[Prion 3:1, 15-26; January/February/March 2009]; ©2009 Landes Bioscience
HLA-B27 plays a central role in the pathogenesis of many
spondyloarthropathies and in particular ankylosing spondylitis.
The observation that the HLA-B27 heavy chain has a tendency
to misfold has raised the possibility that associated diseases may
belong in a rapidly expanding category of protein misfolding
disorders. The synthesis of the HLA-B27 heavy chain, assembly
with β2m and the loading of peptide cargo, occurs in the endo-
plasmic reticulum (ER) before transport to the cell surface. The
evidence indicates that misfolding occurs in the ER prior to
β2m association and peptide optimization and is manifested in
the formation of aberrant inter- and intra-chain disulfide bonds
and accumulation of heavy chain bound to the chaperone BiP.
Enhanced accumulation of misfolded heavy chains during the
induction of class I expression by cytokines, can cause ER stress
resulting in activation of the unfolded protein response (UPR).
Effects of UPR activation on cytokine production are begin-
ning to emerge and may provide important missing links between
HLA-B27 misfolding and spondyloarthritis. In this chapter we
will review what has been learned about HLA-B27 misfolding
in human cells and in the transgenic rat model of spondyloar-
thritis-like disease, considering it in the context of other protein
misfolding disorders. These studies provide a framework to
support much needed translational work assessing HLA-B27
misfolding and UPR activation in patient-derived material, its
consequences for disease pathogenesis and ultimately how and
where to focus intervention strategies.
Ankylosing spondylitis (AS) is a complex genetic trait with
an estimated four to ten genes responsible for the majority of
susceptibility.1 Spondyloarthropathies (SpA) comprise several
disorders that are more heterogeneous clinically and where genetic
susceptibility is likely to be more complex and variable. Defining
genetic loci and ultimately genes that influence susceptibility, is an
area of intense investigation. Family-based linkage studies using
low-density microsatellite markers have been somewhat
disappointing.2,3 However, single nucleotide polymorphism (SNP)
identification and mapping has provided a detailed framework on
which to perform whole genome association studies. This approach
has already provided valuable information on genes involved in
susceptibility to other complex genetic diseases4 and studies on AS
are now emerging.5 In addition to providing markers that will be
useful in identifying AS patients earlier in their disease course, it is
anticipated that a more complete picture of genetic susceptibility
will inform us on pathways that are important in pathogenesis and
identify new therapeutic targets.
Unlike most complex genetic diseases, a single gene (HLA-B)
plays a dominant role in AS. The B27 allele contributes as much
as 40% of the overall genetic load and is a major factor for many
other SpA.6,7 Although the role of HLA-B27 has been the focus
of intense investigation for over 30 years, none of the postulated
mechanisms has been proven or eliminated.8 While it has been
tacitly assumed that a single feature of HLA-B27 is responsible, it
is conceivable that this is not the case9 and that the answer to the
HLA-B27 conundrum will be even more complex than initially
A detailed understanding of pathogenesis requires animal
models that phenocopy the human condition and are amenable
to genetic manipulation and experimentation,10 combined with
translational studies of human material that are confirmatory. The
development of animal models has been attempted over the years
through the generation of HLA-B27 transgenic mice and rats.
Transgenic mouse models of SpA have been disappointing for
several reasons. Initially, no spontaneous inflammatory disease was
observed11 and although attempts to induce disease with infection
revealed some differences in susceptibility,12 the SpA phenotype
was not observed. Subsequent studies suggested that HLA-B27
transgenic mice developed spontaneous arthritis if you deleted
the endogenous gene for (mouse) β2m.13-15 However, the use of
a mixed genetic background may have confounded these studies
making reproducibility and thus interpretation problematic.16
Controlling for mixed backgrounds is very difficult and even-
tual genetic drift can result in loss of the phenotype. Inbred strains
of animals are the genetic equivalent of a single human and thus
it is not surprising that different genetic backgrounds would influ-
ence susceptibility. In humans less than 5% of HLA-B27 positive
individuals develop SpA. The whole genome association studies
*Correspondence to: Robert A. Colbert; NIH/NIAMS; Bldg. 10, CRC, Rm.
1-5142; 10 Center Drive, MSC 1102; Bethesda, MD 20892 USA; Email:
Submitted: 02/03/09; Accepted: 02/03/09
Previously published online as a Prion E-publication:
HLA-B27 misfolding and spondyloarthropathies
Robert A. Colbert,1,2,* Monica L. DeLay,1 Gerlinde Layh-Schmitt1,2 and Dawn P. Sowders1
1Division of Rheumatology; Cincinnati Children’s Hospital Medical Center; Cincinnati, OH USA; 2NIAMS; National Institutes of Health; Bethesda, MD USA
Key words: ankylosing spondylitis, arthritis, protein misfolding, unfolded protein response, interleukin (IL)-17, cytokines
mentioned above are being used to identify other human genes that
affect susceptibility. It may be possible to exploit strain differences
that are important determinants of disease in HLA-B27 transgenic
rodents and use similar genetic approaches to identify the respon-
sible genes. While the rodent genes may not be the same as those
found in humans, by definition they will be involved in pathways
that are important for pathogenesis of HLA-B27-associated disor-
ders and substantial overlap with pathways identified in human
genetic studies would be expected.
The production of transgenic rats expressing HLA-B27 and
human β2m (B27/hβ2m) that develop spontaneous inflamma-
tion resembling SpA signified a major advance in this area.17
This demonstrated that under certain conditions overexpression
of HLA-B27 was sufficient to cause disease, providing the first
evidence that the gene product itself was involved. The SpA-like
phenotype includes gastrointestinal tract inflammation (e.g.,
colitis), arthritis and other inflammatory lesions in the skin and
testicles. The colitis is highly penetrant, while arthritis is less
frequent and depends more on the strain of rat used. Although
axial inflammation can occur, it does not recapitulate the spinal
inflammation and ankylosis seen in humans.18 However, recently
Tran et al. have reported that overexpressing additional hβ2m can
alter the phenotype in transgenic rats that already overexpress
HLA-B27 and hβ2m.19 High copy number B27/hβ2m transgenics
with additional hβ2m develop more severe arthritis and significant
axial disease with no apparentchange in colitis. Interestingly, rats
with low copy number B27/hβ2m that normally do not develop
spontaneous disease, develop axial and peripheral arthritis without
colitis, when additional hβ2m is overexpressed.
