J R Soc Med 2004;97:10-14
doi:10.1258/jrsm.97.1.10
© 2004 Royal Society of Medicine
The ramifications of HLA-B27
Nicholas J Sheehan MD FRCP
Department of Rheumatology, Edith Cavell Hospital, Bretton Gate,
Peterborough PE3 9GZ, UK
E-mail:
njsheehan{at}doctors.org.uk
 |
INTRODUCTION
|
|---|
Thirty years after its
discovery,
1,2
the association between
HLA-B27 and ankylosing spondylitis remains the
strongest known
relationship between a major histocompatibility complex (MHC)
antigen
and a disease.
Epidemiological studies in the 1960s and early 1970s identified close links
between several distinct forms of arthritis that were given the collective
title of the seronegative
spondarthritides.3
Recognition that HLA-B27 was a genetic marker for these diseases led to a
review of the composition of the group, resulting in the exclusion of
Whipple’s disease and Behçet’s syndrome and the inclusion
of other conditions such as undifferentiated and formes frustes of
spondarthritis4 and
HLA-B27 associated isolated peripheral
enthesitis.5
Notwithstanding a 28–44% prevalence of HLA-B27 in affected patients,
Whipple’s disease was excluded after being found to be caused by the
actinobacterium Tropheryma
whipplei,6
whilst Behçet’s syndrome forfeited its place for many reasons
including a lack of association with
HLA-B27.7
Box 1 lists the seronegative spondarthritides currently
recognized—now more commonly known as the seronegative
spondylarthropathies or spondyloarthropathies.
|
PREVALENCE
|
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The prevalence of HLA-B27 varies between populations—
from 50% in
Haida Indians to nil in Australian Aborigines. In
the UK general population it
is about 8%. HLA-B27 is rare in
the American black population whereas Eskimo
populations carry
it much more frequently than Western Europeans, with
prevalence
rates of 25% or
more.
8 This antigen
is associated with ankylosing
spondylitis in virtually all racial groups
studied. In general,
the population prevalence of ankylosing spondylitis
parallels
the frequency of HLA-B27. However, there is some variation in
the
strength of the association, which is weaker in native Indonesians,
Lebanese,
Thais and West
Africans.
9
In the UK, HLA-B27 is present in 90–95% of patients with ankylosing
spondylitis, 60–90% of patients with reactive arthritis, 50–60% of
patients with psoriatic arthritis or inflammatory bowel disease and
spondylitis, and 80–90% of children with juvenile ankylosing
spondylitis.
| Box 1 The seronegative spondarthritides
- Ankylosing spondylitis
- Reactive arthritis (Reiter’s syndrome)
- Psoriatic arthropathy
- Enteropathic arthropathy
- Acute anterior uveitis
- Juvenile spondarthritis
- Undifferentiated spondarthritis
- Isolated peripheral enthesitis
|
|
STRUCTURE AND SUBTYPES
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HLA-B27 is a MHC class I molecule consisting of an alpha chain
encoded in
the MHC region on chromosome 6 and a non-MHC encoded
beta chain,
ß
2 microglobulin. 26 different alleles
have been identified
which code for 24 different proteins designated
HLA-B*2701–B*2725
(B*2722 was deleted on the discovery
that it had the same sequence as
B*2706).
10 These
allotypes
differ from one another by a few aminoacid substitutions and
the
multiple alleles may have evolved from the most widespread
subtype, B*2705.
They vary in frequency among ethnic and racial
groups and at least two of
them, B*2706 in South East Asia and
B*2709 in Sardinia, do not seem to be
linked with ankylosing
spondylitis.
|
ROLE IN AETIOPATHOGENESIS
|
|---|
In a European population study, ankylosing spondylitis was found
in 1.3% of
HLA-B27 positive individuals in the population at
large and in 21% of HLA-B27
positive relatives of B27 positive
patients with spondylitis, giving a 16-fold
risk of ankylosing
spondylitis in HLA-B27 positive relatives compared with B27
positive
individuals in the general
population.
11
HLA-B27 positive Caucasians
have a 20-fold risk of developing any
spondylarthropathy, particularly
ankylosing spondylitis and undifferentiated
spondarthritis.
