Rheumatology 2010;49:621–631

RHEUMATOLOGY doi:10.1093/rheumatology/kep450
Advance Access publication 18 January 2010

Review
HLA-B27: what’s new?
Nicholas J. Sheehan1

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Abstract
The HLA-B27 molecule is one of the most fascinating in medicine. Its contribution to the aetiopathogen-
esis of SpA and other diseases, and its protective action in certain infections, continue to challenge our
understanding of its immunobiology and physiological roles. Animal studies have helped to cast light on
ways in which HLA-B27 exerts its effects. Subtle variations in structure and behaviour between B27
subtypes that are strongly associated with SpA, compared with those whose association is neutral or
weak, are helping to elucidate its pathogenetic mechanisms. However, none of the current hypotheses
fully explains the observed actions of HLA-B27. Consequently, attention is turning to how haplotype
linkages and genetic networks involving other MHC and non-MHC genes influence the penetrance and

R EV I E W
clinical expression of B27. HLA-B27 gives an intriguing insight into the connection between heredity and
disease. As well as its close links with SpA, various other associations have been reported between B27
and diseases of different organs and systems. Evidence is also accumulating that it mitigates the virulence
of HIV and other viral infections. The role of HLA-B27 as an aid to diagnosis, prognosis and disease
management is gradually becoming clearer.
Key words: HLA-B27, Ankylosing spondylitis, Spondyloarthropathy, Infection.

Introduction populations and ethnic groups [4–18]. Most reports have

confirmed the known geographical distribution of the dif-
The HLA-B27 molecule is one of the most fascinating in ferent subtypes of HLA-B27, with HLA B*2705 being
medicine. Since first coming to prominence in 1973 with common in Caucasians and American Indians, HLA
the discovery of its intimate association with AS [1, 2], B*2704 in Asians and HLA B*2702 in Mediterranean pop-
much has been learnt about its immunobiology and its ulations [19]. Each of these alleles shows a strong asso-
involvement both in the aetiopathogenesis and in the pro- ciation with AS, which has also been reported with other
phylaxis of disease. A previous review in 2004 [3] con- rare subtypes, including B*2701, B*2703, B*2707, B*2708,
cluded with the prediction that new associations of B*2710, B*2713, B*2714, B*2715, B*2719 and B*2725
HLA-B27 and novel uses for it as a diagnostic and prog- [19]. HLA-B*2705 is present in nearly all populations and
nostic aid would continue to be discovered as our under- is deemed to be the genetic ancestor from which the other
standing of the functional nature and role of the antigen B27 alleles have evolved.
increased. So, 5 years later, what is new? Although a common HLA-B27 subtype in Southeast
Asia, comprising more than half of all B27 subtypes
Geographical and population variations found in Indonesia, Malaysia and Thailand [20], B*2706
in the prevalence of HLA-B27 and has been reported only sporadically in AS patients in
its subtypes those countries [14]. Similarly, although HLA-B*2709,
which comprises 20% of the B27 alleles in Sardinia
There has been a steady flow of publications describing and 3% in Southern Italy [19], was recently reported in
the geographical prevalence of HLA-B27 and the fre- a Sardinian woman with AS, she also possessed another
quency and distribution of its subtypes in different MHC allele which has been found to confer susceptibility
to AS [21].
Contrary to their reported association with AS in other
1
Department of Rheumatology, Peterborough and Stamford Hospitals populations [19], HLA-B*2707 may be protective against
NHS Foundation Trust, Peterborough, UK.
AS and other HLA-B27-related diseases in Greek Cypriots
Submitted 28 July 2009; revised version accepted 30 November 2009.
[5], whereas HLA-B*2708 may provide protection in
Correspondence to: Nicholas J. Sheehan, Department of
Rheumatology, City Care Centre, Thorpe Road, Peterborough Mestizos [17], since both are found only in healthy con-
PE3 6DB, UK. E-mail: nick.sheehan@pbh-tr.nhs.uk. trols in these populations.

