Hla B27

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The Annual Review of Immunology is online at ankylosing spondylitis, spondyloarthritis, arthritogenic peptide, antigen
immunol.annualreviews.org
presentation, homodimer
This articles doi:
10.1146/annurev-immunol-032414-112110 Abstract
Copyright c 2015 by Annual Reviews. Possession of the human leukocyte antigen (HLA) class I molecule B27 is
All rights reserved
strongly associated with ankylosing spondylitis (AS), but the pathogenic role
of HLA-B27 is unknown. Two broad theories most likely explain the role
of HLA-B27 in AS pathogenesis. The rst is based on the natural immuno-
logical function of HLA-B27 of presenting antigenic peptides to cytotoxic
T cells. Thus, HLA-B27-restricted immune responses to self-antigens, or
arthritogenic peptides, might drive immunopathology. B27 can also be-
have badly, misfolding during assembly and leading to endoplasmic retic-
ulum stress and autophagy responses. 2 m-free B27 heavy chain structures
including homodimers (B272 ) can also be expressed at the cell surface fol-
lowing endosomal recycling of cell surface heterotrimers. Cell surface free
heavy chains and B272 bind to innate immune receptors on T, NK, and
myeloid cells with proinammatory effects. This review describes the natu-
ral function of HLA-B27, its disease associations, and the current theories
as to its pathogenic role.
29
INTRODUCTION
Possession of HLA-B27 is very closely linked with the development of a group of common inam-
matory rheumatic diseases known as the spondyloarthritides (SpA), of which ankylosing spondylitis
(AS) is the prototype. Collectively, the SpA affect approximately 0.61% of the adult US popu-
lation. This review describes the natural function of HLA-B27, its disease associations, and the
current theories as to its pathogenic rolewhich despite intense investigation remains unknown.
The current theories are briey summarized in Figure 1.
THE NATURAL FUNCTIONS OF HLA-B27

Human leukocyte antigens (HLA), encoded on chromosome 6, make up the human major his-
tocompatibility complex (MHC) and are the most polymorphic proteins known. The classical
1 CD8+
TCR B27/2m/
peptide
complex
ER LUMEN
Misfolded
B27 2
Internalization
3
ER stress, UPR,
or autophagy
CD4+
KIR
Triggered
inflammation
Oxidizing
environment
Figure 1
Overview of hypotheses explaining pathogenic role of HLA-B27 in spondyloarthritis. Arthritogenic
peptide hypothesis: Self- and/or pathogen-derived peptides are selected and presented by properly folded
forms of HLA-B27 for recognition by the T cell receptor (TCR) of autoreactive CD8+ T cells. B27
misfolding hypothesis: Misfolding of B27 within the endoplasmic reticulum (ER) causes ER stress, unfolded
protein response (UPR), or autophagy, which has downstream effects on cellular function (for example,
resulting in IL-23 release) that are hypothesized to promote development of spondyloarthritides. Cell
surface B27 free heavy chain expression and immune recognition hypothesis: B27 free heavy chains
including dimers are expressed at the cell surface, where they are recognized by cells bearing killer
immunoglobulinlike receptors (KIR) and/or leukocyte immunoglobulinlike receptors to trigger
inammation.
30 Bowness
class 1 A, B, and C molecules are expressed on the cell surface of almost all nucleated cells. The
B27 allomorph is one of the most common B alleles in white populations. The principle natural
function of HLA-B27 is to present endogenous (i.e., intracellular) peptides to T lymphocytes,
predominantly to the T cell receptor for antigen (TCR) of cytotoxic T cells.
Peptide Presentation by HLA-B27 to CD8+ Cytotoxic T Cells