In this article we will focus on one mechanism that may be
the basis for the striking relationship between HLA-B27 and
spondyloarthritic diseases. We will explain the general concept and
consequences of protein misfolding and then provide a detailed
assessment of the special case of HLA-B27 misfolding and how it
may be linked to disease through an autoinflammatory stimulus.
Usual, Unusual and Unique Features of HLA-B27 and Their
Potential Role in Disease Pathogenesis
Extensive polymorphism at the HLA-B locus results in consid-
erable sequence variation in the HLA-B-encoded heavy chain
across the human population. Over 900 alleles have been reported
to date, encoding over 800 different proteins (www.anthonynolan.
com/HIG/). These amino acid differences affect a number of prop-
erties of class I heavy chains, including peptide binding specificity
and affinity, T-cell recognition (both as a result of and independent
from bound peptide), β2m binding affinity, folding and assembly
efficiency and chaperone interaction (e.g., tapasin) (reviewed in
ref. 20). There are also polymorphisms in the promoter region
of HLA-B at the 5' end of the gene, which could affect baseline
expression level and inducibility.21
Features of HLA-B27 that distinguish it from other alleles
have provided the basis for several hypotheses concerning its
contribution to disease. It is convenient to classify these ideas based
on whether they invoke immunological recognition of some form
of the heavy chain versus intracellular effects.8 Immunological
recognition by antibodies22 or autoreactive T-cells23 supposes that
the form(s) of HLA-B27 being recognized are typical for HLA
class I complexes.
More recently the detection of other forms of HLA-B27, such
as heavy chain homodimers,24 or unusual unfolded monomers,25
has led to ideas about recognition by leukocyte receptors on
NK cells and other leukocytes.26-30 In contrast, the tendency of
HLA-B27 heavy chains to misfold in the intracellular compart-
ment known as the endoplasmic reticulum (ER)31,32 has led
to the notion that intracellular effects of HLA-B27 might be
involved in disease pathogenesis. Misfolding was hypothesized
to result in activation of an intracellular stress response pathway
known as the unfolded protein response (UPR),33 which has
been shown to occur in B27/hβ2m transgenic rats.34,35 The
consequences of HLA-B27-induced UPR activation will be
discussed in detail later in this chapter. Finally, the observation
that cell lines transfected with HLA-B27 but not other alleles
exhibit increased bacterial survival36,37 could be important for
pathogenesis, particularly in reactive arthritis. Recent evidence
suggests that bacterial replication is increased38 and that the
p38 MAP kinase pathway may be disrupted.39 This most likely
represents an intracellular or at least nonantigen-presenting
effect of HLA-B27.40 Experiments using site-directed mutants
of HLA-B27 show that the biological effect correlates with heavy
chain misfolding, but is not associated with acute UPR activation
and therefore the molecular mechanism remains to be defined.
It will be important to determine whether the expression of
heavy chains that misfold is responsible for this effect, since a
related phenomenon has been observed for a mutant of surfac-
tant protein-C that misfolds.41 These authors demonstrated that
adaptation to chronic ER stress was associated with modification
of an NFκB-dependent pathway, reminiscent of what has been
observed in HLA-B27-transfected cells.42
In this chapter we will focus on HLA-B27 misfolding, consid-
ering it in the context of other proteins that misfold, the cause of
misfolding and more importantly, what we have begun to learn
about its consequences.
There has been a tendency to assume that only one hypothesis,
or one aspect of the immunobiology of HLA-B27, will eventu-
ally be tied to its role in pathogenesis. However, this may not be
correct, particularly when one considers phenotypic differences in
the diseases associated with HLA-B27 such as reactive arthritis,
uveitis, AS and other forms of undifferentiated SpA.
Importance of Protein Folding
The information required for a protein to fold into its native
conformation is contained within its primary sequence, yet a great
deal of energy is expended to ensure that this occurs efficiently and
without error (reviewed in ref. 43). For multi-subunit proteins or
those that transport cargo, the process is even more complex, with
many opportunities for errors in the formation of stable, properly
folded complexes. It has become increasingly apparent over the last
decade that many genetic diseases result from protein misfolding,
either due to inherent properties of the mutated gene product,
or in some cases as a consequence of abnormalities in the cellular
pathways that handle misfolded proteins.
HLA-B27 and disease
16Prion 2009; Vol. 3 Issue 1
HLA-B27 and disease
aminopeptidase regulator of TNF receptor (TNFR1) shedding
(ARTS-1), but also regulates shedding of IL-6 and IL-1 decoy
Consequences of Protein Misfolding
The vast majority of proteins are made in the cytosol, or
cotranslationally inserted into the ER in the case of membrane
bound and secreted proteins. In these two compartments, there
are parallel molecular chaperone systems that assist and monitor
the folding process to ensure high fidelity production of proteins
that can function properly. When protein folding goes awry, due to
mutations or polymorphisms that alter the amino acid sequence, or
abnormalities in components of the chaperone systems, misfolding
can result (reviewed in ref. 43). The consequences of misfolding
depend on the site of synthesis of the protein, the nature and
severity of the folding defect, the relative importance of the gene
product and whether protein quality control (PQC) processes have
intervened sufficiently. Many misfolded and even incompletely
folded ER proteins can be eliminated efficiently by ER-associated
degradation (ERAD) if they have remained in the ER for a
sufficient time. Diseases that ensue are typically due to loss-of-
function with classic examples being hemophilia (Factor VIII
mutations) and hereditary emphysema (α-1-antitrypsin deficiency)60
(Fig. 1). Gain-of-function phenotypes are more common and more
varied. Misfolded proteins that accumulate within (e.g., forming
aggresomes or inclusion bodies) or outside the cell (e.g., amyloid
fibrils) can be toxic either to the involved cell or surrounding cells.
Alpha-1-antitrypsin mutations can also cause pathology due to
ER retention, aggregation and mitochondrial injury in the liver,61
providing a striking example of phenotypic variation due to cell-
specific differences in the handling of misfolded proteins.