! The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Nicholas J. Sheehan
In contrast to other Asian populations, such as
Han [22] and Taiwan [14] Chinese or the Japanese [15],
the predominant HLA-B27 subtype associated with AS in
Koreans is B*2705 rather than B*2704 [15, 16]. In Taiwan
Chinese, susceptibility to AS is determined by homozyg-
osity for HLA-B*2704, whereas B*2705 may confer pro-
tection [23]. The first association of B*2724 in a Chinese
Han with juvenile AS was reported in 2006 [13]. HLA-B27
homozygosity does not affect the clinical manifestations
of AS in Korean patients [24]. HLA-B27 is virtually absent
in Zambian patients with AS [25].
Mechanisms of action of HLA-B27
How HLA-B27 predisposes to the development of AS and
other SpAs remains unknown. The classic role of MHC
Class 1 molecules is to present peptides to CD8+
T cells, but HLA-B27 may also possess functions, which
are unrelated to antigen presentation [19].
Studies of transgenic rodents, which indicated that
HLA-B27 is directly involved in disease pathogenesis
rather than merely being a marker for a linked disease-
associated gene [26], have spawned various hypotheses
attempting to explain how its immunobiological effects are
mediated.
The ‘arthritogenic peptide’ hypothesis proposes that
particular properties of the HLA-B27 peptide binding
groove enable the molecule to display microbial peptides
that exhibit molecular mimicry with specific arthritogenic
self-peptides. This would allow the response of HLA-B27-
restricted cross-reactive cytotoxic T-lymphocytes to a
foreign peptide to be directed against self-peptides as
well. The autoimmune reaction might then lead to chronic
inflammation. The finding of a viral peptide and two
self-peptides that exhibit HLA-B27 subtype-dependent
molecular mimicry supports the concept of the hypothesis
[27], but there is no proof for the involvement of these
peptides in the pathogenesis of AS.
Structural and behavioural differences between individ-
ual subtypes, with differing strengths of association with
AS, are believed to be instrumental in the pathogenesis of
SpA. Subtypes HLA-B*2706 and B*2709 are, at most,
weakly associated with AS [19]. HLA-B*2706 differs from
B*2704 by only two amino acid residues and B*2709 dif-
fers from B*2705 by just one [19]. However, while differ-
ences in amino acid sequences that involve the peptide
binding groove and hence determine peptide specificity
could contribute to the different strengths of association
with AS, they do not provide the whole answer.
It has been suggested that B*2709 arose in the
Mediterranean region by a single mutation from B*2705
on a haplotype associated with low susceptibility for AS
and that it is the haplotype that is more important for dis-
ease predisposition than the immunobiological differ-
ences between B*2705 and B*2709 [19]. In Sardinia,
most of the B*2709 and B*2705 alleles are inherited on
different haplotypes [20] and it is feasible that B*2709 has
remained strongly linked to a low-risk haplotype. Where
AS has been reported in association with B*2709, other
genetic factors are liable to have been implicated. In
622
two recent cases of AS in Southern Italy and Sardinia,
in which the patients carried HLA-B*2709, one had
co-existing ulcerative colitis [28] and the other possessed
HLA-B*1403, an allele that was found to be associated
with AS in a small study of B27 Togolese (West
African) patients [29]. Additional genetic differences
between populations possessing B*2709 and B*2705
might also contribute to their differing associations with
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SpA [19].
Being present in a much larger and probably more
genetically diverse population, the case for a lack of asso-
ciation between B*2706 and disease is more compelling,
but patients with this subtype and AS have been reported
as well [14, 30].
The HLA-B27 heavy chain has a tendency to misfold.
Misfolding appears to occur in the endoplasmic reticulum
prior to conjugation of the heavy chain with b2 microglo-
bulin (b2m) and its cargo peptide. Formation of disulphide
bonds between the cysteine residue at position 67 (cys
67) in the B pocket of the peptide binding groove of two
separate heavy chain molecules creates homodimers
without the participation of b2m. Endoplasmic reticulum
stress resulting from the accumulation of misfolded heavy
chains activates the unfolded protein response, which
may induce cytokine production by macrophages and
thereby promote inflammation [31]. However, while the
misfolding hypothesis gains support from the observation
that HLA-B*2706 and B*2709 fold much more efficiently
than disease-associated subtypes B*2705, B*2704 and
B*2702, it is undermined by the fact that HLA-B*2707,
which is associated with AS in most populations in
which it is found, folds as efficiently as B*2706 and
B*2709 [32].
b2m-free homodimers of B27 can also be expressed on
the cell surface where they are capable of binding with
immunoregulatory receptors of other cells, including
killer immunoglobulin-like receptors (KIRs) and leucocyte
immunoglobulin-like receptors (LILRs). Ligation of their
receptors promotes the survival of NK cells and T cells
expressing KIRs, and modulates immune cytokine pro-
duction [33]. LILRs, which are mainly expressed on lym-
phoid and myelomonocytic cells, are also involved in the
activation and regulation of the immune system [34].
Potentially, the interaction of cell surface b2m-free B27
homodimers with these immune receptors could play
a part in the pathogenesis of autoimmune disorders,
including SpA.
A pathogenetic role has also been mooted for b2m.
It has been postulated that, following its release from a
subpopulation of cell surface-expressed HLA-B27 mole-
cules, it is deposited within synovial tissues, provoking
an inflammatory process that culminates in a destructive
arthropathy [35]. This hypothesis is given weight by new
findings in transgenic rats [27].
It is well established that AS has a polygenic aetiology.
Whereas HLA-B27 accounts for over half of the genetic
susceptibility, other genes involved in inflammation, such
as ARTS1, IL23R and IL1A, have also been shown to be
associated with susceptibility to AS and they may interact
www.rheumatology.oxfordjournals.org

