binding of possible arthritogenic
]. It has been suggested that three
of the above-mentioned amino acid positions
within HLA-DRB1 (11/13, 71, 74) and in two
non-DRB-1 HLA (position 9 of HLA-B, position
9 of HLA-DPB1) account for the majority of
HLA-associated genetic susceptibility to RA
]. HLA-DRB1 haplotypes also influence
disease severity, mortality, and therapy response.
Valine in amino acid position 11 of
HLADRB1 has the strongest genetic association with
radiologic damage independent of shared
epitope status as well as with clinical and
laboratory markers of inflammation and overall
mortality. Positions 71 and 74 are also
associated with erosive damage [
findings underline the additional importance of
non-shared epitope polymorphisms.
Shared epitopes are associated significantly
only with ACPA-positive RA [
antigens bind preferentially to HLA-DRB1 with
shared epitope sequences leading to the
activation of autoreactive T-cells and subsequently to
the expansion of autoantibody-secreting
B-lymphocytes. Patients carrying shared epitope
motifs were more frequently ACPA positive in a
dosage-dependent manner. Cigarette smoking,
a major environmental risk factor of RA, has
been shown to induce citrullination of proteins
in the lung and its harmful effect may be due to
interactions with HLA-DRB1 molecules and
trigger the excessive immune reaction [
Indeed, heavy smoking increased risk of
developing ACPA-positive RA in the presence of
shared epitope-containing HLA-DRB1 alleles,
although no significant association has been
found in patients with ACPA-negative RA
Regarding the clinical usefulness of genetic
testing in patients with suspected or diagnosed
RA HLA-DRB1 analysis is neither included in
current classification criteria nor recommended
as a diagnostic tool by current ACR/EULAR
In a case–control study HLA-DRB1*0401 and
*0404 had a sensitivity of 60% and a specificity
of 64% as indicators for the future development
of RA. The combination of anti-CCP2
antibodies and the testing of these two HLA-haplotypes
proved to be the best approach for detecting RA
]. Other authors found no
benefit of additional shared epitope testing
owing to its strong association with ACPA [
Genotyping of shared epitopes and
HLADRB1 variants may provide valuable
information regarding the choice of treatment options.
A triple therapy containing methotrexate,
hydroxychloroquine, and sulfasalazine is more
effective in the presence of shared epitopes than
methotrexate monotherapy. No significant
difference between therapy regimes was observed,
however, in shared epitope-negative patients
]. The efficacy of TNF-alpha inhibitors may
also be influenced by HLA-DRB1 haplotypes.
TNFi response was not associated with the
presence of shared epitopes but rather with
amino acid position 11. Patients with valine at
this position had significantly better EULAR
responses independent of zygosity and ACPA
status compared to noncarriers [
In concluding this section, it should be
reemphasized in light of current evidence that the
contribution of HLA-DRB1 to RA susceptibility
is far weaker than those of HLA-DQ2/DQ8 to
CD or HLA-B27 to SpA, respectively.
Nevertheless, HLA-DRB1 analysis is available in several
commercial medical laboratories. Results
should be interpreted with caution: on one
hand a positive result merely indicates genetic
predisposition and is not suitable for the
diagnosis of RA. On the other hand, RA can
certainly not be excluded in case of absence of
shared epitopes, especially in non-Caucasian
Funding. No funding or sponsorship was received for this study or publication of this article.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Disclosures. Gergely Bodis, Victoria Toth, and Andreas Schwarting have nothing to disclose.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not contain any studies with human
participants or animals performed by any of the
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons license, and
indicate if changes were made.
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