12
Family and twin studies of ankylosing spondylitis have shown a polygenic
pattern of genetic susceptibility with heritability in excess of 90%. The
contribution of HLA-B27 to genetic susceptibility has been estimated to be
20–50% of the
total.13 Other HLA
alleles, most notably HLA-B60 and HLA-DR1, may predispose to ankylosing
spondylitis either independently of B27 or in conjunction with
it.14 Homozygosity
for HLA-B27 does not appear to enhance the risk of developing ankylosing
spondylitis.11
Non-MHC susceptibility loci have been identified on other
chromosomes,15
whilst other HLA genes may have a protective effect against ankylosing
spondylitis.16
Thus, whereas HLA-B27 is almost essential for the development of ankylosing
spondylitis, other genetic factors may determine which B27 carriers manifest
disease. The gender bias in ankylosing spondylitis is not due to X-chromosome
encoded genetic
effects.17
|
PATHOGENETIC MECHANISMS
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The main natural function of HLA-B27 is to form a complex with
ß
2 microglobulin which can bind short antigenic peptides such
as
those derived from intracellular microorganisms. Following presentation
at
the cell surface, the complexes are specifically recognised
by cytotoxic
lymphocytes which then kill the infected cell.
Although early studies demonstrated an association between the presence of
Klebsiella pneumoniae in the faeces and inflammatory activity in
ankylosing
spondylitis,18 no
organism has been convincingly shown to initiate idiopathic ankylosing
spondylitis. However, organisms have been shown to trigger reactive arthritis,
including Salmonella, Shigella, Yersinia, Campylobacter, Chlamydia,
Mycobacteria and possibly Brucella, all of which habitually
survive intracellularly. HLA-B27 appears to enhance the invasion of
Salmonella into intestinal epithelial
cells.19 It has
proved difficult or impossible to find live bacteria or DNA in the joint but
fragments of Chlamydia, Yersinia or Salmonella have
occasionally been found in
patients.20,21
Several theories have been proposed to explain the various ways in which
HLA-B27 might predispose to spondarthritis
(Box 2). Supporting evidence
has been provided for some but not all. For example, HLA-B27 is capable of
presenting potentially arthritogenic peptides to cytotoxic T lymphocytes and
it also has unusual cell
biology.22 By
contrast, the bacteria implicated in reactive arthritis have not been found to
produce superantigens and there is little evidence to support antibody
cross-reactivity or receptor-mediated
mechanisms.22
Although molecular mimicry has been described between an aminoacid sequence in
HLA-B*2705 and Klebsiella and Shigella products, this exact
aminoacid sequence is not found in HLA-B*2702 or B*2704 which are also
disease-associated
subtypes.23 Strong
evidence that it is HLA-B27 rather than a closely linked gene which is
directly involved in pathogenesis is provided by rodents possessing HLA-B27 as
a transgene, which can develop conditions similar to the
spondarthropathies.24
The development of ankylosing spondylitis may be promoted by increased
expression of HLA-B27 on the surface of peripheral blood mononuclear
cells.25
|
OTHER DISEASE ASSOCIATIONS
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Approximately 1% of people who are HLA-B27 positive develop
acute anterior
uveitis (AAU).
26
Overall, about 55% of cases
of AAU are associated with an HLA-B27 positive
serotype, rising
to about 70% in patients with recurrent episodes of acute
iritis.
27 84% of
HLA-B27 positive patients with AAU have other B27-associated
diseases—specifically
Reiter’s syndrome, ankylosing spondylitis or
psoriatic
arthritis. Conversely, about 20–30% of patients with
ankylosing
spondylitis or Reiter’s syndrome develop
AAU.
28
Of the two clinical forms of psoriasis, HLA-B27 is linked (along with
HLA-Cw2) only to type
II,29 the lateonset
variety which has a closer temporal association with
arthritis.30 In
patients with psoriatic arthropathy, there is a strong association between
HLA-B27 and palmoplantar pustulosis whilst scalp psoriasis may occur less
frequently in patients with
B27.31
Upper lobe fibrosis is the lung condition best known to correlate with
HLA-B27. The antigen may be
positively,32
neutrally33 or
negatively34
associated with asbestosis. Contradictory claims have also been made for an
association with other pulmonary diseases, especially pleurisy, pleural
abscess, bronchitis and pneumonia and pneumothorax, independently of the
presence of ankylosing
spondylitis.35,36
Aortic regurgitation occurs in 2–10% of patients with ankylosing
spondylitis, and cardiac conduction abnormalities including atrioventricular
and intraventricular blocks have been found in one-third of patients with
spondylitis.37
HLA-B27 related cardiac lesions may be found in the absence of other
rheumatological manifestations. Indeed, an HLA-B27 associated cardiac syndrome
comprising severe cardiac conduction system abnormalities and lone aortic
regurgitation has been defined, whose link with B27 is almost as strong as
that between B27 and ankylosing spondylitis.