with HLA-B27 to predispose to the development of
SpA [36].
Although there is evidence that HLA-B27 modulates the
interaction between ReA-triggering bacteria and the host
cell [37], the finding that the presence of HLA-B27 on the
surface of human cells does not alter the degree of bac-
terial invasion by Salmonella typhimurium or Yersinia
enterocolitica suggests that this factor should not neces-
sarily be implicated in the pathogenesis of ReA triggered
by these bacteria [38].
Effect of HLA-B27 on disease
presentation in inflammatory arthritis
The antiquity of the link between AS and HLA-B27 has
been highlighted by the identification of HLA-B27
sequences in the mediaeval skeletal remains of a man
with classical features of AS [39]. In contrast with
an early report [40], a recent Finnish study showed
that HLA-B27 homozygosity is associated with a moder-
ately increased risk of AS compared with B27 heterozyg-
osity [41].
AS develops at an earlier age in patients who are
HLA-B27+ than in those who are HLA-B27 [42, 43]. In a
Chinese population, the earliest age of onset of AS is
associated with the HLA-B*2715 subtype [43].
In patients with early inflammatory back pain, a combi-
nation of severe sacroiliitis and HLA-B27 positivity has
a high specificity for the development of AS compared
with mild or no sacroiliitis, which confers a low likelihood
of developing AS, regardless of HLA-B27 status [44].
Nonetheless, HLA-B27 is associated with the severity
and the persistence of MRI-demonstrated inflammatory
changes in the SI joints and the lumbar spine in early
SpA [45].
Expression of HLA-B27 mRNA correlates with clinical
disease activity in patients with HLA-B27+ AS compared
with unaffected B27+ family members and unrelated
healthy B27+ control subjects [46].
In a recent study, HLA-B27+ individuals were at greater
risk of experiencing severe joint pain following gastro-
enteritis. However, a significant association between
self-reported reactive joint pain and HLA-B27 was found
only for Salmonella, Shigella and Yersinia and not for
Campylobacter or Esherichia. coli [47].
As well as conferring increased susceptibility to psoria-
tic SpA, HLA-B27 is associated with earlier age of onset of
psoriasis and arthritis, bilateral sacroiliitis and male
gender, but not with severity or extent of the spondylitic
process or with functional impairment [48]. In a study of
Brazilian patients with PsA, carriage of HLA-B27 was
associated positively with spondylitis and negatively with
oligoarthritis [49].
Sacroiliitis is common in patients with established
Crohn’s disease and is symptomatic in the majority of
cases. In this disease, possession of HLA-B27 is asso-
ciated with the development of AS but not with isolated
sacroiliitis [50, 51].
www.rheumatology.oxfordjournals.org
HLA-B27
The HLA-B27 antigen is detected in patients with RA no
more often than would be expected by chance [52].
However, when present, most studies have shown that
possession of B27 influences the radiographic features
in subjects with classical seropositive RA, particularly pre-
disposing to an increased frequency of SI joint involve-
ment [52, 53]. In an early study, HLA-B27+ patients with
classical RA also had more subcutaneous nodules, worse
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functional class and higher ESR and haptoglobin levels
[53], but these findings have not been confirmed.
Ochronotic SpA, especially axial involvement, may
be more severe in HLA-B27+ individuals [54]. Although
the spinal changes resemble those of AS, erosion and
fusion of the SI joints, annular ossification and syndesmo-
phytes do not occur [54].
Clinical and laboratory features are of limited help in
predicting the course and severity of juvenile idiopathic
arthritis. In a Scandinavian study [55], the presence of
HLA-B27 was associated with an older age of onset and
a higher risk of more joint involvement, including involve-
ment of small joints in the lower extremities in boys. In the
first 3 years of disease, B27 was also associated with
enthesitis in boys and with inflammatory back pain
in both sexes [55].
In patients with juvenile SpA in India, urinary tract
infection, diarrhoea and constipation were more
common in HLA-B27+ cases [56]. In Indian patients with