The cellular response to ER protein misfolding referred to as
the UPR (unfolded protein response), is part of a more global
homeostatic response to ER stress.60 The UPR also plays a key role
in ER expansion during the differentiation of certain cell types,
such as plasma cells that become highly specialized to produce
and secrete large amounts of immunoglobulins.62 The UPR can
also contribute to the pathogenesis of certain diseases with the
most clear-cut examples being situations where UPR-induced
apoptosis results in the loss of important cells, such as pancreatic
b-cells in the Akita mouse model of diabetes63,64 or neural tissue
in Pelizaeus-Merzbacher disease (proteolipid protein 1 in spastic
paraplegia).65 Another interesting example may be idiopathic
inflammatory myositis. In certain forms of the disease muscle
tissue (myocytes) exhibits robust UPR activation.66 This has been
associated with caspase-12 activation and it has been postulated
that the UPR plays a role in myositis pathogenesis by promoting
apoptosis, although additional mechanisms are possible.66,67
Enforced class I upregulation (H-2Kb) via a tetracycline-regulated
transgene driven by a muscle-specific promoter can result in an
inflammatory phenotype that recapitulates much of the pathology
seen with human disease.68 This is interesting and may represent
an example of inappropriate expression of a class I protein, perhaps
with insufficient concomitant expression of peptides, β2m and/or other
chaperones such as tapasin, leading to ER stress and UPR activation.
HLA class I folding and assembly. HLA class I complexes of
heavy chain, β2m and peptide represent an example of a protein
(heavy chain) that transports ‘cargo’ (β2m and peptide) to the
cell surface. To perform this function and display self-peptides or
pathogen-derived cargo to T-cells during an immune response,
HLA class I heavy chains must fold properly, bind β2m and then
load peptide prior to exiting the ER compartment (reviewed in
ref. 44). High stability of the trimolecular complex is critical for
efficient transport through the Golgi, a long half-life on the cell
surface and ultimately a productive immune response. The stability
of HLA class I complexes is critically dependent on early events in
the folding and assembly process, including the formation of two
intrachain disulfide bonds.45 The α3 domain folds very rapidly
and is stabilized by an intradomain disulfide between Cys-203
and Cys-259. The α1 and α2 domains fold more slowly and this
is not complete until peptide is stably bound.46 A second disulfide
between the α1 and α2 domains (Cys-101-Cys-164) maintains the
integrity of the peptide-binding groove47 as the heavy chain/β2m
heterodimer interacts with tapasin, ERp57 and the transporter
associated with antigen processing (TAP) to form the peptide
loading complex (PLC). Although there are allelic differences in
the need to interact with tapasin (and thus the PLC), in general
this process facilitates the binding of high affinity peptides. For
example, HLA-B27 (the B*2705 subtype) is expressed relatively
efficiently in tapasin-deficient cells48 and is frequently referred
to as a tapasin-independent allele. However, it interacts with
tapasin when present and this affects the peptide repertoire.49 It is
possible that the ability of HLA-B27 to be expressed at high levels
on tapasin-deficient cells may reflect its tendency to fold slowly
and be retained in the ER in a peptide-receptive state without
tapasin-PLC interaction. This could favor the binding and optimi-
zation of available peptides without tapasin-mediated retention.
ERp57 binds to tapasin via a disulfide (ERp57-Cys-57-
Cys-95-Tapasin) and plays an important role in disulfide bond
isomerization in the heavy chain during class I assembly.50 Recent
evidence indicates that formation of the ERp57-tapasin conjugate
prevents ERp57-mediated reduction of the a1-a2 interdomain
disulfide in the class I heavy chain, thus maintaining the peptide
binding groove in a receptive state.45 When tapasin is missing
or mutated at Cys-95 and thus unable to form a complex with
ERp57, the class I heavy chain a1-a2 disulfide is reduced until suit-
able peptide cargo can bind. Free ERp57 (or ERp57-calreticulin
complexes) appears to catalyze this reduction in the absence of
tapasin leading to the concept that tapasin performs its function
by sequestering ERp57.
The final stages of peptide binding to HLA class I molecules
includes trimming by the ER aminopeptidase associated with
antigen processing (ERAP1).51-56 Peptides appear to be nestled
into the peptide-binding groove at their C-terminus first with
ERAP1-mediated N-terminal trimming to their final size of 8–11
amino acids. In humans, L-RAP or ERAP2 may also play a role
in this process. In addition to peptide trimming for presenta-
tion by class I molecules, ERAP1 appears to have another role
in the immune system. It was discovered independently as
HLA-B27 and disease
30-fold higher concentration of peptide (on average) to achieve
the same half-maximal binding as B27.A2B. This suggests that
the folding abnormality exhibited by HLA-B27 may be related
to peptide binding. In other words, this allele might require more
peptide to achieve release from the PLC and exit from the ER.
It would follow that in situations where the supply of peptides
into the ER is restricted and/or the synthesis of heavy chains is
increased, HLA-B27 folding might be disproportionately adversely
affected in comparison to other alleles.
Further exploration of events occurring in the ER for HLA-B27
revealed that the heavy chain has a tendency to form disul-
fide-linked complexes with itself (and possibly other proteins;
unpublished observations) and exhibit prolonged association with
the ER chaperone BiP (Grp78/Hspa5).32,71,72 These features also
map to the B pocket and are not exhibited by B27.A2B or other
naturally occurring alleles examined to date. Further mutagenesis
experiments have defined two B pocket residues that are key for
HLA-B27 misfolding; Glu-45 and Cys-67 (reviewed in ref. 73).
The single substitution of Met for Glu at position 45 restores rapid
folding to the HLA-B27 molecule and eliminates the formation of
While gain- and loss-of-
function classification schemes
are useful, disease pathogenesis
is often complex and may result
from more than one consequence
of protein misfolding. This is best
exemplified by α-1-antitrypsin
mutations that result in both
types of sequelae.
The first indication that
HLA-B27 had a tendency to
misfold came from mutagenesis
experiments where the entire ‘B
pocket’ was changed by substi-
tuting residues from the HLA-A2
allele (creating a hybrid referred
to as B27.A2B).69 Remarkably,
this dramatically altered the
folding and assembly characteris-
tics of the heavy chain with B27.
