HLA-B 27 in Spondyloarthritis

Best Practice & Research Clinical Rheumatology 31 (2017) 797e815
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh
The role of HLA-B*27 in spondyloarthritis

Robert A. Colbert*, Fatemeh Navid 1, Tejpal Gill 1
Pediatric Translational Research Branch, NIAMS Intramural Research Program, NIH, USA
a b s t r a c t
Keywords:
Spondyloarthritis The mechanism by which HLA-B*27 predisposes to spondyloar-
Ankylosing spondylitis thritis remains unresolved. Arthritogenic peptides have not been
Arthritogenic peptides defined in humans and are not involved in experimental models of
Protein misfolding spondyloarthritis. Aberrant properties of HLA-B*27 can activate
Endoplasmic reticulum-associated the IL-23/IL-17 axis in HLA-B*27 transgenic rats and humans. In
aminopeptidase-1 (ERAP1)
HLA-B*27-independent rodent models, spondyloarthritis can be
Endoplasmic reticulum-associated
degradation (ERAD)
driven by IL-23 triggering entheseal-resident CD4-/CD8- T cells or
Autophagy CD4þ Th17 T cells. These findings point toward noncanonical
Microbiota mechanisms linking HLA-B*27 to the disease and provide a po-
Dysbiosis tential explanation for HLA-B*27-negative spondyloarthritis. Gut
Inflammatory bowel disease microbial dysbiosis may be important in the development of
spondyloarthritis. HLA-B*27-induced changes in gut microbiota
are complex and suggest an ecological model of dysbiosis in
rodents. The importance of the IL-23/IL-17 axis in ankylosing
spondylitis has been demonstrated by studies showing efficacy of
IL-17. Although deciphering the precise role(s) of HLA-B*27 in
disease requires further investigation, considerable progress has
been made in understanding this complex relationship.
© 2018 Published by Elsevier Ltd.
Introduction
The relationship between HLA-B*27 and spondyloarthritis has been recognized since the 1970s
when two groups independently reported that HLA-B*27 (called HL-A 27 or W27 at the time) is
markedly increased in patients with ankylosing spondylitis [1,2]. During the last decade, several large
* Corresponding author.
E-mail addresses: colbertr@mail.nih.gov (R.A. Colbert), fatemeh.navid@nih.gov (F. Navid), tejpal.gill@nih.gov (T. Gill).
1
These authors contributed equally to this review.
https://doi.org/10.1016/j.berh.2018.07.012
1521-6942/© 2018 Published by Elsevier Ltd.
798 R.A. Colbert et al. / Best Practice & Research Clinical Rheumatology 31 (2017) 797e815
genome-wide association studies have revealed more than 100 additional common variants across the
genome that contribute to disease risk, but to date, they account for only a fraction of the overall
heritability of ankylosing spondylitis [3], which is dominated by HLA-B*27. Potential mechanisms
linking HLA-B*27 to the disease are numerous, yet each lacks sufficient evidence to fully explain this
remarkable relationship. It is useful to categorize hypotheses into those that involve the canonical
function of HLA class I, such as peptide presentation to CD8þ cytotoxic T lymphocytes (CTLs) or
recognition by natural killer (NK) cells, and those invoking “aberrant” features of HLA-B*27 such as
misfolding and dimerization. There is nearly complete overlap between amino acids that affect peptide
binding to HLA-B*27 and those that are responsible for its aberrant features, thus making it impossible
to separate the importance of these properties to pathogenic mechanisms. The purpose of this review
is to provide an overview and update on current research into the role of HLA-B*27 in spondyloarthritis
and to identify key gaps in our knowledge. We wish to acknowledge the key contributions of numerous
individuals to this area of research and apologize for not being able to cite every important contribution
because of space limitations.
HLA class I structure and function
Structure
HLA class I genes are located in the major histocompatibility complex (MHC) and encode poly-
peptides that are expressed in virtually all nucleated cells. HLA-B*27 refers to a family of closely related
HLA-B alleles, with variants referred to as subtypes. HLA class I proteins (heavy chains) are expressed
on the cell surface in a complex with two additional polypeptides: beta2-microglobulin (b2m) and a
short peptide that is typically 8e12 amino acids in length with a variable sequence. The a1 and a2
domains of the folded heavy chain form a groove that accommodates the peptide, while the peptide
heavy-chain structure is stabilized by noncovalent association with b2m (Fig. 1). All three components
Fig. 1. Structure of HLA-B*27 heterotrimer. Properly folded HLA-B*27 heavy chain is shown in blue, with the a1, a2, and a3 domains
indicated. Peptide is shown in yellow as seen from the end of the peptide-binding groove, with b2m bound beneath the a1/a2
domains and to the a3 domain of the heavy chain. MHC class I heavy chains also have transmembrane and intracellular domains that
are not shown. Reproduced from Bowness P,s Ann Rev Immunol 2015; 33:29-48 with permission.
R.A. Colbert et al. / Best Practice & Research Clinical Rheumatology 31 (2017) 797e815 799
are necessary for stable expression and efficient recognition by T cell receptors (TCRs) on CD8þ T cells.
HLA-B*27 works like other HLA class I proteins to display a variety of different peptides on the cell
surface where they are surveyed by CD8þ T cells.
Allelic variation and peptide binding
Genetic polymorphisms in HLA alleles result in the expression of a vast array of protein variants
across the population. Much of the variation is in amino acids that line the peptide-binding groove,
therefore influencing the nature of the peptide that can bind. Peptide-binding requirements for specific
alleles are also somewhat loose, and hence, thousands of different peptides can be displayed by the
same allele as long as they share minimum requirements for binding. Allelelic differences are sufficient
to restrict overlap in peptide repertoires or “peptidomes,” although this varies among different alleles
[4]. Within HLA allele designations, there are subtypes (see below) that are more closely related and
thus exhibit considerably more overlap in their peptidomes. HLA polymorphisms can also directly
affect TCR or NK cell receptor recognition.
HLA-B*27 peptidome
Analysis of the HLA-B*27 peptidome reveals a strong preference for peptides that have a length of
9e11 amino acids (93% of 1151 peptides), with only 2% of peptides being shorter than nine residues [5].
Virtually all HLA-B*27-bound peptides have arginine (Arg) at position 2, which is a consequence of “B
pocket” specificity [6], although there are examples of peptides with glutamine or lysine in this
position [7,8]. HLA-B*27-bound peptides frequently have basic or hydrophobic amino acids at their
C-terminus. There is much greater tolerance for different amino acid side chains in other positions of
the peptide, partly because there is less contact with the heavy chain [9]. Although each molecule of
HLA-B*27 carries a single peptide, each cell can express in the range of 105 class I molecules and thus
display several thousand different peptides. The immune system ignores these peptides when they are
derived from self-proteins, as most self-reactive CD8þ CTLs have been deleted or rendered anergic.
However, when peptides derived from foreign organisms such as viruses, bacteria, or parasites are
displayed, CTLs react and kill the infected cells. HLA-B*27 appears to be particularly adept at this and
has been associated with better outcomes in HIVe and hepatitis C-infected individuals [10e13].
Recognition by KIRs
HLA class I complexes can also be recognized by killer immunoglobulin-like receptors (KIRs)