severe haemophilia, HLA-B27 is a strong risk factor for
chronic synovitis [57].
Organ disease associated
with HLA-B27
Ocular
Recent studies have confirmed that an HLA-B27-
associated extra-ocular disorder, most commonly AS or
undifferentiated SpA, occurs in three-quarters of cases of
B27-associated uveitis in French [58] and Chinese [59]
patients. Uveitis is frequently the first indication of a pre-
viously undiagnosed HLA-B27-associated extra-ocular
disease [58].
In Turkish citizens, HLA-B27+ acute anterior uveitis
(AAU) is more common in males and B27 AAU in
females. Unilateral or bilateral alternating AAU as well as
fibrinous reaction and hypopyon formation are more
common in B27+ patients [60].
HLA-B*2705 is the predominant allele in Brazilian
patients with SpA and anterior uveitis [61], whereas
HLA-B27 subtypes may [62], or may not [63], be important
in the development of HLA-B27-associated AAU in
Japanese patients.
HLA-B27+ SpA expresses its visual features mainly
in the form of anterior uveitis and anterior scleritis but
posterior scleritis has recently been reported in patients
with the B27 haplotype, suggesting a probable associa-
tion [64].
The long-term prognosis for vision in HLA-B27-
associated AAU is favourable, regardless of frequent
attacks of severe AAU [65]. Despite more severe
623
Nicholas J. Sheehan
inflammation and hypopyon formation, and a higher rate
of recurrence of attacks, the ocular and visual outcomes
are similar in HLA-B27+ AU, compared with B27 idio-
pathic AU, in Korean patients [66]. However, the visual
outcome of B27-associated uveitis is worse where there
is posterior segment involvement [67]. Hypotonic maculo-
pathy should be considered as a possible cause of vision
loss in patients with B27-associated anterior uveitis [68].
Paradoxically, uveitis is milder in patients with
HLA-B51+ Behçet’s disease who also possess the
HLA-B27 haplotype, owing to less posterior segment
involvement and complications, and a less chronic
course [69].
Herpes simplex virus is the leading cause of infectious
corneal blindness in the developed world. HLA-B27 pre-
disposes to recurrence of herpetic eye disease and graft
failure following penetrating keratoplasty for herpetic cor-
neal scars, and prophylactic anti-viral therapy should be
considered seriously in these patients [70]. HLA-B27 does
not influence the risk of AAU following laser in situ kera-
tomileusis (LASIK) [71].
Recurrent AAU has been reported as the initial manifes-
tation of ochronotic arthropathy in a HLA-B27+ man [72].
The occurrence of AAU in a male patient with HLA-B27,
after recovery from the systemic features of Q fever, was
thought to be a reactive complication triggered by Coxiella
burnetii [73].
The pro-inflammatory cytokine TNF-a may participate
actively in the pathogenesis of clinical uveitis as patients
with HLA-B27+ uveitis have significantly higher concentra-
tions of TNF-a in their aqueous humour than patients with-
out HLA-B27 [74].
Aural
Ear involvement is not generally regarded as a complica-
tion of SpA. However, studies have shown that sensori-
neural hearing loss (SNHL), especially at high frequencies,
is common in patients with AS [75–78], suggesting that
it may be an extra-articular feature of the disease.
A reported case of SNHL in a patient with HLA-B27+
sclero-uveitis has hinted at a possible association
between HLA-B27 and Cogan’s syndrome [79], an
immune-mediated systemic disorder characterized by
ocular and audiovestibular inflammation. In a Chinese
series of patients with AS, autoantibodies directed against
the inner ear were positive in a quarter of cases [75].
Pulmonary
Although lung involvement was initially described in 1941,
it has been considered as an extra-articular manifestation
of AS only since 1965. In a prospective study of patients
with AS without respiratory symptoms, non-specific sub-
clinical pulmonary involvement [including altered plain
chest radiograph (8%), restrictive pattern on pulmonary
function tests (52%) and abnormalities on thoracic high
resolution CT (40%)] was common in AS but was not
associated with HLA-B27 [80]. Whereas pooled immuno-
genetic data revealed an association between HLA-B27
and pulmonary sarcoidosis in Czech and Italian
624
populations [81], this has not been confirmed conclusively