A2B behaving more like HLA-A2
and other alleles that exhibit
rapid folding and assembly kinet-
ics.31 Evidence that the heavy
chain was in fact misfolding,
came from experiments looking
at where it was being degraded.
Normally, HLA class I heavy
chains are internalized from the
cell surface and broken down in
lysosomes. However, a propor-
tion of HLA-B27 heavy chains
were found to be dislocated from
the ER membrane shortly after synthesis and before becoming
associated with β2m (and probably peptide) and then degraded
in the cytosol by proteasomes. This ERAD pathway is used to
eliminate ER-synthesized proteins that misfold and/or fail to
assemble rapidly.70 B27.A2B, as well as other naturally occurring
HLA alleles that were examined, did not exhibit this behavior, thus
tying misfolding to B pocket composition and the slow folding
characteristic of HLA-B27.32 ERAD of HLA-B27, but not the
other expressed alleles, was also detected in EBV-transformed
human B-cells indicating that it occurs when there is only a single
copy of the HLA-B27 gene and is not merely a consequence of
Interestingly, the B pocket was also found to have an unex-
pected dramatic effect on peptide binding affinity, in addition
to its predicted effect on peptide binding specificity.31 Since this
pocket binds the side chain of the second amino acid in the peptide
(P2), the specificity conferred by the HLA-A2-like B pocket was
almost identical to what is found in peptides that bind to HLA-A2
(Leu/Met), rather than the Arg P2 specificity of HLA-B27.
However, what was surprising was that HLA-B27 required a
Figure 1. Consequences of protein misfolding. Proper folding of newly synthesized proteins is critical for normal
function. Protein misfolding has been linked to a number of diseases that can be broadly categorized as loss-
of-function or gain-of-function. Loss-of-function phenotypes result from destruction of partially folded or misfolded
proteins by elaborate quality control processes. Gain-of-function phenotypes can result from toxicity if the gene
product accumulates and/or activation of cellular stress response pathways such as the UPR. HLA-B27 misfold-
ing is hypothesized to result in gain-of-function abnormalities through sensitization of immune response cells such
as macrophages to other exogenous stimuli as reviewed in this chapter.
18 Prion2009; Vol. 3 Issue 1
HLA-B27 and disease
predominantly peripheral, although rats overexpressing additional
hβ2m were shown recently to develop more severe arthritis with
axial involvement19 (discussed below). While transgenic rats do not
provide a precise phenocopy of human disease, B27/hβ2m trans-
genics with and without extra hβ2m provide reproducible animal
models that can be used to investigate pathogenic mechanisms that
are likely to have relevance to human disease. Unfortunately rats
are not as amenable to experimental manipulation as mice.
For example, targeted gene deletion is not currently possible
due to the lack of embryonic rat stem cells. Production of trans-
genics is more expensive and labor intensive, ex vivo transduction
of bone marrow cells with retroviruses is not readily achievable
and many antibodies useful to visualize and/or block the function
of mouse proteins are not available for rats. Nevertheless, a great
deal has been learned about the cellular requirements for disease
in high copy B27/hβ2m transgenic rats (reviewed in ref. 18).
HLA-B27 must be expressed in the bone marrow compartment for
the colitis/peripheral arthritis phenotype to occur and ubiquitous
expression is not necessary.76 In addition, the spontaneous inflam-
matory disease appears to be mediated by CD4 rather than CD8
T-cells.77,78 The presence of gastrointestinal flora is also required,
yet normal flora is sufficient to trigger inflammation, especially
bacteroides spp.79,80 These findings have provided strong evidence
against a role for arthritiogenic (or ‘colitogenic’) peptides playing
a central role in pathogenesis, but rather suggest that HLA-B27-
expressing cells arising from the bone marrow are either targeted
by CD4 T-cells or alternatively serve as a stimulus for these cells to
Is HLA-B27 recognized by CD4 T-cells? Reports that CD4
T-cells can recognize normal and abnormal forms of HLA-B27
have emerged,81 raising the question of whether this might
explain the importance of these cells for SpA-like disease in B27/
hβ2m transgenic rats and also be involved in human disease. For
human studies, CD4 T-cells were raised by stimulation with T2
cells transfected with HLA-B27.81 T2 cells are missing a large
region of the major histocompatibility complex (MHC) including
TAP1 and TAP2 genes and thus are unable to transport peptides
into the ER from the cytosol. They have been reported to express
HLA-B27 homodimers,24 although this was not observed in other
Evidence supporting the idea that CD4 T-cells could recognize
HLA-B27 came from experiments using a monoclonal antibody
(ME1) that recognizes HLA-B27 and could block recognition.
When cells with an intact antigen presentation pathway were
used, including patient-derived B-cells, HLA-B27 was poorly
recognized. In a follow-up study CD4 T-cells from two more AS
patients were raised using similar methods.82 These T-cells failed
to recognize HLA-B27 on T2 cells, but instead appeared to be
reacting to other HLA class I alleles expressed at low levels on
these cells, perhaps presenting peptides derived from degraded
HLA-B27 heavy chains. In separate studies, double transgenic
mice expressing HLA-B27 and a human T-cell receptor (TCR)
that recognizes the HLA-B27-restricted NP383-391 flu peptide,
developed CD4 as well as CD8 T-cells capable of recognizing
this peptide presented by HLA-B27.83 If CD4 T-cells that can
disulfide-linked complexes and prolonged BiP binding (misfolding)
even in the presence of Cys-67. Furthermore, the single substitu-
tion of Ala for Cys at position 67 also prevents misfolding, even
when Glu-45 is intact. These observations suggested a model
where two features of the HLA-B27 heavy chain might be required
for misfolding to be prominent; slow folding and the ability to
form aberrant disulfide-linked dimers via Cys-67.73
While Glu-45 and Cys-67 are not unique to HLA-B27, they
are very uncommon among other alleles. In addition, there is a
Lys residue at position 70 that has been reported to increase the
reactivity of the sulfhydryl group on Cys-67,74 although it has not
been studied in the context of misfolding. These three residues
(Glu-45, Cys-67 and Lys-70) are virtually unique to HLA-B27,75
(www.anthonynolan.com/HIG/) and thus would support the
idea that misfolding is extremely uncommon if not unique to
Additional support for this model comes from the observation
that an imposed reduction in folding rate caused by incubating
cells at reduced temperature also exacerbates dimer formation and
BiP binding to heavy chains.72 In this study, evidence was provided
that Cys-164, in addition to Cys-67, was involved in dimer forma-
tion. This observation has several possible implications since
Cys-164 is involved in the intrachain disulfide bridge between the
α1 and α2 domains of the class I heavy chain (Cys-101-Cys-164),
which normally forms quite rapidly after heavy chain synthesis and
is important for maintaining the integrity of the peptide-binding
groove (see above).