An increased risk of leukaemia in ankylosing spondylitis has been
attributed to therapeutic spinal irradiation, which consequently fell from
favour three decades ago. However, a significant association has been reported
between HLA-B27 and acute leukaemia, particularly acute myeloid
leukaemia.38
HLA-B27 carriers may have an increased risk of acute leukaemia whilst those
with concomitant ankylosing spondylitis may be predisposed to lymphoid
malignancies.
While infection with HIV predisposes to
spondyloarthropathy,39
HLA-B27 is the HLA class I molecule most closely associated with
non-progression of HIV infection to
AIDS.40
|
DIAGNOSTIC UTILITY
|
|---|
As the population prevalence of HLA-B27 in the UK is approximately
8% and
only around 1% of B27 positive individuals develop ankylosing
spondylitis,
screening the general population for the antigen
would not be helpful for
identifying cases of spondylitis. The
predictive value of testing for HLA-B27
depends upon the particular
clinical situation. Beginning with a clinical
estimate of the
likelihood of ankylosing spondylitis or a related
spondarthropathy,
Bayes’ theorem can be used to calculate the
probability
that a patient has the disease, depending on whether they
transpire
to be HLA-B27 positive or
negative.
41 The
usefulness of a positive
result will be greatest in populations, such as the
Japanese,
that have a low general prevalence of HLA-B27 and yet its
association
with ankylosing spondylitis is strong. For the other
spondarthritides,
which are less strongly linked with HLA-B27, diagnosis is
based
primarily on the associated clinical features.
Thus, in practice, typing for HLA-B27 can be helpful in a patient
complaining of low back pain of an inflammatory character in the absence of
radiological signs of sacroiliitis or in patients with an asymmetrical
oligoarthritis but without other features of spondarthritis. This has been
acknowledged with the inclusion of HLA-B27 positivity as a criterion in the
Amor classification criteria for
spondyloarthropathy.42
Likewise, testing for HLA-B27 can help to differentiate between alternative
aetiologies in iritis and aortic regurgitation.
|
PROGNOSTIC VALUE
|
|---|
Whereas HLA-B27 does not seem to influence the severity of ankylosing
spondylitis,
43 in
psoriatic spondylarthropathy it may determine not only susceptibility
to the
condition but also its clinical
expression.
44 It
correlates
most strongly with isolated axial disease and it may confer
some
protection against peripheral joint erosions.
Patients with Reiter’s disease and Yersinia and
Salmonella triggered reactive arthritis who are HLA-B27 positive have
more severe acute disease, more extra-articular features and more frequent
chronic back pain and
sacro-iliitis.45,46
In C. trachomatis reactive arthritis, more severe or chronic disease
could be due to lower concentrations of interferon-
in the synovial
fluid of patients who are HLA-B27 positive than those who are HLA-B27
negative, with consequent impaired clearance of infective
agents.47
With regard to cardiac disease, the relative risk that a HLA-B27 positive
man will need a permanent pacemaker has been calculated to be 6.7 compared
with a man who has other B
alleles.37 This
association is not, however, present in female patients.
A poor outcome of back surgery has been found in patients possessing
HLA-B27.48 Whether
this was because a substantial number of patients operated on had
spondarthritis rather than mechanical back pain, or because HLA-B27
predisposes to a poor outcome in back surgery, was not clear.
Atlanto-axial subluxation can occur in both rheumatoid arthritis and
ankylosing spondylitis. Compared with HLA-B27 negative patients, HLA-B27
positive patients with rheumatoid arthritis have about twice the risk of
developing subluxation of the cervical spine and an almost threefold risk of
subaxial
subluxation.49,50
Thus, HLA-B27 may transpire to be a useful prognostic indicator for the later
development of instability of the cervical spine and its complications in
rheumatoid arthritis.
|
CONCLUSION
|
|---|
The discovery of the link between HLA-B27 and a large family
of
inflammatory rheumatic diseases was one of the seminal advances
in
rheumatology in the last century. Associations have subsequently
been
identified with other musculoskeletal and non-rheumatic
diseases. The
distinction between the disease-associated and
non-associated subtypes may
give an insight into precisely how
HLA-B27 contributes to pathogenesis in the
seronegative spondarthritides,
whilst some of the pathogenesis hypotheses may
help to elucidate
the mechanisms of disease susceptibility, initiation and
progression.
New ways to employ HLA-B27 as a diagnostic and prognostic aid
will
continue to emerge.
|
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TOP
INTRODUCTION
PREVALENCE