expressed on NK cells. KIRs, like TCRs, are capable of distinguishing between the peptides displayed by
HLA class I [14e16], although KIReHLA class I interactions are not as finely tuned as TCReHLA class I
interactions [17]. A major difference between KIR and TCR recognition of HLA class I is that NK cells are
usually turned off by this interaction (although this depends on the balance between their activating
and inhibitory receptors), whereas CTLs become activated. KIR3DL1 has been shown to recognize HLA-
B*27, and interactions between leukocyte immunoglobulin-like receptors B1 (LILRB1) and LILRB2 and
HLA-B*27 have also been reported, but less is known about their specificity [18].
HLA-B*27 subtypes. There are more than 200 HLA-B*27 subtypes reported to date based on nucle-
otide sequence polymorphisms that correspond to at least 160 protein variants [19]. These variants are
designated as subtypes that are more closely related to one another than to other HLA-B alleles
(Immunogenetics/HLA Database; http://www.ebi.ac.uk/ipd/imgt/hla/align.html). Many common
HLA-B*27 subtypes are known to be associated with spondyloarthritis [19]. However, two subtypes
appear to be different. HLA-B*27:06 is not associated with ankylosing spondylitis [20], and B*27:09,
which is found predominantly in Sardinia, either lacks association or confers a weak risk for disease.
B*27:09 has been reported in several patients with spondyloarthritis or ankylosing spondylitis
[21e25]. Common subtypes like B*27:05, B*27:04, and B*27:02 are strongly associated with disease.
Because the majority of the subtypes are rare, with some representing single reports, larger population
studies are needed to determine the relative strength of association for each subtype.
HLA class I folding and assembly
Although HLA-B*27 functions like other MHC class I proteins, it also exhibits aberrant properties
[26]. To understand these properties and their implications for disease requires an in-depth insight into
how MHC class I complexes assemble in the endoplasmic reticulum (ER) (Fig. 2). Nascent heavy chains
bind transiently to ER chaperones (BiP, calnexin, and calreticulin) and the oxidoreductase ERp57 during
acquisition of their secondary and tertiary structure. These early events prevent aggregation (mis-
folding) of prefolded heavy chains and enable proper folding to proceed. This includes the formation
of intrachain disulfide bonds that stabilize the heavy chain, thereby enabling b2m binding and the
generation of a peptide-receptive heterodimer (heavy chain [HC]/b2m). Heterodimers that do not
readily bind optimal peptides to them can be retained in the peptide-loading complex (PLC) by tapasin
(Tap-binding protein; TAPBP), an MHC class I-specific chaperone that forms a bridge to the peptide
transporter (TAP1/TAP2). Most peptides that are eventually loaded onto MHC class I molecules are
generated by proteasomal degradation of cellular proteins in the cytosol. Cytosolic peptides gain access
to the ER through TAP1/TAP2 but in many cases require further trimming by the ER aminopeptidases
ERAP1 and/or ERAP2. Heavy chain/peptide/b2m complexes are released from tapasin and undergo ER-
to-Golgi transport and eventually traffic to the cell surface. Further “proofreading” can occur in the
ER/Golgi through interaction with the tapasin homolog TAPBPR (Tap-binding protein-related; TAPBPL).
While tapasin serves to accelerate peptide loading and the formation of stable complexes, TAPBPR may
promote editing by stabilizing MHC class I molecules that have escaped the PLC with suboptimal
peptides [27]. Detailed structural analysis has shown that TAPBPR binds to the MHC heavy chain and
Fig. 2. Assembly of HLA class I complexes. The HLA class I heavy chain is synthesized and co-translationally inserted into the ER
lumen (not shown). The heavy chain (left to right) interacts transiently with ER chaperones BiP (HSPA5), calnexin (CANX), and
calreticulin (CALR) before becoming part of the peptide-loading complex. ERp57 (PDIA3) interacts with the heavy chain through
calnexin and calreticulin and is part of the peptide-loading complex. Tapasin (TAPBP) binds to the heavy chain and TAP1/TAP2 to
form the peptide-loading complex. Proteasome-derived peptides enter the ER through the peptide transporter (TAP1/TAP2) and may
be trimmed by ERAP1/ERAP2 to optimize their length for binding to MHC class I heterodimers. (Rodents lack the ERAP2 gene.)
TAP-binding protein-related protein (TAPBPR, encoded by TAPBPL) binds to MHC class I complexes with suboptimal peptides and
may facilitate their removal so that heavy chain/b2m heterodimers can be recycled to the PLC. Stable heterotrimers traffic to the cell
surface to display their peptides.
alters the structure of an a2 domain helical region (Fig. 1), inserting a loop into the peptide-binding
groove [28]. This may facilitate the release of low-affinity peptide [29]. This keeps the groove empty
and re-directs HC/b2m heterodimers back to the PLC, fine-tuning the selection of optimal peptides for
presentation on the cell surface [30]. All these events emphasize that our immune system focuses on
folding and assembly of HLA class I alleles and presenting optimal peptides on cell surface.
Cross presentation
In addition to the standard assembly pathway where newly formed MHC class I complexes are
transported from the ER to the Golgi and then the cell surface, they also participate in cross presen-
tation. Cross presentation is the mechanism by which extracellular protein antigens are taken up,
processed, and loaded onto MHC class I proteins [31] and is critical for dendritic cell (DC) priming of
CD8þ T cells to generate an immune response. Other cells are also capable of cross presentation,
although the relevance is less clear. Phagosomes that have taken up exogenous antigen form a loading
compartment with endosomes to provide antigens for cross presentation [32e34]. In DCs, phagosomes
acquire components from the ER [35] and lysosomes, as well as recycling endosomes. Proteasomes
have also been implicated in generating peptides for cross presentation, thus implying that antigens
may gain access to the cytosol [36,37]. There is evidence that ERAP1 is involved in cross-presentation of
an immune complex-derived antigen in DCs, whereas cross presentation of a soluble form of the same
antigen was not ERAP1-dependent [38]. Because ERAP1 resides in the ER, it could be provided when
phagosomes mature and acquire components of this organelle. However, there are also reports that
ERAP1 can be secreted from LPS/IFN-g-activated cells [39e41], including in exosomes [42], and hence,
other mechanisms are possible. Secreted ERAP1 also enhances macrophage phagocytic activity [39].
Other endosomal/lysosomal proteases implicated in cross presentation include cathepsin S and
insulin-regulated aminopeptidase (IRAP) [43,44]. At this point, details regarding the specific pathways
and additional proteins involved in cross presentation are the subject of ongoing investigation.
Aberrant features of HLA-B*27 e misfolding and dimerization
Intensive study of HLA-B*27 has led to the discovery of unusual or aberrant features not shared with
other HLA class I alleles (Fig. 3), which have been linked to disease mechanisms [17,26,45]. The HLA-
B*27 heavy chain has a propensity to misfold during assembly and before acquisition of b2m and
peptide in the ER. Misfolded heavy chains are detectable immediately after synthesis as disulfide-
linked complexes. They are approximately the size of dimers, and can associate with BiP [46,47], but
can also exist as larger oligomers [48]. Misfolding includes the formation of aberrant interchain and
probably intrachain disulfide bonds [46,49]. Misfolded heavy chains exhibit prolonged association with