The involvement of Cys-164 residue in oxidative dimerization
of HLA-B27 heavy chains is potentially important as it suggests
two possible scenarios related to HLA-B27 misfolding. First, if the
Cys-101-Cys-164 disulfide bridge forms quickly in HLA-B27 as in
other alleles, then it must not be completely protected from reduc-
tion/isomerization if it is eventually involved in dimerization, since
the latter process requires it to reform a disulfide with another
HLA-B27 heavy chain. Since protection of the Cys-101-Cys-164
disulfide from reduction is a key function of tapasin-ERp57,45
the formation of dimers via Cys-164 could reflect HLA-B27 not
interacting efficiently with this complex in the ER. Alternatively,
it may be that the a1-a2 domain disulfide does not form normally
in HLA-B27, making Cys-164 available to enter into an interchain
disulfide linkage. Additional studies are needed to fully delineate
the earliest events in HLA-B27 folding that lead to misfolding and
its cellular consequences.
Evaluating the Role of HLA-B27 in Disease
A major advance toward understanding the role of HLA-B27
in SpA was made in the 1990s when Taurog and colleagues first
produced transgenic rats overexpressing HLA-B27 and human
β2m (hβ2m) (B27/hβ2m).17 High copy number B27 transgenic
rats were found to develop a ‘spontaneous’ inflammatory disease
that includes gastrointestinal inflammation (colitis), arthritis,
alopecia with psoriasis-like skin lesions, dystrophic nails and
testicular inflammation.18 These phenotypic features are only
partially penetrant and are variable in frequency with the exception
of colitis, which occurs in 100% of transgenics. The arthritis is
HLA-B27 and disease
activation in BM macrophages from B27/hβ2m transgenic rats.
First, BM macrophages expressing HLA-B27 that exhibit no UPR
at ‘baseline’ (i.e., without stimulation) will activate the UPR in
response to IFN-γ treatment.34,35
This is temporally related to heavy chain upregulation
and accompanied by a striking increase in the accumulation
of BiP-bound heavy chains and disulfide-linked heavy chain
complexes.35 In contrast, IFN-γ does not activate the UPR in
cells from nontransgenic (wild type) or B7/hβ2m transgenic
animals. (It should be noted that there is low-level BiP induction
and XBP-1 splicing (<2-fold increase) with IFN-γ treatment of
macrophages from these animals, but the response in B27/hβ2m
transgenics is substantially higher.34 IFN-γ has been reported
to cause ER stress in oligodendrocytes, but this response was
also quantitatively small (~2-fold BiP induction) and required
prolonged (48 h) stimulation.85 This is not surprising given that
cytokines and other exogenous stimuli can upregulate hundreds
of proteins, including membrane bound and secreted proteins
that are produced in the ER. This low level UPR is likely part
of the normal physiologic response that enables cells to handle
the increased load. It is worth emphasizing that exacerbated
HLA-B27 misfolding and UPR activation occur in the face of
IFN-γ-mediated upregulation of multiple components of the
class I assembly pathway including TAP1/2, tapasin, proteasome
subunits LMP2 and LMP7, ERAP1 and β2m. This implies that
HLA-B27 misfolding and ER stress occur despite an increased
source of cargo (β2m and peptide) as well as equipment neces-
sary to load the cargo. This seems paradoxical and could indicate
that one or more of these components exacerbate HLA-B27
misfolding, although an alternative explanation is that they may
merely be insufficient to prevent misfolding.
When splenocytes are treated with IFN-γ, we see only low-
level upregulation of HLA-B27 and minimal UPR activation.
Examination of inflamed colon tissue reveals evidence for UPR
activation, although the magnitude of increases in BiP and CHOP
transcripts are smaller (<3-fold) than observed in isolated cells
such as BM macrophages (reviewed in ref. 34). Together, these
data indicate that UPR activation occurs in cells and inflamed
tissues from B27/hβ2m transgenic rats, is specific for HLA-B27
and is temporally related to and strongly correlated with HLA-B27
misfolding. Macrophages are particularly affected by HLA-B27
misfolding in terms of UPR activation, while splenocytes, whole
spleen and whole thymus tissue are not.35 These results are consis-
tent with HLA-B27 upregulation being a key component of robust
In preliminary studies we have observed UPR activation in
BM-derived dendritic cells (DCs) from B27/hβ2m transgenic rats
treated with IFN-γ, but it does not appear to be as robust as in
macrophages. However, since additional stimuli can contribute to
class I upregulation and we have not exhaustively examined other
cell types, our understanding of the extent of UPR activation in
these rats remains incomplete.
IFN induction by the UPR. The second part of the IFN story,
is the question of whether IFN expression is upregulated by the
UPR. We found low-level induction of the Type I IFN, IFN-b,
recognize HLA-B27 develop in rats and humans, this could have
implications for disease. However, these transgenic mice represent
an unusual situation where there is forced expression of the same
TCR on every T-cell regardless of the costimulatory CD4/8 mole-
cule and thus the question of whether this might occur with TCRs
directed against other alleles needs to be addressed. The possibility
that CD4 T-cells capable of recognizing HLA-B27 exist in trans-
genic rats has not, to our knowledge, been examined.