in clinical practice [82].
Cardiovascular
Morbidity and mortality from cardiovascular diseases are
increased in inflammatory rheumatic diseases, including
SpA [83] and RA [84]. HLA-B27 has been identified as a
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risk factor for a cardiovascular event in RA and is asso-
ciated with a decreased lifespan [85]. Although the risk of
requiring a permanent cardiac pacemaker has been
reported to be substantially increased in men carrying
HLA-B27 when compared with other B alleles [86], in an
observational study, patients with a permanent pace-
maker attending a cardiac clinic were no more likely to
be HLA-B27+ than controls [87].
Aortic regurgitation in patients with AS may be due to a
combination of inflammation and dilatation of the aorta
and fibrosis of the valve itself [88]. While aortitis is usually
a feature of long-standing AS, it may also occur early and
acutely in young patients with HLA-B27 and SpA [88].
Acute aortitis can lead to abdominal aortic aneurism [89]
or non-traumatic dissection of the aorta [90] in HLA-B27+
individuals with AS.
Retroperitoneal
Chronic periaortitis (CP) is a rare condition characterized
by retroperitoneal periaortic fibro-inflammatory tissue,
which commonly obstructs neighbouring structures [91].
The conditions that it encompasses include idiopathic
retroperitoneal fibrosis (RPF) and inflammatory abdominal
aortic aneurism [91]. RPF may result from a local immune
response to products of aortic atheromatous plaques with
subsequent periaortic deposition of fibrous tissue [92].
Extra-articular fibrosis, including apical pulmonary fibrosis
and fibrosis of the aortic valve and aorta, is recognized
as a feature of AS. In the reported cases of concomitant
RPF and SpA, patients developed SpA several years
before RPF [92]. Around one-third to a half of reported
cases of CP occurring in association with SpA have
been HLA-B27+ [91, 93]. HLA-B27 has also occasionally
been reported in black American patients with RPF in the
absence of SpA, although the antigen has a low preva-
lence in this population [94]. However, the hypothesis that
HLA-B27 might be a genetic risk factor for CP [93] was not
supported by a recent immunogenetics study [95].
Haematological
A case of myelodysplastic syndrome in a patient with
AS prompted further speculation that HLA-B27 might
also increase the risk of haematological diseases [96].
Multiple myeloma has occasionally been reported in
patients with AS and it has been postulated that persistent
reticuloendothelial cell stimulation due to chronic subcli-
nical gastrointestinal infection may lead to activation and
proliferation of IgA-producing plasma cells and the sub-
sequent development of IgA myeloma [97].
Female patients with seropositive RA who possess
HLA-B27 may be at increased risk of developing
drug-induced agranulocytosis, especially if they also
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have ANA [98] and HLA-B27 alone may confer an
increased risk of this complication in other individuals
[98]. Antibody to HLA-B27 has been implicated in a case
of neonatal alloimmune thrombocytopenia [99].
Renal
Renal involvement is rare in SpA but includes amyloidosis
and GN [100], especially IgA nephropathy [101]. Eighteen
per cent of patients with IgA nephropathy carry the
HLA-B27 gene [102]. Where IgA nephropathy has been
reported in association with SpA, spondylitis has usually
preceded the renal lesion, whereas renal involvement has
occurred simultaneously in Reiter’s syndrome [103].
In a study of renal transplant recipients in the USA,
HLA-B27 was positively associated with IgA nephropathy-
induced end-stage renal disease in African-American
and white patients compared with race-matched controls
[104]. HLA-B27 is the Class 1 antigen most closely linked
with childhood minimal change nephritic syndrome
in Egypt [105]. It is also associated with augmented
cyclosporine blood availability in renal allograft recipients
[106].
Endocrine
A 4-fold increased frequency of HLA-B27 has been found
in patients with autoimmune thyroiditis when compared
with controls [107]. Possession of HLA-B27 has previously
been reported to be associated with an increased risk of
developing Icenko–Cushings disease [108] and apparently