BiP, can accumulate in the ER particularly when HLA class I synthesis is upregulated [50,51], and can
cause ER stress.
HLA-B*27 also forms interchain disulfide-linked homodimers after reaching the cell surface
[46,52,53] during endosomal recycling [54]. HLA-B*27 also accumulates on the cell surface as unfolded
or free heavy chain (FHC) monomers lacking b2m. The term free heavy chain is frequently used to
describe cell surface monomers or homodimers (B*27-B*27) because both lack b2m. HLA-B*27
homodimers were initially shown to form in vitro during refolding of recombinant heavy chains
lacking transmembrane and cytoplasmic domains, and their formation was dependent on the Cys
residue at position 67 (Cys67) [52]. Misfolding and homodimer formation are related, as they are a
consequence of some of the same heavy chain amino acids, but they are separated temporally and
spatially (Fig. 3) [46]. They also have distinct implications for disease mechanisms, which will be
further discussed below in the section on pathogenesis.
Quality control mechanisms e ER-associated degradation and autophagy
Cells make a concerted effort to eliminate proteins that misfold to prevent accumulation, which can
be toxic. This may be less of a problem for cells that are constantly turning over, while consequences to
the nervous system can be devastating. For some proteins, elimination is quite robust that there is
Fig. 3. Aberrant features of HLA-B*27. In the endoplasmic reticulum, newly synthesized HLA-B*27 heavy chains dimerize and
accumulate bound to BiP (Misfolded HLA-B*27). ER quality control (ERQC) of HLA-B*27 includes ER-associated degradation (ERAD)
and autophagy of misfolded heavy chains. Buildup of misfolded HLA-B*27 bound to BiP can contribute to ER stress and trigger
signaling through PERK (as well as IRE1a and ATF6; not shown). One outcome of PERK activation is increased synthesis of the
transcription factor ATF4, which induces C/EBP homologous protein (CHOP; DDIT3). CHOP has proapoptotic effects and also
contributes to super-induction of IL-23p19. Heterotrimeric complexes of HLA-B*27 that have reached the cell surface and lost
peptide and b2m can remain as free heavy chains (monomers) or undergo endosomal recycling and reappear as free heavy chain
homodimers.
insufficient gene product resulting in loss-of-function phenotypes. For proteins synthesized and
assembled in the ER, the ER stress response (also known as the unfolded protein response [UPR] or the
integrated stress response [ISR]) can exert gain-of-function effects on immune responses [55].
Disruption of other processes is also possible. For example, mutations in superoxide dismutase-1
(SOD1), which can cause amyotrophic lateral sclerosis, impair ER-to-Golgi transport. This is unusual
because SOD1 is not typically associated with this pathway [56]. Misfolded proteins can also have
“bystander” effects, inducing collateral damage on other unrelated proteins [57]. Bystander effects can
be cell specific despite widespread expression of the misfolded protein if expression of the target
protein is limited to specific cell types [57], and bystander effects as well as impaired ER-to-Golgi
transport can occur without UPR activation. Extending this concept to HLA-B*27, its aberrant prop-
erties might have a greater impact on DCs than on other cell types (even other antigen-processing
cells).
Newly synthesized misfolded HLA-B*27 heavy chains can be degraded by the ER quality control
pathway known as ER-associated degradation (ERAD) (Fig. 3) [58], similar to what occurs with HLA
class I heavy chains synthesized in the absence of b2m or TAP [59], conditions that promote heavy chain
misfolding. ERAD is a multistep process that involves recognition and targeting of the misfolded
protein, followed by dislocation from the ER membrane into the cytosol. For this to occur, intra- and
inter-chain disulfide bonds need to be eliminated (reduced) and carbohydrate side chains removed
(de-glycosylation). Once in the cytosol, the ubiquitin-tagged protein is typically directed to a protein-
degrading structure known as the proteasome. ERAD of HLA class I heavy chains involves ubiquiti-
nation by the E3 ubiquitin ligase HRD1 (SYVN1 or synoviolin) and the E2 ubiquitin-conjugating enzyme
UBE2J1 [60]. These components are also essential for the degradation of misfolded HLA-B*27 [61].
ERAD can be enhanced by overexpression of the ER degradation-enhancing a-mannosidase-like
protein 1 (EDEM1), which is involved in the recognition of proteins that have failed repeated cycles of
refolding and are therefore deemed ready for elimination. EDEM1 overexpression helps to degrade
misfolded HLA-B*27 and reduces the accumulation of HLA-B*27 dimers in the ER [61].
Autophagy
We recently demonstrated that misfolded HLA-B*27 heavy chains can be eliminated by autophagy
as well as ERAD (Fig. 3) [48]. Autophagy is the process by which cells sequester their own material into
vesicles for delivery to, and degradation in, lysosomes [62]. This can occur in bulk for the whole
mitochondria (mitophagy) or portions of the ER (ER-phagy) or for specific substrates recognized by
chaperones (chaperone-mediated autophagy) [63]. Autophagy contributes to ER quality control and
may be particularly important when the proteasomal degradation pathway is inefficient or over-
whelmed [64]. When we examined quality control of HLA-B*27 heavy chains expressed in rat mac-
rophages from HLA-B*27/hb2m transgenic rats, we found that blocking autophagy during HLA-B*27
upregulation led to accumulation of misfolded heavy chains (dimers and oligomers) as well as some
monomers, comparable to blocking ERAD [48]. We found no evidence that HLA-B*27 expression could
activate autophagy even during upregulation nor that autophagy pathways were disrupted in HLA-
B*27-expressing cells. We also examined the degradation of HLA-B7 overexpressed in rat macrophages
from HLA-B7/hb2m transgenic rats and discovered that HLA-B*27 heavy chains were not effectively
ubiquitinated compared to HLA-B7. Because HLA-B7 does not misfold or form disulfide-linked dimers,
this suggests that HLA-B*27 misfolding might be responsible for inefficient ubiquitination and
degradation, perhaps exacerbating accumulation during upregulation [48]. This is important because
upregulation and accumulation of misfolded HLA-B*27 are associated with the activation of the UPR
[50,51].
As might be expected, the aberrant features of HLA-B*27 arise from differences in its primary amino
acid sequence that distinguish it from other alleles. The same amino acids also have a profound
influence on peptide-binding specificity [6,58]. The most striking example is the “B pocket” of HLA-
B*27. This region of the peptide-binding groove is responsible for both misfolding and homodimeri-
zation [46,58,65] and also confers specificity for peptides with Arg at P2 in part due to Glu45 at the base
of the pocket [6]. Moreover, creating a different B pocket in HLA-B*27 increases the rate of heavy chain
folding and affinity for peptide and eliminates misfolding and dimerization [58]. Polymorphisms in the
F pocket at the opposite end of the peptide-binding groove can also affect folding/misfolding and
chaperone interaction [61,66]. Thus, aberrant properties of HLA-B*27 are inextricably associated with
characteristics of peptide binding, including specificity and affinity, and indirectly its peptidome. This
has implications for understanding how other components of the HLA class I assembly pathway affect
the behavior of HLA-B*27.
HLA-B*27 and the pathogenesis of spondyloarthritis
Understanding the mechanism (or mechanisms) by which HLA-B*27 contributes to spondyloar-