What are the consequences of HLA-B27 misfolding? The
observation that HLA-B27 had a propensity to misfold, as defined
by the formation of disulfide-linked heavy chains and stable BiP
binding, was confirmed and extended in B27/hβ2m transgenic
rats.71 Using several transgenic lines with variable transgene copy
number and phenotype, Tran et al. demonstrated a quantita-
tive correlation between the biochemical features of HLA-B27
misfolding in splenocytes and the development of SpA-like disease
(colitis and arthritis). This correlation was further supported by the
absence of disease in HLA-B7 (B7/hβ2m) transgenic rats, consis-
tent with the evidence that this allele does not misfold, even when
The unfolded protein response. One of the consequences
of protein misfolding in the ER can be activation of the
UPR (reviewed in ref. 84). Some of the earliest cellular events
that mark this response are phosphorylation and activation of
PERK (PKR-like ER kinase) and IRE1 (inositol requiring-1) and
proteolytic cleavage of ATF6 (activating transcription factor-6).
Immediate downstream events include IRE1-mediated splicing of
the mRNA encoding XBP-1 (X-box binding protein-1), PERK-
mediated phosphorylation of eIF2α (eukaryotic initiation factor
2 α) and increased transcription of UPR target genes (e.g., BiP,
CHOP and many others). The transcriptional response is medi-
ated by activated (cleaved) ATF6, ATF4 (produced in response to
eIF2a phosphorylation) and the gene product translated from the
spliced XBP-1 mRNA (XBP-1s), all of which are active transcrip-
Several reagents used to measure proximal UPR activation
(e.g., antibodies to ATF6 and phosphorylated forms of PERK and
IRE1) are not available for rats. Furthermore, since the response
is transient, it is more convenient to assess induction of mRNAs
encoding BiP and CHOP and splicing of XBP-1 transcripts
(XBP-1s). Using these markers, we found that spleen and thymus
cells isolated from B27/hβ2m transgenic rats (F344 33.3 line)
exhibited little or no evidence of UPR activation.34 Similarly, bone
marrow (BM)-derived macrophages from premorbid rats showed
minimal differences in BiP mRNA (50% or 1.5-fold increase),
whereas when BM macrophages were prepared from animals with
disease, a robust UPR was observed (5-fold increase in BiP mRNA
and up to a 10-fold increase in CHOP). Microarray analyses
revealed the UPR to be accompanied by an interferon (IFN)
signature raising the question of whether IFN exposure is causing
UPR activation via HLA-B27 upregulation. The converse was also
possible: the UPR might cause IFN upregulation. It was conceiv-
able that both events were occurring simultaneously.
IFN regulation of HLA-B27 expression and UPR activation.
Subsequent studies have revealed a dual role for IFNs in UPR
20Prion2009; Vol. 3 Issue 1
HLA-B27 and disease
transcription factor through STAT1 signalling, which in turn acti-
vates Th1-specific genes.
Recently, a third subset of effector CD4 T-cells characterized
by IL-17 production (‘Th17’) has been discovered.97-99 Th17
cells may have evolved as another arm of the adaptive immune
response for enhanced protection against extracellular bacteria
(i.e., Klebsiella pneumoniae), protozoa and fungi (e.g., Pneumocystis
carinii) by recruiting neutrophils. However, additional roles for
Th17 in immune defense are possible. What has become very
clear, is that Th17 cells play a crucial role in chronic inflamma-
tion in animal models of human autoimmune/autoinflammatory
diseases such as RA, MS,100,101 IBD102,103 and psoriasis104 and
there is growing evidence that IL-17 is a crucial pro-inflammatory
cytokine in the human disease counterparts. In addition to IL-17,
Th17 cells can produce TNF-α and IL-6.100,102 IL-17 can act on
several cell types including macrophages, fibroblasts, endothelial
cells and epithelial cells, to upregulate TNF-α, IL-6, IL-1, as well
as several chemokines and metalloproteases (including MMP-3
which has been shown to be a good biomarker for AS).105-107
Thus, downstream effects of IL-17 are diverse and highly pro-
Several cytokines play key roles in Th17 development and the
balance between Th17 and regulatory T-cells (Treg) in mice. For
example, the combination of TGF-b and IL-6 drives naïve CD4
T-cells to become Th17-committed108,109 through induction of
the retinoic acid orphan receptor (RORγt) in naïve T-cells, which
then leads to upregulation of the IL-23 receptor (IL-23R).110
IL-23 can then act on Th17-competent cells stimulating robust
and prolonged IL-17 upregulation111,112 (and reviewed in ref.
113). In addition, TCR stimulation by MHC class II-restricted
antigens can induce IL-17 production without IL-23.
In mice it appears that CD4 T-cells producing IFN-γ (Th1)
and IL-17 (Th17) are distinct populations, while in humans
CD4 T-cells producing IFN-γ and IL-17 (Th1/Th17) have been
documented in the gut of humans with Crohn’s disease.114 In
addition, the factors that regulate Th17 development in humans
appear to be different from mice with IL-23 and IL-1b playing a
more important role than IL-6.115 In addition to the predominant
form of IL-17 (IL-17A or CTLA-8) produced by CD4 T-cells,
there is an extended family with five additional IL-17 molecules
whose cellular source and regulation need to be further defined.107
Other cells that have been reported to produce IL-17 include CD8
and gamma/delta T-cells, neutrophils and even macrophages and
lymphocytes at sites of infection.