HLA-B27 heavy chains are synthesized in the endoplasmic reticulum (ER), where they form
part of a multiprotein complex known as the peptide-loading complex. Following the original
observation of MHC restriction by Zinkernagel & Doherty (1, 2), Townsend and McMichael,
studying recognition of inuenza-infected cells by cytotoxic T cells, showed rstly that the primary
antigenic target was the internal nucleoprotein (rather than the expected surface hemagglutinin)
and secondly that this target was a relatively short peptide (3). The denition of HLA-B27-
restricted epitopes from HIV (4) and inuenza (5) suggested common structural features but could
not distinguish between those required for B27 binding and those affecting T cell recognition.
Subsequently, Madden and colleagues solved the crystal structure of HLA-B27 (the second to be
determined, after that of HLA-A2) (6, 7). This structure, shown in Figure 2, includes a peptide-
binding groove with a B pocket (comprising residues different from those of HLA-A2) perfectly
orientated to bind the positively charged side chain of an arginine residue at the second position of
bound peptide (6, 7). B27 residues, including a glutamic acid residue at position 45 and a cysteine
at 67, contributed to the B pocket specicity. At the same time, peptide elution from a human B27
Peptide
1 domain
2 domain Cys67
2 microglobulin
3 domain
Position of cell membrane
Figure 2
Molecular structure of HLA-B27. See the Protein Data Bank (http://www.rcsb.org/pdb/explore.do?
structureId=1hsa) and References 6 and 7. 1, 2, and 3 domains of B27 are shown in ribbon format in
blue, and 2 m in green. Note that the structure does not include the transmembrane and intracellular
domains.
www.annualreviews.org HLA-B27 31
homozygous B lymphoblastoid cell line not only conrmed that all peptides carry an arginine at
the second residue from the N terminus, but also showed that many thousands of different peptides
are bound to the B27 molecules expressed at the cell surface, and that these are most commonly
derived from self-proteins, including HLA molecules (8). Identication of additional naturally
processed and presented viral epitopes (9) conrmed that immunodominant B27-binding epitopes
all possess arginine as their second residue. Subsequent studies using synthetic peptides have
shown that peptides with nonarginine P2 (including glutamine, methionine, and postsynthetically
modied residues; 10) are capable of binding to HLA-B27, but the physiological importance of
this observation is not known.
HLA-B27 heavy chains form heterotrimeric complexes with 2 m and intracellular peptides
within the ER, where they are part of a multimolecular peptide-loading complex that includes
calnexin, calreticulin, tapasin, and the thiol oxidoreductase ERp57. The pathways of antigen pro-
cessing are reviewed by Blum, Wearsch, and Cresswell (11). This complex facilitates correct MHC
folding, 2 m binding, and peptide loading. Tapasin is thought to play a key role in optimization
of the cargo of bound peptides, although HLA-B27 is less dependent on tapasin than other alleles
such as B 4402 (12). These heterotrimeric complexes (henceforth called HLA-B27) egress to the
cell surface, where they are recognized by CD8+ cytotoxic T lymphocytes (CTL).
HLA-B27-restricted CTL responses to viruses are often tightly focused, resulting in immun-
odominant responses to small numbers of epitopes. In HIV infection, viral mutation leading to
loss of CTL recognition is consistently associated with disease progression, providing strong evi-
dence for a key role of CTL in viral control (13). Epidemiological studies have also supported the
concept that HLA-B27 confers protection against viral infectionsindeed, it gives a prognostic
advantage following both HIV (14) and hepatitis C infection; in the latter case escape from CD8-
mediated CTL is limited by loss of viral tness and T cell cross-reactivity (15). Thus HLA-B27
may act as a double-edged sword, simultaneously enhancing antiviral immunity and predisposing
carriers to the development of SpA (16). It should be pointed out that such a property could result
either directly from its peptide-binding properties or indirectly from adjuvant-like effects detailed
below.
Over 100 subtypes of HLA-B27 are now recognized. They differ in primary amino acid se-
quence but share key structural, peptide-binding, and antigenic features. This is discussed below,
in the section HLA-B27 Subtypes and AS. The underlying (and unproven) assumption is that this
broad HLA polymorphism is driven by the need during infection for diversity in peptide binding
and presentation to T cells.
Peptide Presentation by HLA-B27 to NK Cells

NK cells use specic receptors for HLA recognition, such as the killer immunoglobulinlike re-
ceptors (KIR). Shortly after the discovery that the cognate KIR for B27 recognition is KIR3DL1
(17) came the appreciation that this recognition is sensitive to the nature of peptide bound to
the B27 molecule (18). These key functional studies were subsequently conrmed using pep-
tide substitutions guided by crystal structures. Thus, B27 complexed with the immunodominant
Epstein-Barr virus (EBV) epitope (EBNA3C 258-266 RRIYDLIEL) does not bind to KIR3DL1;
however, binding occurs if the P8 glutamate is changed to threonine (19). Rather than KIR3DL1
selectively or specically recognizing a given peptide, it is likely that KIR3DL1 recognition of
HLA-B27 will occur unless there is steric inhibition, with KIR3DL1 recognition of B27 exquisitely
sensitive to the nature of the P8 amino acid side chain. The leukocyte immunoglobulinlike re-
ceptors LILRB1 and LILRB2 both recognize HLA-B27/peptide complexes (20), but evidence for
peptide specicity has been conicting (21).
32 Bowness
Atypical Peptide Presentation by HLA-B27