thritis has proven to be a formidable challenge. Here, we will provide an overview of proposed
mechanisms, and then comment on areas of investigation that, in our opinion, may prove fruitful.
Autoreactivity. An autoantibody cross-reacting with altered self, such as a covalently modified form
of HLA-B*27, could play a role in initiating or perpetuating disease. Alternatively, CD8þ CTLs that
normally recognize foreign peptides presented by HLA-B*27 during an infection might cross-react with
arthritogenic self-peptides displayed by HLA-B*27 (Fig. 4). Such autoreactive antibodies or CTLs could
then mediate chronic inflammation. To date, direct evidence that recognition of canonical forms of
HLA-B*27 and its peptides by the immune system, and in particular CD8þ T cells, is necessary to initiate
or perpetuate disease is lacking and be conducted in humans and rodent models.
Analysis of peptide binding to closely related HLA-B*27 subtypes differentially associated and not
associated with ankylosing spondylitis has been used as an approach to identify key disease-related
properties. Detailed structural studies comparing B*27:05 and B*27:09 revealed that B*27:05 can
Fig. 4. Forms of HLA-B*27 and potential mechanisms of pathogenesis.
display at least one self-peptide in two different conformations that can be distinguished by CD8þ CTL,
while the same self-peptide appeared in only one conformation when crystallized with B*27:09 [67].
This suggested that altered display of a self-peptide (“dual peptide conformations”) might generate
autoreactivity [67]. These studies were extended to B*27:04 and B*27:06 crystallized with the same
peptide. Contrary to the results with B*27:05 and B*27:09, the disease-associated B*27:04 subtype
displayed only a single peptide conformation, whereas the nonassociated B*27:06 subtype exhibited
two conformations [68]. In the latter study, the disease-associated subtypes (B*27:04 and B*27:05)
showed significant heavy chain conformational flexibility when probed by infrared spectroscopy,
whereas the nonassociated subtypes (B*27:06 and B*27:09) did not [68] show flexibility. While greater
overall flexibility of the heavy chain bound to peptide and b2m (rather than different peptide con-
formations) could conceivably lead to altered T cell receptor recognition, it is equally plausible that
conformational flexibility contributes to aberrant properties of HLA-B*27 during assembly, quality
control, and/or endosomal recycling from the cell surface [69]. For example, it is interesting that the a2
domain of HLA-B*27 that exhibits conformational flexibility between subtypes includes the region of
TAPBPR binding, which is necessary to recapture complexes that may need further editing. Whether or
not conformational flexibility affects TAPBPR is unknown and is worth further investigation. Impaired
binding might explain the predilection of HLA-B*27 to display long peptides [70], particularly notable
when ERAP1 activity is low [71e73]. This might also reduce recycling and overall ER retention of
HLA-B*27.
Extensive analysis of eight of the most common HLA-B*27 subtypes expressed in the same cell type
has led to the observation that there is a considerable overlap between peptidomes, and the suggestion
that quantitative rather than qualitative differences in peptide repertoires might underlie differential
disease association [74]. This led to the identification of 26 peptides presented in lower abundance by
B*27:06 and B*27:09 than disease-associated subtypes [75]. This is an interesting observation and
provides a tractable list of putative arthritogenic peptides that can be used to search for autoreactive
CD8þ T cells in patients with ankylosing spondylitis.
Plausible links between autoantibody or autoreactive CTL recognition of HLA-B*27 and the spon-
dyloarthritis phenotype (e.g., enthesitis, gut inflammation, eye inflammation, and bone formation)
would need to be established given compelling evidence from animal models that spondyloarthritis
can develop from IL-23 triggering of non-canonical entheseal-resident T cells [76] or CD4þ Th17 T cells
that accumulate in SKG mice [77]. Interestingly, there are cells resembling type 3 innate lymphoid cells
that are enriched in entheseal tissue from humans [78]. These cells are innate immune lymphocytes
that resemble Th17 T cells in their cytokine production.
Although no arthritogenic peptides have been identified to date, recent results from TCRb repertoire
sequencing of T cells from patients with ankylosing spondylitis positive for HLA-B*27 revealed
evidence for a shared motif that was enriched in some patients compared to HLA-B*27-positive con-
trols [79]. Confirming and extending these findings and identifying the target peptide(s) would
represent an important advance in the field.
Recognition of aberrant forms of HLA-B*27
Considerable evidence supports the idea that “aberrant” cell surface forms of HLA-B*27 (FHC dimers
and monomers) can be recognized by the immune system and trigger proinflammatory responses
(Fig. 4) [17]. Initially, in vitro refolded dimers were shown to interact with innate immune receptors
including the killer immunoglobulin receptors KIR3DL1 and KIR3DL2, as well as immunoglobulin-like
transcript 4 (ILT4) [53] The KIR3DL2eHLA-B*27 interaction can promote survival of NK cells [80] and
trigger Th17-like CD4þ T lymphocytes to produce IL-17 [81]. KIR3DL2þ CD4þ Th17 T cells are also
increased in patients with ankylosing spondylitis [82]. While initial studies showing triggering of
innate immune receptors utilized in vitro refolded HLA-B*27 homodimers, this was extended to
tapasin-deficient cells that express more cell surface homodimers [46,82], but similar effects can be
seen using transfected cells that overexpress HLA-B*27 [83]. Specifying interactions between KIR3DL2
on CD4þ Th17 T cells and HLA-B*27 homodimers on antigen-presenting cells is difficult because
antigen-presenting cells also express monomeric FHCs that can interact with KIR3DL2 [81]. Antibodies
such as HC10 recognize FHCs whether they are monomers or homodimers and also cross-react with
certain HLA-B and eC allele FHCs [84]. The development of HD6, an antibody that recognizes HLA-B*27
homodimers but not heterotrimers (HC/peptide/b2m), also reacts with at least some forms of mono-
mers and thus does not definitively distinguish between monomeric and dimeric HLA-B*27 FHCs [85].
Thus, KIR3DL2 recognition of HLA-B*27 often refers to FHCs and does specify whether the target is a
homodimer or a monomer [17]. The degree to which innate immune receptors like KIR3DL2 distinguish
between dimeric and monomeric FHCs of HLA-B*27 remains unclear.
HLA-B*27 misfolding and ER stress
One consequence of HLA-B*27 misfolding is the activation of an ER stress response pathway known
as the UPR (Fig. 4). In cells from HLA-B*27/hb2m transgenic rats, upregulation of HLA-B*27 leads to the
accumulation of misfolded proteins, which activates XBP1 splicing and leads to the upregulation or
activation of UPR transcription factors (e.g., XBP1s, ATF4, and ATF6a) and downstream target genes
including BiP (Hspa5) and CHOP (Ddit3) (Fig. 3) [26,50]. The UPR intersects with innate immune
signaling pathways to synergistically upregulate IFNb and IL-23 and to promote expression of other
cytokines in response to toll-like receptor (TLR) agonists [26,86e88]. The discovery of HLA-B*27
misfolding and UPR/TLR synergy led us to the observation that there is striking CD4þ Th17 T cell
expansion and activation in the gastrointestinal tissue of HLA-B*27/hb2m transgenic rats [89]. The
PERK/ATF4/CHOP axis appears to play a key role in synergy between TLR and UPR signaling pathways
in upregulation of IL-23 [90]. HLA-B*27 misfolding and UPR activation also promote TNF-induced
osteoclast formation through increased production of IL-1a [91].
ER stress-related consequences of HLA-B*27 misfolding are more pronounced in cells from trans-
genic rats where HLA-B*27 and hb2m are overexpressed. Nevertheless, HLA-B*27 misfolding occurs at
physiological levels of heavy chain expression [58], and evidence for UPR activation has been reported
in cells from patients with spondyloarthritis [92], including BiP overexpression in synovial macro-
phages [93] and DCs [94], but results have been inconsistent [95e97], and no clear link between HLA-
B*27 and IL-23 production in humans has been found. As the ER stress response (e.g., UPR activation) is
transient, there is a need to better define conditions and cell types where HLA-B*27 is robustly
upregulated in the context of impaired ERAD or autophagy. For example, during proinflammatory DC
maturation, ubiquitinated proteins aggregate in cytosolic structures (aggresome-like structures) to