causes lower levels of glucocorticoid receptors on blood
lymphocytes [109].
Osseous
An early [110], but unconfirmed [111], report that one-third
of patients with Forrestier’s disease (DISH) possessed
HLA-B27 suggested a possible association between the
antigen and genes controlling bone formation. This appar-
ent increased frequency of B27 could not be explained by
the rare simultaneous occurrence of DISH and AS [112]
and no further evidence has been presented linking
Forrestier’s disease with HLA-B27.
AS is characterized by both reduced (osteoporosis) and
increased (syndesmophytes, joint ankylosis) bone forma-
tion. Vertebral osteoporosis is common in patients with
AS and appears to be related to disease activity [113].
The spine is a key fracture site in AS, with the reported
risk of vertebral fractures varying from 0.4 to 58% [113].
Although vertebral fractures appear to be linked to the
duration and severity of the disease rather than to BMD
[113], they can also occur in individuals with undiagnosed
benign SpA [114]. In a study of family members of a
patient with AS and osteogenesis imperfecta (OI), several
of whom also had OI and/or possessed HLA-B27, more
severe osteoporosis was found in those with HLA-B27
[115]. Recent research involving HLA-B27 transgenic
rats has shown an association with bone fragility [116].
www.rheumatology.oxfordjournals.org
HLA-B27
Dermatological
As well as its recognized link with psoriasis, through asso-
ciation with PsA, HLA-B27 is a component of several hap-
lotypes associated with vitiligo in Chinese Han patients
[117]. In a Turkish study, erythema nodosum (EN) was
more common in patients with IBD who were HLA-B27+
than in B27 individuals [118]. This contrasts with earlier
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data indicating a negative association between EN and
HLA-B27 in post-Yersinia ReA [119].
Neurological
Although spinal cord and cauda equina compression may
complicate cervical subluxation or lumbar canal stenosis
in SpA [100], these neurological manifestations have
not been reported to be associated with HLA-B27. While
a multiple sclerosis (MS)-like syndrome was recently
described in a patient with AS and HLA-B27 [120], MS
has also been reported in a patient with HLA-B27
AS [121].
Infections
A wider understanding has been gained about the role of
HLA-B27 in host defence against infections and how it
exerts its protective effect. Virus-specific CD8+ T cell
responses play an important role in the natural course of
infection. Cytotoxic T lymphocyte responses, activated
by HLA antigen presentation, especially HLA-B27, are
implicated in the control of HIV replication, thereby retard-
ing the progression to AIDS and conferring a better prog-
nosis [122].
HLA-B27 also promotes spontaneous CD8+ T cell-
mediated viral clearance of HCV [123] and is associated
with a more favourable course in certain other virus infec-
tions as well, including influenza virus, EBV and HSV-2
infections [122].
The frequency of HLA-B27 is lowest (0%) in the equa-
torial region and highest (40%) in the arctic and most
northerly populations [30]. Its geographic spread broadly
follows a latitude-related gradient which is inverse to that
of endemic malaria [124]. In Western India, Plasmodium
falciparum is more likely to infect HLA-B27+ individuals
[125]. If it confers greater susceptibility to more severe
forms of malaria, the B27 gene will be negatively selected
in endemic regions, thereby explaining the observed
inverse relationship.
In a study of Indian patients with juvenile SpA, tubercu-
losis was diagnosed in 14.3% of cases of whom 60%
possessed HLA-B27, suggesting that B27 positivity may
also predispose to tuberculosis [56]. An association has
also been reported between HLA-B27 and tuberculosis in
Tuvinian nationals in the Republic of Tyva in Central Asia
[126].
The musculoskeletal system is involved in 30–85% of
patients with brucellosis, with peripheral arthritis and
sacroiliitis being the commonest articular manifestations
[127]. An early report from Hungary suggested that
patients with chronic brucellosis who possessed the
HLA-B27 antigen had a considerably increased risk
of SpA [128]. However, while brucellosis may be an
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Nicholas J. Sheehan