There is evidence that HLA-B27 can interact in noncanonical ways with both peptide and T cells.
Thus, B27 is capable of binding peptides signicantly longer than the usual 912 amino acids.
These complexes are recognized by the MARB4 antibody (22), which also detects a population of
2 m-free, peptide-containing B27 complexes at the cell surface (23). Atypical peptide presentation
by HLA-B27 also occursthus, Boyle and colleagues (24) demonstrated that human CD4 T cells
can recognize HLA-B27. This was conrmed in a human TCRtransgenic HLA-B27-positive
murine model (25).
Another possibility is that the peptide-binding groove of B27 might accommodate a small
molecule (perhaps a gut microorganism metabolite) that consequently alters the B27 repertoire,
similar to the effect of the antiretroviral drug abacavir on HLA-B 5701 (26). This could then
result in neoimmune responses to novel antigens or a heightened multispecic immune response
akin to alloreactive immune responses.
Other Functions of HLA-B27 Heterotrimers and Free Heavy Chains

HLA molecules play a central role in thymic selection of the T cell repertoire, and therefore indi-
viduals carrying the HLA-B27 allotype will almost certainly harbor both potentially autoreactive
TCR specicities and gaps in their TCR repertoire, either or both of which could be important
in SpA pathogenesis.
HLA class molecules, and in particular 2 m-free heavy chains, are expressed on activated and
transformed lymphoblastoid cells (27). Furthermore, HLA class 1 heavy chains can also be secreted
extracellularly under these circumstances (28). These ndings suggest that changes in HLA heavy
chain expression may be indicative of cellular status or activationhowever, relatively little is
known of their sensing and downstream effects in cis or trans.
HLA class 1 molecules have also been shown to have a role in both neurodevelopment (29) and
mate selection (30). It is thus possible that HLA-B27 has a selective developmental or reproductive
advantage that maintains its prevalence in multiple human populations despite the almost certain
evolutionary disadvantages associated with increased SpA prevalence. Unexpectedly the prevalence
of HLA-B27 has been found to decrease with age, suggesting that possession of B27 effects a
survival disadvantage after middle age (31). This is an intriguing nding that requires replication
in different populations. Although no explanation for these ndings has been found, one testable
hypothesis is that B27-positive individuals have slightly higher levels of chronic inammation,
predisposing them to a variety of ischemic and neoplastic diseases.
It is likely that HLA-B27 might have interactions with gut microbiota. HLA-B27 might act as
a receptor for bacterial dissemination; alternatively, microorganisms or their metabolic products
might have effects on peptide binding (as described in the section Atypical Peptide Presentation by
HLA-B27). Another possibility is that HLA-B27 shapes the bacterial microbiome through effects
on gastrointestinal (type 17) immune responses and that this altered microbiome subsequently
drives SpA.
HLA-B27 AND SPONDYLOARTHRITIS

Possession of HLA-B27 is strongly associated with development of SpA. Collectively the SpA,
which are listed in Table 1, may affect approximately 0.61% of the adult US population (32).
AS is the prototypic and most common of the SpA, affecting approximately 0.3% of the adult
US population (32) and 0.4% of the adult French population (31). Notably, the prevalence is
Table 1 HLA-B27-associated spondyloarthritidesa

HLA-B27 approximate
Disease Clinical features frequency (%) Reference
Ankylosing spondylitis Inammation and new bone formation involving 94 (OR 171) 41
sacroiliac and spinal joints
Reactive arthritis Nonseptic large joint arthritis following certain 3075 38
gastrointestinal or genitourinary bacterial infections
Colitis-associated Sacroiliac, spinal, and large joint arthritis associated 3375 106
spondyloarthritis with Crohn disease and ulcerative colitis
Psoriatic spondyloarthritis Sacroiliac, spinal, and large joint arthritis associated 4050 106
with skin psoriasis
Juvenile enthesitis-related Large joint arthritis associated with enthesitis, 76 107
arthritis usually presenting in teenage boys
Acute anterior uveitis Acute sterile inammation of the anterior chamber of 50 40

the eye
Abbreviation: OR, odds ratio.