determine whether HLA-B*27 misfolding has more profound consequences [98].
There is increasing interest in targeting ER stress and autophagy pathways for therapeutic benefit
[99]. We found that activating autophagy in HLA-B*27-expressing rat macrophages or transfected cells
with rapamycin increases the degradation of misfolded HLA-B*27, including cell surface homodimers
[48]. Whether this can reduce HLA-B*27-induced ER stress or other consequences of misfolding is an
important question with potential therapeutic implications.
Dendritic cells
HLA-B*27-expressing DCs have been implicated in the pathogenesis of spondyloarthritis in trans-

genic rats [100e102]. They exhibit impaired antigen-independent immunological synapse formation
with T cells [103], perhaps because of disrupted cytoskeletal dynamics [101]. They are more susceptible
to apoptosis when stimulated [101] or when derived in vitro using Flt3 ligand [102], which results in
partial loss of a CD103þ population. Splenic DCs isolated from HLA-B*27 transgenic rats overexpress ER
stress-induced proteins including BiP, calreticulin, gp96, and Pdia3 (ERp57) [101], thus suggesting that
they have undergone a UPR in vivo. Loss of CD103þ DCs may be important for disease, as they help
maintain tolerance to intestinal bacteria [104], and DC populations that are depleted of CD103þ cells
promote Th17/Th1 polarization [105] and colitis in mouse models [106]. Indeed, DCs from HLA-B*27
transgenic rats exhibit characteristics similar to those of CD103-depleted DCs, thereby promoting
induction of Th17 T cells expressing IL-17, TNF, and IFNg [107]. This T cell phenotype resembles
expanded populations in the gut [89] and lymph nodes draining arthritic joints [107] of HLA-B*27
transgenic rats. Although the molecular mechanism by which HLA-B*27 exerts these effects on
CD103þ and other DCs remains undefined, several possibilities are worth considering. Enhanced
apoptosis of a population of DCs secondary to ER stress is supported by the proteomics studies dis-
cussed above [101]. It is also worth noting that because the pro-Th17-inducing DC phenotype can be
reproduced in HLA-B*27-expressing cells with Flt3L, which sustains mammalian target of rapamycin
(mTOR) activation and suppresses autophagy [108], it could be that suppressing autophagy promotes
the death of HLA-B*27-expressing cells during their development. Although this idea is plausible, it
may not completely explain the DC phenotype where immunological synapse formation is impaired.
Further studies are needed to elucidate mechanisms underlying HLA-B*27-expressing DC abnormal-
ities in rodents as well as humans [94].
ERAP1 and the biology of HLA-B*27
The discovery that common nonsynonymous coding variants in ERAP1 influence risk/protection for
ankylosing spondylitis has led to a series of studies examining the effect of ERAP1 gain or loss-of-
function on HLA-B*27. It was initially reported that the effect of ERAP1 was limited to individuals
positive for HLA-B*27 [109], but this was subsequently corrected when a similar interaction was
observed for HLA-B*40:01 [110]. The most likely explanation for this geneegene interaction would be
based on the peptide trimming function of ERAP1 rather than its role as a secreted protein in
macrophage activation [39], although the latter cannot be ruled out. ERAP1 has a predilection for
peptides that are 9e16 amino acids in length but does not cleave 8e9 amino acid peptides, thereby
resulting in an increase in the pool of shorter peptides that are optimally sized for stable binding to
MHC class I molecules in the ER. It is also clear from genetic studies that ERAP1 variants that correspond
with reduced ERAP1 aminopeptidase activity (i.e., loss of function) are protective for ankylosing
spondylitis while gain-of-function confers greater risk [111]. Further evidence that gain-of-function
confers risk comes from a study of three single nucleotide polymorphisms (SNPs) that form an
ERAP1 haplotype [112]. The haplotype associated with the higher ERAP1 mRNA and protein expression
was associated with greater risk, consistent with the potential for gain-of-function biological effects.
Although genetic studies are consistent with gain-of-function ERAP1 conferring risk, and loss-of-
function being protective for ankylosing spondylitis, what has been less clear is how ERAP1 function
influences HLA-B*27. Early studies of ERAP1 (ERAAP) knockout mice revealed reduced MHC class I
expression and increased presentation of N-terminally extended peptides [113e115], although effects
on expression of different MHC class I alleles and individual peptide epitopes varied [116,117]. For HLA-
B*27, expression of properly folded forms was either unchanged [71,118], increased [119,120], or
decreased [121], perhaps depending on the cell type studied and level of expression. Intracellular FHCs
(lacking b2m) and cell surface HLA-B*27 displaying longer peptides were both reportedly increased in
transfected cells [71]. Peptides eluted from cell surface HLA-B*27 expressed in transfected cells
revealed increases in longer (11e13 amino acid) peptides, while nine-amino acid ligands were reduced
[72], and overall expression of FHCs was reduced [118]. We studied b2m-free and aberrant disulfide-
linked heavy chains of HLA-B*27 in monocytic cells and demonstrated that ERAP1 knockdown
increased their accumulation on the cell surface [73]. We also confirmed the increased expression of
HLA-B*27 with longer peptides when ERAP1 was knocked down. Interestingly, when we examined cell
surface FHCs of other B alleles expressed in these cells (B*18 and B*51), ERAP1 knockdown did not
increase their expression despite their being more abundant than HLA-B*27. Importantly, these cells
expressed levels of HLA-B*27 that were comparable (or less than endogenous) with HLA class I alleles.
Moreover, upregulation of all class I alleles with IFN-g diminished some of these differences. This is
consistent with loss-of-function ERAP1 having effects that depend on the level of expression of the HLA
allele being studied and may explain some of the apparently discrepant results in the literature. HLA-
B*27 also displays more longer peptides (10e14 amino acids) in cells from HLA-B*27/hb2m transgenic
rats where ERAP1 expression was knocked out [122]. Preliminary studies also indicate that ERAP1
deficiency increases the ratio of folded to HLA-B*27 FHCs and decreases HLA-B*27 misfolding in
transgenic rat cells and mitigates ER stress (unpublished observations). Interestingly, ERAP1 deficiency
has opposing effects on HLA-B*07 in cells from HLA-B*07/hb2m transgenic rats, where it decreases the
ratio of folded heavy chains to FHCs. Thus, the results, although still preliminary, suggest that two
different HLA-B alleles behave quite differently in the absence of ERAP1 (Tran T and Colbert RA, un-
published observations). We speculate that this could be a consequence of the ability of HLA-B*27 to
form more stable complexes with long peptides and escape the ER.
HLA-B*27 and gut microbiota
Trillions of microorganisms from prokaryotic archaea and bacteria to eukaryotes and viruses exist
on and in humans [123] and has been referred to as our “second genome” [124]. The relationship
between humans and our “bugs” is complex and is the consequence of millions of years of co-
evolution. Hostemicrobe interactions in the gut, where an estimated 70% of our microbiota reside
and microbial density and diversity are at their maximum, are only beginning to be understood.
Microbes have been implicated in the pathogenesis of HLA-B*27-associated diseases for many years.
Perhaps, the most striking example is reactive arthritis triggered by gastrointestinal (or genitourinary)
infection with various intracellular organisms [125] HLA-B*27/hb2m transgenic rats provided the first
direct evidence that gut microbiota, in this case commensals, are important in the development of
spondyloarthritis. Transgenic rats in conventional and even specific pathogen-free facilities develop
spontaneous arthritis and gastrointestinal inflammation, while animals raised under gnotobiotic
(germ-free) conditions remain healthy [126]. Moreover, recolonization of HLA-B*27/hb2m transgenic
rats with normal commensals was sufficient to induce inflammatory gut and joint disease to occur
[127].
In humans, Klebsiella pneumoniae has long been proposed as a trigger or possible promoting factor
for ankylosing spondylitis based on proposed molecular mimicry with self-antigens [128,129].
Recently, a screen of pooled sera from patients with ankylosing spondylitis against a random peptide
library identified a peptide (RIGHVGARPSRH) with sequence similarity to certain fibrocartilaginous
proteins. The authors also reported homology with a proline dipeptidase from K. pneumoniae (peptide
DPP121-145; sequence AARGNIGYIG PVPERALGLG IAADK). The region of proposed homology contains
five to six amino acids (bold underline) interspersed with nonhomologous amino acids and altered