HLA-B27 misfolding, the UPR and the IL-23/IL17 axis:
refining the hypothesis. Preliminary results linking HLA-B27
misfolding and the UPR to enhanced IL-23 induction in
macrophages in response to TLR agonists, together with evidence
for activation of the Th17 axis in transgenic rats, suggests a novel
paradigm for the development of HLA-B27-associated colitis
(Fig. 2). In the gastrointestinal tract, a low level immune response
to bacterial colonization could result in increased expression
of IFNs (Type I and/or Type II), perhaps via innate immune
stimuli (IFN-b) and/or NK cell activation (IFN-γ). This would
result in upregulation of class I expression and, in cells expressing
in BM macrophages undergoing a UPR, either due to HLA-B27
upregulation or in cells treated with pharmacologic agents (tuni-
camycin or thapsigargin) that cause ER stress,86 consistent with
a previous report of low-level induction in tunicamycin-treated
fibroblasts.87 IFN-b has well-recognized autocrine effects at low
concentrations,88-90 and thus UPR-induced IFN-b may have
immunological consequences including a pro-survival effect on
macrophages.91 However, perhaps more important is the response
observed when macrophages undergoing a UPR are exposed to
ligands for pattern recognition receptors (e.g., Toll-like receptors
or TLRs). TLR4 and TLR3 agonists such as LPS and dsRNA, that
upregulate IFN-b via the TRIF (Toll-like receptor/IL-1 receptor
related adaptor protein inducing IFN-b)-dependent pathway,
cause robust synergistic IFN-b production in cells exhibiting ER
stress. The synergistic response appears to require XBP-1s, but not
PERK or ATF6 activation. These results suggest a fundamental
relationship between ER stress and innate immune signaling
with implications beyond HLA-B27 and disease, as well as a
novel function of XBP-1 in the convergence of these important
The UPR and cytokine production. Links between the UPR
and cytokine induction have been reported in the literature. IL-6
production from plasma cells after activation by LPS or CD40
ligation is influenced by XBP-1, although this effect is considerably
delayed and may be secondary to other changes.62 Macrophages
loaded with cholesterol exhibit UPR activation and increased
production of TNF-α and IL-6, effects that appear to be secondary
to NFκB, JNK1/2, p38 and/or Erk1/2 activation.92 Using a
microarray-based screening approach, we identified IL-23p19
(the unique subunit of the active IL-23 cytokine), as being syner-
gistically induced by LPS-treatment of cells with an active UPR
(reviewed in ref. 86). We have found IL-23p19 upregulation in
inflamed tissue and myeloid cells derived from the tissue, in B27/
hβ2m transgenic rats. Il-23p19 is upregulated in a temporal and
spatial manner that is consistent with it being involved in the
development of colon inflammation. In addition, there is robust
upregulation of IL-17 in the inflamed colon that localizes to CD4
T-cells in the lamina propria and draining mesenteric lymph nodes
(reviewed in ref. 93). These findings are of interest in the context
of several recent developments in our understanding of T-cell
biology, as well as new evidence for genes involved in susceptibility
Th1, Th2 and Th17. Upon antigenic stimulation, naïve
CD4 T-cells differentiate into T helper (Th) cells with specialized
cytokine production profiles and effector functions. The Th1/Th2
paradigm established over 20 years ago was that Th1 cells produce
large quantities of IFN-γ and are essential for clearing intracellular
pathogens, while Th2 cells produce IL-4, 5 and 13 and are impor-
tant for clearance of extracellular organisms and robust humoral
immunity.94,95 Key cytokines that drive these two pathways are
IL-12 (IL-12p70) and IL-4. IL-12 induces Th1 differentiation
through STAT4 activation in T-cells and IL-4 promotes Th2 devel-
opment through STAT6 and GATA-3 activation, promoting more
IL-4 production.96 IFN-γ from an initial innate immune response
(e.g., activated NK cells) is also important for activating the T-bet
HLA-B27 and disease
this might be expected given the overlap in effects of Type I and
Type II IFNs. These and other questions, including the relative
importance of the Th1 axis in transgenic rats, need to be further
HLA-B27 Subtypes and Spondyloarthritis
There is heterogeneity within the HLA-B27 group of alleles
referred to as subtypes (www.anthonynolan.com/HIG/). The
numerical classification for subtypes is to designate them with an
asterisk preceding the number (e.g., B*2701, B*2702, etc.,). More
than 30 subtypes have been reported for HLA-B27 and since most
occur infrequently, little is known about their association with
AS or SpA. While most of the relatively common subtypes (e.g.,
B*2705, B*2702, B*2704) have been associated with disease, for
some time B*2706 and B*2709 have been thought to be excep-
tions. Since hypotheses explaining how HLA-B27 might cause
disease have been driven by our understanding of how it differs
from other HLA-B alleles, it should be possible to refine our
ideas based on properties of subtypes differentially associated with
disease. However, the caveat with this approach is that incomplete
or incorrect information about disease associations may lead to
incorrect conclusions. There are now new data suggesting that
B*2709 may be associated with disease, or at the very least the situ-
ation is more complex than previously thought.118 Patients with
B*2709 who developed SpA were reported several years ago,119,120
and now there are reports of this subtype in AS patients.121,122
A recent examination of the existing data suggests that B*2709
occurs in these individuals at a greater frequency than by chance
alone,118 thus supporting the idea that this subtype may indeed be
associated with disease. The occurrence of B*2709 on a distinct
HLA-B27, activation of the UPR. Macrophages would then
become sensitized to TLR agonists such as LPS and other bacterial
products, polarizing them toward increased production of IFN-b
and IL-23 and possibly more IL-6. IL-23 would then drive IL-17
production from CD4 T-cells that have become committed to
the Th17 lineage. While IL-6 and TGF-b have been shown to be
important for the development of Th17 T-cells,99 there is evidence
that cells with the capacity to produce IL-17 are normally present
in the colon.102,103 Thus, in this unique mucosal environment,
increased IL-23 expression could be a sufficient stimulus for
chronicgastrointestinal inflammation. This is supported by the
observation that IL-23p19 transgenic mice develop widespread
inflammation without any other additional stimulus.116 In the
HLA-B27 transgenic rats, increased IFN-b expression might serve
to promote HLA-B27 upregulation and also activate NK cells.117
It is also possible that unusual forms of HLA-B27 expressed on
the cell surface might engage leukocyte receptors and serve as an
activating stimulus for NK cells.30
It is interesting to note that IFN-γ can inhibit the Th17
axis.97,98 In the model we propose for the development of colitis,
IFNs would play an important role in promoting IL-23 produc-
tion via class I upregulation and subsequent UPR activation, but
could conceivably inhibit the IL-23/IL-17 axis through effects on
Th17 development. We and others, have documented IFN-γ over-
expression in the inflamed colon,18,34 but since CD4 T-cells with
the capacity to produce IL-17 may already exist in this location,
IFN-γ may have little effect on their development. Furthermore,
we do not know the relative importance of Type I vs Type II IFNs
in HLA-B27 upregulation in rats in vivo, nor whether Type I IFNs
have the same inhibitory effect on Th17 development, although
Figure 2. Proposed paradigm linking HLA-B27 misfolding to innate immune activation. The tendency of HLA-B27 to misfold and activate the UPR when
upregulated sensitizes cells to certain pathogen-associated molecular patterns and possibly damage-associated molecular patterns, many of which signal
through pattern recognition receptors such as the Toll-like receptors (TLR Agonists). Enhanced upregulation of IL-23 promotes IL-17 production from CD4
T-cells of the Th17 lineage. Th17 cells can produce TNFα and IL-6 and IL-17 is also a potent pro-inflammatory cytokine that acts on many tissue cell types
and further induces TNFα, IL-6 and IL-1 as well as chemokines and metalloproteinases. IL-17 is hypothesized to be a key pro-inflammatory cytokine in
the immunopathology that develops in the colon of HLA-B27 transgenic rats.