a
The spondyloarthritides comprise a group of diseases sharing key clinical features and an HLA-B27 association.
even higher in northern populations, and lower in Africa, roughly following the prevalence of
HLA-B27 (33). Although roughly 94% of AS patients are HLA-B27 positive and B27 is the most
important genetic factor, it still only contributes about 1/3 of the total heritability of AS (which
is remarkably high at approximately 90%). Over 40 other contributory genetic loci have been
identied in GWAS studies (34, 35). The second most important identied locus is ERAP1,
discussed below, and other peptidases (e.g., ERAP2 and LNPEPS) and genes involved in antigen
processing have also been identied (34, 35). Genes involved in type 17 immune responses (IL-23
receptor, STAT3, IL1RB), microbial sensing (GPR35), and development of innate lymphoid cells
(e.g., EOMES and RUNX3) have also been implicated (34, 35). Undoubtedly, many more genes
remain to be identied. These will almost certainly include noncoding RNAs and other epigenetic
factors, as well as rare variants. Their functions and interactions with HLA-B27 will all need to
be elucidated.
HLA-B27 Disease Associations

Caffrey & James (36) and Schlosstein and colleagues (37) independently described the association
of AS with the HLA allele A27, as it was then designated, in 1973. Disease association with reactive
arthritis was reported shortly afterward (38). The separation of the seronegative arthritides
from rheumatoid arthritis (usually but not invariably rheumatoid factor seropositive) had only
been made in the 1950s. Subsequently the appreciation that the spondyloarthritides (or spondy-
loarthropathies) are a group of diseases sharing key clinical features and genetic factors (primarily
but not only HLA-B27) has proved useful in developing our understanding of pathogenesis and
treatment. Thus, for example, not only do at least 25% of patients with AS develop anterior uveitis
(inammation of the anterior chamber of the eye) over their lifetime (39), but this condition can
occur without concomitant AS and as such is still associated with B27 (40). The different SpA, to-
gether with their HLA-B27 associations, are briey described in Table 1. AS is the most common
among the SpA and is the most strongly associated with B27. In the United Kingdom, over 90%
of white AS patients are HLA-B27 positive, with an odds ratio of 171 (41). The prevalence of AS
34 Bowness
Table 2 HLA-B27 subtypes in different populations and their disease associations

National/racial group HLA-B27 subtypea,b Reference(s)
White European/American (US) B 2705 B 2702 42
China (Han) B 2705 B 2704 43
India B 2706c 44, 108
B 2704 B 2705 B 2707
Thailand B 2706 B 2707 B 2704 44
West Africa (Gambia) B 2703 B 2705 109
Sardinia B 2705 B 2709d 45
B 2707 B 2702 B 2713
a
The most abundant subtype is shown rst.
b
Disease-associated subtypes are in boldface.
c
B 2706 is not disease associated and is likely protective.

d
B 2709 may be protective or neutral.
in different populations broadly reects the prevalence of HLA-B27. Thus, in the United
Kingdom approximately 9% of the population is HLA-B27 positive, and 0.23% of the popu-
lation has AS (33, 41). In northern Scandinavian and northern Native American and Canadian
populations both the prevalence of B27 and the prevalence of SpA are higher, whereas in
sub-Saharan Africa both B27 and AS are rare. The inuence of different HLA-B27 subtypes is
discussed in the following section.
HLA-B27 Subtypes and AS

Over 100 subtypes of HLA-B27 are currently recognized and are designated HLA-B 2701 to
HLA-B 27106, as dened by their DNA sequence. B 2705, by far the most common subtype in
white populations, is thought to be the ancestral subtype. All B27 subtypes share common amino
acid residues within the B pocket (including E45 and C67) and a very strong preference for arginine
at the second position of bound peptide. The relative prevalence of the different common B27
subtypes is summarized in Table 2 and is reviewed by Kahn (42). The common subtypes in white
European populations are B 2705 and B 2702. In Thai and Indonesian populations B 2704 and
B 2706 predominate. B 2704 is denitely associated with AS (43), but B 2706 is weakly or not
associated (44). B 2709, a rare subtype found almost exclusively in people of Sardinian descent,
has been reported to be weakly or not associated with AS (45), although given that it is found on
an extended haplotype on chromosome 6, which contains alleles of many other immunologically
important genes, linkage to protective alleles cannot be completely discounted. Notably, B 2709
has been found in patients with AS, although even here the carriage of this allele on the second
haplotype (i.e., the allotype is a passenger rather than a disease driver) cannot, of course, be
excluded.
B 2706, which is protective or not associated with AS, differs from the strongly disease-
associated B 2704 only at positions 114 and 116 and from B 2705 at a single additional residue,
152. B 2709 differs from B 2705 only at a single residue, position 116, although this appears
to be sufcient to subtly alter the repertoire of peptides bound (46; see section Presentation of
Arthritogenic Peptides). Positions 114 and 116 lie at the base of the peptide-binding groove and
contribute to the F pocket. These amino acid substitutions have been shown to inuence the
nature of the amino acid side chain at the C terminus, although the overall peptide repertoires
show considerable overlap (47). Interestingly the aspartic acid residue at P116 of B 2705 has been
shown to variably form a salt bridge with the P5 residue of bound peptide, with B 2705 capable
of binding a single peptide in two conformations (48).
HLA-B27 PATHOGENIC MECHANISMS