sequence order for the last two amino acids. Further analysis showed that sera of 85% (170/200) of
patients with ankylosing spondylitis reacted with the DPP peptide, compared to 1.5% (3/200) of pa-
tients with rheumatoid arthritis, 1% (1/100) of patients with psoriatic arthritis, and 0/100 healthy
controls. If these findings are confirmed and the antibody is found in early disease, it could be a useful
test for ankylosing spondylitis. A role for this antibody in pathogenesis, for K. pneumoniae in triggering
this response in ankylosing spondylitis, and any relationship with HLA-B*27 remain to be established
[130].
The mechanistic link between HLA-B*27 and reactive arthritis remains unclear. Although HLA-B*27-
restricted T cell responses to bacteria can be found [131], autoreactive CD8þ CTL and arthritogenic
self-peptides remain elusive. HLA-B*27 expression has also been reported to alter the cellular invasion
and survival of certain organisms [132,133], and the ability of HLA-B*27 to confer enhanced survival to
microbes appears to be related to its B pocket [134], which also disrupts signaling pathways in
transfected cells [135,136]. However, molecular mechanisms remain unclear.
The concept of dysbiosis dates back to the 1990s and refers to microbial imbalance or maladaptation
[137] Culture-dependent isolation and cataloguing of organisms was limited by the lack of knowledge
of conditions required to culture certain organisms and the sheer complexity of microbial commu-
nities. Culture-independent high-throughput DNA sequencing technology has resulted in an explosion
of studies cataloguing bacteria based on their 16S ribosomal RNA genes and led to descriptive and
currently more mechanistic studies. Important new concepts underlying immuneemicrobe in-
teractions in health and disease have emerged [138].
Dysbiosis can occur on or inside the body and is often linked to illness. Species that normally
dominate can become underrepresented, allowing others to overgrow and fill the void, or dysbiosis
may start with overgrowth of certain organisms. Dysbiosis can cause or promote disease, or may result
from disease, and thus merely be associated. Dysbiosis does not imply the presence of pathogenic
organisms but rather may reflect an imbalance of “normal” or commensal organisms. It should be
emphasized that there is a large amount of variation between individuals within and across pop-
ulations resulting from genetic differences, environmental factors including diet, lifestyle, and medi-
cations [139,140]. This variation does not necessarily represent dysbiosis but, unless these factors are
controlled for, can be misinterpreted as such.
Microbial imbalances can also lead to overgrowth of pathogens that may be present but are usually
in such small amounts that they are not clinically significant. Because the function of different
microbiota varies considerably, imbalances can change metabolic profiles or contribute microbial
products that affect the immune system. Similarly, gut luminal contents are significantly altered by
dietary composition including ingestion of other organisms, medications, host genetic differences, and
other often unidentified environmental exposures.
The first culture-independent study of whether HLA-B*27 can alter gut microbiota was done in
HLA-B*27/hb2m transgenic rats. This revealed that HLA-B*27 as well as human b2m can affect cecal
microbiota composition [141]. Prevotella spp. increased, and Rikenellaceae spp. decreased. Bacteroides
vulgatus was increased in HLA-B*27/hb2m and hb2m transgenic rats compared to that in wild-type
controls. HLA-B7/hb2m transgenic rats have also been used as controls for overexpression of a
different HLA class I allele. These rats remain healthy and also exhibit differences in gut microbiota
[141]. It should be noted that these studies utilized a strain of HLA-B*27/hb2m transgenic rats that
harbors a locus (21-3) with 20 and 15 copies of the HLA-B*27 and hb2m transgenes, respectively. This
strain does not develop colitis or arthritis (although males develop epididymo-orchitis) unless 35
additional copies of hb2m (283-2 transgene locus) are present (21-3x283-2). The 21-3x283-2 rats with
extra hb2m overexpression develop severe arthritis for reasons that remain unclear but remain free
from gastrointestinal disease [142]. This study did not completely resolve effects of HLA-B*27 from
those of hb2m on gut microbiota, although it suggested that HLA-B*27/hb2m co-expression had
different effects compared to HLA-B7/hb2m.
More recently, HLA-B*27/hb2m transgenic rats with 55 copies of HLA-B*27 and 66 copies of hb2m
(33-3 transgene locus) that develop gastrointestinal inflammation and arthritis, and epididymo-
orchitis in males, were used to probe early changes in microbiota in relation to immune activation
in the gut [143]. Immune activation and expansion of CD4þ Th17 T cells preceded microbial dysbiosis.
Microbial changes were first apparent at 8e10 weeks when histology scores were first elevated,
whereas CD4þ Th17 T cells were expanded in the cecum and colon as early as 6 weeks of age.
Expression of cytokines such as IL-1b and TNF was increased even earlier at 3 weeks of age, while
increases in IFNg and IL-17 became apparent at 6 weeks. Measurable differences in IL-23p19 were not
apparent until 8e10 weeks of age. This study suggests that HLA-B*27-induced immunological changes
occur before microbial dysbiosis [143]. However, the relative frequency of microbes was assessed
predominantly at the phylum level by quantitative PCR rather than unbiased 16S rRNA gene
sequencing, and thus, it is possible that subtle changes in microbiota could precede inflammation
[143,144].
We asked whether HLA-B*27/hb2m-induced microbial changes in the gut were consistent and
predictable on different genetic backgrounds or in different environments, anticipating that this might
reveal key organisms that drive gut inflammation in spondyloarthritis. Three different rat strains with
the same transgene locus (33-3) (Fischer [F344], Lewis and Dark Agouti [DA]) were compared. We were
surprised to find that HLA-B*27hb2m-induced dysbiosis was strikingly different on different back-
grounds/environments (Fig. 5) [144]. For example, changes in the relative frequency of microbes at the
species level in the inflamed cecum (mucosa and lumen) and colon (lumen) were largely nonover-
lapping in HLA-B*27/hb2m transgenic Lewis and Fischer rats, which have very different genetic
backgrounds and were housed in different facilities. In contrast to microbial changes, the cytokines and
immunological changes driving gut inflammation were largely the same, with overexpression of TNF,
IL-1a/IL-1b, IL-23, Th17 (IL-17A, IL-22), and Th1 (IFNg) cytokines. These findings implicate an ecological
model of dysbiosis induced by HLA-B*27 rather than selection for one or a small number of microbes
that may contribute to disease. This is important because comparing different rat strains and incor-
porating different environments into the study may better reflect inter-individual genetic and
environmental differences across the population. Current efforts are focused on determining whether
the dysbiotic microbiota found in Lewis and Fischer rats reflect common microbial functions.
Taken together, this model of experimental spondyloarthritis suggests that in rats, HLA-B*27 has an
early effect on the innate immune system with increased expression of innate cytokines, and subse-
quent accumulation of Th17 T cells in susceptible animals. Effects of HLA-B*27 on DC populations and
function may be a driving force in Th17 expansion and activation through sustained immune deviation
and increased IL-23 production. Given that microbes are critical to disease development in this model,
they must play an important role in developing and sustaining inflammation. This role is remains to be
determined but could include metabolites [145] or other bacterial products that affect the immune
system.
Fig. 5. The role of HLA-B*27 in gut microbial dysbiosis. Schematic diagram depicting differences in gut microbial dysbiosis in
different strains of HLA-B*27/hb2m transgenic rats. Dark agouti (DA) rats are resistant to the effects of HLA-B*27 expression and
exhibit normal cecum and colon histology scores, as well as minimal changes in gut microbes. By contrast, HLA-B*27 expression on
both Fischer and Lewis backgrounds results in gut inflammation and marked changes in gut microbes (dysbiosis). Disease is
accelerated in Fischer rats compared to Lewis. Despite similar immune/inflammatory gene expression signatures in the gut tissue
from Fischer and Lewis rats (upper right circle encompassing both rodent strains), dysbiotic organisms are largely nonoverlapping in
Fischer and Lewis (upper right starbursts with different colors). Reprinted from Colbert, RA, Arthritis & Rheumatology Clinical
Connections, John Wiley and Sons, Mar 29, 2018, with permission.
Summary
Defining the role or roles of HLA-B*27 in spondyloarthritis pathogenesis continues to be a challenge.