TABLE 1 Associations between extra-articular organ disease and HLA-B27

Associated disease

Organ or system Definite or probable Possible

Ocular Acute anterior uveitis Posterior scleritis

Anterior scleritis Predisposition to recurrent herpetic eye disease

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following corneal surgery
Aural SNHL
Pulmonary Upper lobe fibrosis Asbestosis
Pleurisy
Pleural abscess
Bronchitis
Pneumonia
Pneumothorax
Sarcoidosis
Cardiovascular Aortic regurgitation CP
Cardiac conduction
abnormalities
Aortitis, aortic aneurism,
aortic dissection
Haematological Acute leukaemia Myelodysplastic syndrome
Drug-induced agranulocytosis
Renal IgA nephropathy Childhood minimal change nephritic syndrome
Endocrine Autoimmune thyroiditis
Cushing’s disease
Bone Osteoporosis
Skin Type II psoriasis Vitiligo
Palmoplantar pustulosis
Immune system Attenuation of viral infections, including HIV, Increased susceptibility to malaria
HCV, influenza, EBV, HSV-2 Increased susceptibility to tuberculosis

occasional triggering infection for ReA in HLA-B27+ indi-
viduals [129], no association was found between HLA-B27
and brucellosis-associated SpA, including ReA and spon-
dylitis, in Peruvian and Spanish patients when compared
with healthy individuals [130, 131].
Likewise, although the frequency of HLA-B27 was
found to be higher in Turkish patients with brucellosis
complicated by osteoarticular involvement, particularly
spondylitis, when compared with patients without osteo-
articular involvement or healthy controls, the difference
was not statistically significant [132]. Yersinia entero-
colitica pneumonia is rare but has been reported in a
patient with diabetes mellitus and HLA-B27+ SpA [133],
raising the question of whether HLA-B27 may have played
a role in the infection.
Miscellaneous
HLA-B27 positivity may contribute to an increased fre-
quency of sacroiliitis in patients with FMF [134]. The
reported associations between HLA-B27 and diseases
of different organs and systems are summarized in
Table 1.
Conclusion
The exact role of HLA-B27 in pathogenesis remains
unclear but features that distinguish it from other genes
and differences between its many subtypes have provided
the basis for several putative explanations as to how it
might predispose to and mediate disease. Most hypoth-
eses seeking to explain the association between HLA-B27
and AS take into account the existence of differentially
associated B27 alleles, on the grounds that the small dif-
ferences between healthy and disease-associated sub-
types may help to characterize the peptides that are
involved in the pathogenesis of SpA. However, none of
the current hypotheses, including those based on the
peptide binding properties of HLA-B27 or the aberrant
folding of its heavy chain, fully explains its immunobiolo-
gical activity or the variation in the strength of association
of the different B27 subtypes with AS. Whereas research
has hitherto focused predominantly on the HLA-B27 mol-
ecule itself, recent discoveries have highlighted the role of
networks of interacting genes in mediating and modulat-
ing disease expression. Haplotype linkages could tran-
spire to be more important than subtle differences in the
B27 subtypes.
While its relationship is strongest with SpA, associa-
tions have also been reported between HLA-B27 and
many other diseases or particular clinical features. Some
are indisputable, whereas, for others, time will tell whether
they are true associations or merely chance occurrences.
Other genes, or gene combinations, are likely to be iden-
tified that influence the penetrance and phenotypic
expression of HLA-B27. These and other factors may
also clarify our understanding of how HLA-B27 protects

626 www.rheumatology.oxfordjournals.org

against certain infections, while possibly increasing
susceptibility to others. Additionally, they may provide
pointers for the development of specifically targeted
therapies. Although HLA-B27 still harbours many secrets,
this fascinating and versatile molecule continues to give
an intriguing insight into the connection between heredity
and disease.
Rheumatology key messages
. HLA-B27 affects clinical expression in SpA and
other diseases.
. HLA-B27 mitigates the virulent effects of certain
viruses, including HIV and HCV, but may increase
susceptibility to malaria.
Disclosure statement: The author has declared no
conflicts of interest.
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