The mechanism by which HLA-B27 causes disease is not known. Here the three currently most
favored hypotheses will be discussed in detail, together with the role of the aminopeptidase ERAP1,
which is coimplicated in pathogenesis by genetic studies. HLA-B27 may present arthritogenic
peptides to CD8 T cells, but B27 can also adopt aberrant forms both in the ER and at the cell
surface, both of which can stimulate inammation.
Presentation of Arthritogenic Peptides

Following the discovery that the immunological function of MHC class I molecules is to
bind peptides derived from intracellular proteins (described in section Peptide Presentation by
HLA-B27 to CD8+ Cytotoxic T Cells), Parham and Benjamin proposed that spondyloarthritis
might be caused by HLA-B27 binding a peptide derived from a microorganism and eliciting a
CD8 T cell response cross-reactive with a B27/self-peptide combination (49). They further showed
that HLA-B27 is capable of binding peptides at the cell surface (50). This process we now fre-
quently call molecular mimicry, although, somewhat confusingly, the term molecular mimicry
was previously coined in the context of B27 to describe a process whereby a pathogenic factor
modied B27 to make it antigenic and to generate an autoantibody response.
A number of lines of evidence, summarized in Table 3, support the arthritogenic peptide
hypothesis. Firstly, HLA-B27-restricted CD8 T cell responses specic for Salmonella or Chlamydia
have been identied in patients developing reactive arthritis following these infectious triggers (51,
52). The latter were detected in the affected joints using tetrameric HLA-B27/peptide complexes
but at low frequency (52). In patients with SpA, Fiorillo and colleagues (53) identied cross-reactive
CD8 T cell responses that recognized both an epitope from EBV and a self-peptide derived from
the vasoactive intestinal protein receptor VIPR. However, it should be pointed out that EBV is
not recognized as a trigger for SpA, and so the implications of this nding are uncertain. Thus,
although cross-reactive and potentially arthritogenic CD8 responses undoubtedly occur, those
identied are not consistently or temporally related to disease. Nevertheless it is entirely plausible
that T cell responses to as yet undened antigens play a signicant role in SpA pathogenesis,
particularly given that in these diseases (unlike, for example, autoimmune thyroid disease) there is
not a readily apparent autoantigenic target tissue. Indeed oligoclonal T cell expansions have been
detected in the joints of SpA patients (5456). Determining the specicity of these responses will
be important, given that an autoantigen has not been clearly identied in SpA. New technologies to
determine T cell specicities in an unbiased manner will likely assist in this search. One intriguing
possibility is that B27-restricted responses may be driven by intestinal microora.
The differential association of different HLA-B27 subtypes, which differ only in residues of their
peptide-binding groove, broadly supports arthritogenic peptide mechanisms of disease causation.
The non-disease-associated HLA-B 2709 subtype differs from HLA-B 2705 only at position 116,
where it carries histidine as opposed to aspartic acid (45). This residue in the oor of the peptide-
binding groove contributes to the F pocket, and this change appears to be sufcient to subtly
alter the repertoire of bound peptides (46). Thus, peptides eluted from HLA-B 2709 generally
contained hydrophobic C termini and did not accommodate tyrosine at this position (46).
The strong genetic association of AS with endoplasmic reticulum aminopeptidase 1 (ERAP1),
which is found only in HLA-B27-positive individuals (34), strongly suggests that ERAP1 most
36 Bowness
Table 3 Theories explaining pathogenic role of HLA-B27 in AS