Animal models with and without HLA-B*27 expression have been informative but also have limita-
tions. HLA-B*27/hb2m transgenic rats provided the first direct evidence that gut microbiota and CD4þ T
lymphocytes rather than CD8þ CTLs were important for disease development, and then a critical link to
CD4þ Th17 T cell expansion and activation of the IL-23/IL-17 axis in gastrointestinal inflammation and
arthritis. IL-17 blockade is currently recognized as an important therapeutic tool in ankylosing spon-
dylitis. Novel entheseal-resident T cells in mice and type 3 innate lymphoid cells in humans may
provide clues to the unique spondyloarthritis phenotype and have shifted the focus from adaptive
immune targets in the joint. The role of additional hb2m expression in promoting axial disease in
HLA-B*27/hb2m transgenic rats is intriguing, but it remains unclear whether this effect is related to
HLA-B*27. Peptides that can bind to HLA-B*27 continue to be a focus of research, particularly given the
role of ERAP1 in modifying disease risk, but whether their role is to modify HLA-B*27 folding, assembly
and dimerization or as targets of the immune response requires further study.
Funding
This work was supported by the Intramural Research Program of the National Institute of Arthritis
and Musculoskeletal and Skin Diseases, Pediatric Translational Research Branch of the National
Institutes of Health (ZO1-AR041184).
Practice points
Testing for HLA-B*27 is neither necessary nor sufficient to diagnose ankylosing spondylitis
or other forms of spondyloarthritis.
HLA-B*27 testing is useful for classification of childhood arthritis [146], which is usually done
for research purposes.
HLA-B*27 testing is also used as an aid for classification of adult patients with possible axial
and peripheral spondyloarthritis [147].
Research agenda
Identify predominant cell types producing IL-23 in patients with spondyloarthritis.