22 Prion 2009; Vol. 3 Issue 1
HLA-B27 and disease
since UPR activation was not examined after upregulation of
HLA-B27, which we have shown is critical for this response.34,35
In addition, since there is some cell type specificity to HLA-B27-
induced UPR activation, it will be important to examine cells
that are likely to be relevant to disease pathogenesis. Preliminary
experiments suggest that while the additional hβ2m reduces the
magnitude of UPR activation when HLA-B27 is upregulated, it
does not eliminate it (unpublished observations) and thus the role
of HLA-B27 misfolding in the spondyloarthritis phenotype will
require further investigation.
It is also important to consider that UPR activation might be a
‘double-edged’ sword in the pathogenesis of inflammatory disease.
Its consequences could depend on the magnitude of the response.
For example, it is well known that a strong and unresolved UPR
can lead to apoptosis.
If UPR activation in macrophages drives an inflammatory
process due to abnormal cytokine production, one could envision
downstream effects being different if the cells causing the problem
are destined to undergo UPR-induced apoptosis. The conse-
quences of inappropriate in vivo UPR activation in the immune
system are relatively unexplored and it is also likely that we do not
yet appreciate precisely what needs to be examined. Our ability to
approach these questions would be aided greatly by the develop-
ment of a mouse model, where many more tools are available to
address these complex issues.
Recent advances in deciphering genetic susceptibility to AS
point toward the IL-23 receptor (IL23R) gene.5 This gene encodes
a protein that combines with another subunit IL-12Rb1 to
form the active IL-23 receptor expressed on developing Th17
T-cells,113 making them responsive to IL-23. IL23R polymor-
phisms have also been implicated in susceptibility to Crohn’s
disease and psoriasis, other diseases that have phenotypic overlaps
with spondyloarthritis.128,129 Preliminary data indicating that
HLA-B27 misfolding may be a stimulus for activating the IL-23/
IL-17 axis, suggests a novel mechanism that may explain, at least in
part, the role of HLA-B27 in colitis in transgenic rats. The striking
convergence of the human genetic data and results from HLA-B27
transgenic rats provides a compelling argument that this axis needs
to be further examined in SpA and AS.
This manuscript has been previously published: Colbert RA,
Delay ML, Layh-Schmitt G, Sowders DP. HLA-B27 misfolding
and spondyloarthropathies. In: Molecular Mechanisms of
Spondyloarathropathies. López-Larrea, C and Díaz-Peña, R ed.
Austin and New York: Landes Bioscience and Springer Science and
Business Media, 2009 In Press.
haplotype from B*2705 in the same population,123 along with
genetic evidence that additional MHC-encoded genes influence
susceptibility,3,124 raises the possibility that the offending alleles
are not present on the B*2709 haplotype.123 It is well known
that most individuals with HLA-B27 (and B*2705 by inference)
do not develop AS/SpA and HLA-B27-positive family members
of patients with AS are at much higher risk for disease than the
general HLA-B27-positive population. One recently proposed
hypothesis is that B*2709 arose by a single mutation from B*2705
on a low-risk haplotype and that it may be the low-risk haplo-
type that is more important for disease predisposition than the
immunobiological differences between the B*2705 and B*2709
proteins.118 Additional genetic differences between populations
with B*2709 and B*2705 might also contribute.
The case for a lack of association between B*2706 and disease
is more compelling, in part because it is present in a much larger
and probably more genetically diverse population.125 However,
patients with AS and this subtype have also been reported126 with
two additional cases described recently.127
Subtype associations (or lack thereof ) need to be extended to
larger populations and investigated for the possible existence of
MHC haplotypes such as those uncovered in Sardinia.123
Another pitfall of using the genetic association data to drive
hypotheses about disease causation is that subtyping of HLA-B27
has traditionally focused on coding sequence variation, with little
attention to the promoter region of the gene. Promoter polymor-
phisms, which are known to exist,21 could have consequences for
baseline and inducible HLA-B27 subtype expression.
Overexpression of Additional hb2m: The New Model of SpA
The phenotype exhibited by high copy B27/hβ2m transgenic
rats, where colitis and peripheral arthritis predominate, does not
include an important component of AS—axial inflammation and
ankylosis. Recently Tran et al. found that overexpressing more
hβ2m by introducing an additional 35 copies of the hβ2m trans-
gene altered the phenotype of high copy B27/hβ2m transgenic rats
(55 copies of HLA-B27 and 66 copies of hβ2m).19 Rats with 55
copies of HLA-B27 and 101 copies of hβ2m had more frequent and
more severe arthritis involving the axial skeleton, while colitis was
not affected. In addition, the extra 35 copies of hβ2m were able to
induce arthritis in intermediate copy B27/hβ2m transgenic rats (20
copies of HLA-B27 and 15 copies of hβ2m) that normally remain
free of any spontaneous disease. Thus, spondylitis was induced by
additional hβ2m even in the absence of colitis. These observations
are potentially important as they provide a model system that may
be relevant to the pathogenesis of axial inflammation.
The mechanism by which additional hβ2m modifies the
phenotype of B27/hβ2m transgenic rats is not clear. Based on
observations that the additional hβ2m increased the folding kinetics
of HLA-B27, reduced the formation of aberrant disulfide linked
heavy chain complexes and resulted in a reduction of BiP mRNA
expression (~25–30%) in splenocytes, the authors concluded that
while HLA-B27 misfolding was still associated with intestinal
inflammation, it was not critical to the development of HLA-B27-
associated arthropathy. However, this conclusion is premature,
HLA-B27 and disease
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