Theory Supportive evidence Contrary evidence
Arthritogenic peptide Unique B27 peptide specicity CD8/ or depleted B27-transgenic rats still
HLA-B27-restricted CD8 immune responses to develop disease (57, 58)
bacteria known to trigger ReA (51, 52) No clear peptide identied
ERAP1 and (amino-) peptidase disease Different B27 subtypes bind overlapping
associations (34, 35). repertoires of peptides (47)
B27 subtypes bind peptides with differing
C-terminal residues (46)
Self-reactive CD4 T cells present in AS (53)
Expanded T cell clones detected in reactive
arthritis and AS patients (54, 56)
ER stress IL-23 sufcient to cause enthesitis in mice (59) Excess 2 m relieves colitis but not arthritis in
Chlamydia and other intracellular bacteria can B27-transgenic rats (70).
trigger ER stress and IL-23 production (67) No ER stress seen in gut of AS patients (72)
No ER stress seen in AS-associated ERAP1 alleles
(103)
Cell surface free heavy Cell surface B27 FHC are expressed in SpA No direct evidence of pathogenicity in humans
chain including (75, 84) No evidence of allelic variation in KIR3DL2
homodimer recognition B27 FHC are strong ligands for KIR3DL2 (78) contributing to AS susceptibility
and LILR (77)
Increased numbers of NK and T cells express
KIR3DL2 in SpA (79)
Amelioration of disease in B27-transgenic murine
model with HC10 antibody treatment (90)
Microbial dysbiosis Evidence of local gut inammation in >50% of No evidence of B27 role or association
(increased gut AS patients (85) AS does not share autophagy-related genetic
inammation) Shared genetic associations with inammatory associations with Crohn disease
bowel disease
Altered cecal microbiome in B27-transgenic
Lewis rats (86)
Abbreviations: AS, ankylosing spondylitis; ER, endoplasmic reticulum; FHC, free heavy chains; KIR, killer immunoglobulinlike receptors; LILR,
leukocyte immunoglobulin-like receptors; ReA, reactive arthritis; SpA, spondyloarthritides.
likely acts directly on the function of HLA-B27 within the antigen-processing and presentation
pathway. This is discussed in detail in the section Interaction of HLA-B27 with ERAP1 and
Other Peptidases in AS Pathologies. Although at rst sight this association would seem to favor
the arthritogenic peptide hypothesis, it would also be compatible with the intracellular misfolding
and cell surface free heavy chain hypotheses discussed in the following two sections.
In addition to the difculty of demonstrating pathogenic CTL responses to arthritogenic
peptides, studies using animal models have generally not supported this model. Thus, CD8
T cells do not appear to be required for disease in HLA-B27 transgenic rat models. This has
been demonstrated by both antibody-mediated depletion (57) and CD8 knockout (58).
Recently Sherlock and colleagues (59) elegantly demonstrated that IL-23 (expressed using
minicircle technology) alone is sufcient to drive murine SpA-like disease by acting on entheseal-
resident CD3+ CD4 CD8 ROR-t-expressing T cells. These data would suggest that B27 need
only act at the site of IL-23 production to have its pathogenic effect and would argue against an
arthritogenic peptide model. They also highlight the importance of inammation of the enthesis
(the anatomical site where ligament or tendon attaches to bone, for example, where the Achilles
tendon is inserted into the heel) in SpA. The immunology of this organ complex has been little
studied; further investigation is required, particularly in humans.
HLA-B27, the Unfolded Protein Response and the Endoplasmic