Systematically analyze CD8þ and CD4þ T lymphocytes in patients with early disease.
Probe interactions between HLA-B*27 subtypes and TAPBPR and whether this is affected by
conformational flexibility.
Determine whether HLA-B*27 impacts cross presentation of antigen.
Determine how HLA-B*27 impacts dendritic cell function in animal models and humans.
Identify microbes, microbial communities, and microbial products that promote inflamma-
tion in spondyloarthritis.
Conflicts of interest
The authors have no conflict of interest to declare.
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HLA-B 27 in Spondyloarthritis

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Best Practice & Research Clinical Rheumatology 31 (2017) 797e815

Contents lists available at ScienceDirect

Best Practice & Research Clinical

The role of HLA-B*27 in spondyloarthritis

HLA class I structure and function

Allelic variation and peptide binding

HLA class I folding and assembly

Aberrant features of HLA-B*27 e misfolding and dimerization

Quality control mechanisms e ER-associated degradation and autophagy

HLA-B*27 and the pathogenesis of spondyloarthritis

Understanding the mechanism (or mechanisms) by which HLA-B*27 contributes to spondyloar-

Fig. 4. Forms of HLA-B*27 and potential mechanisms of pathogenesis.

Recognition of aberrant forms of HLA-B*27

HLA-B*27 misfolding and ER stress

maturation, ubiquitinated proteins aggregate in cytosolic structures (aggresome-like structures) to

HLA-B*27-expressing DCs have been implicated in the pathogenesis of spondyloarthritis in trans-

ERAP1 and the biology of HLA-B*27

HLA-B*27 and gut microbiota

Deﬁning the role or roles of HLA-B*27 in spondyloarthritis pathogenesis continues to be a challenge.

Identify predominant cell types producing IL-23 in patients with spondyloarthritis.

The authors have no conﬂict of interest to declare.

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