Reticulum Stress Response
Shortly after demonstration in 1999 of the ability of HLA-B27 to form homodimers (60), Mear
and colleagues (61) demonstrated that HLA-B27 misfolds in the ER (with subsequent cytoso-
lic degradation). This misfolding phenotype could be corrected by replacing key B27 B pocket
residues with those from HLA-A2i.e., H9F (F for H at position 9), T24A, E45M, I66K, C67V,
and H70K. Notably the ability to form homodimers is not unique to HLA-B27. Homodimeriza-
tion can be induced in other class 1 molecules by slowing the rate of egress from the ER (e.g., by
culture at 26 C) and can be mediated by cysteines other than Cys67, including Cys164 (62).
HLA-B27 transgenic rat bone marrowderived macrophages (but not splenocytes) show ev-
idence of HLA-B27 misfolding after cytokine stimulation, and this correlates with augmented
production of IL-23 (63, 64). HLA-B27 transgenic rats exhibit functional alterations in a number
of cell populations, which might correlate with misfolding. Both defects in dendritic cell popula-
tions and function (65) and enhanced ability to form osteoclasts have been described (66).
Appreciation of the molecular mechanisms underlying these changes has come from discovery
that activation of the ER-stress-induced transcription factor C/EBP homologous protein (CHOP)
can lead to IL-23 expression in dendritic cells (67). Interestingly, enhanced Salmonella replication
has been described within HLA-B27-transfected U937 monocytic cells, possibly mediated through
effects of B27 heavy chains on the RNA-stabilizing protein Human antigen R (68).
Although these data (reviewed by Colbert and colleagues, 69), demonstrate that HLA-B27 is
capable of driving an inammatory ER stress response, alternate lines of evidence have argued
against this mechanism as an important pathological mechanism in driving spondyloarthritis.
Thus, in the B27 transgenic rat model, introduction of additional copies of the human 2 m gene
reduced B27 misfolding (and colitis) while increasing the incidence and severity of arthritis (70).
Studies of tissue from AS patients have not convincingly shown evidence for UPR or ER stress
in association with inammation (71, 72), with the exception of one study showing upregulation
of GRP78 in the peripheral joints of AS patients (73). Interestingly, the study of Ciccia and
colleagues (72) provided evidence implicating autophagy, but not UPR, in the gastrointestinal
tract of AS patients. They studied intestinal biopsies from patients with AS and saw upregulation
of autophagy-associated factors LC3II, ATG5, and ATG12 by immunohistochemistry and gene
expression. They also found that autophagy but not UPR was necessary for enhanced IL-23
expression by gut-derived AS mononuclear cells (72).
Thus, B27 is capable of ER misfolding and stimulation of ER stress and unfolded protein
responses in vitro and in animal models. However at the current time there is relatively little
direct evidence of this in human spondyloarthritis. Further investigation of the interaction of
HLA-B27 with the autophagy pathway is clearly also warranted.
Cell Surface Expression of Free Heavy Chain Forms of HLA-B27

Heavy Chain, Including Homodimers, and Their Recognition
by NK Family Immunoreceptors
The ability of HLA-B27 to form 2 m-free, Cys67-mediated disulde-bonded homodimers (B272 )
was rst observed when refolding recombinant HLA-B27 in vitro (60). Several forms of B27 free
38 Bowness
T cell expressing KIR3DL2 Inhibition of

T
T activation-induced
cell death
T T b
KIR3DL2
Stimulus Proinflammatory
a cytokine production
Induction of B27 IL-17 HLA-B27

homodimer expression
B27+APC
APC
B27 homodimer
Chronic inflammation
c
TCR
CD8 T
CD8 T
Figure 3
Model for cell surface HLA-B27 free heavy chain induction and proinammatory effects. (a) Initiating stimulus (such as gut
microorganisms or cellular stress) induces expression of cell surface B27 heavy chain forms on an APC, which drives (b) CD4 T cell
proliferation and IL-17 cytokine production through interaction with KIR3DL2. (c) Inammation may be further promoted by
activation of CD8 T cells and/or unfolded protein responses (not shown). Abbreviations: APC, antigen-presenting cell; KIR3DL2,
killer cell immunoglobulinlike receptor 3DL2; TCR, T cell receptor for antigen.
heavy chain (FHC), including B272 , are also expressed at the cell surface following endosomal
recycling of heterotrimers (74). The ability of B27 to form disulde bonds through its unpaired
cysteine at position 67 is both highly unusual for HLA class 1 molecules and important for cell
surface homodimer expression (74), although B27 as well as other HLA allotypes have been shown
to be capable of homodimerization under appropriate conditions, with roles for other cysteine
residues demonstrated (62). Cell surface B272 and FHC bind to innate immune receptors on T,
NK, and myeloid cells. These include the killer immunoglobulin receptors KIR3DL1, KIR3DL2,
and LILIRB2 in humans (75) and the rodent paired immunoglobulin receptors (PIR) (76). The
binding specicity of B272 and B27 FHC for these receptors is different from that of heterotrimeric
HLA-B27 complexes, which while binding KIR3DL1 and LILRB2 are also ligands for LILRB1
but do not bind KIR3DL2 with signicant afnity. Furthermore, B272 and FHC bind with higher
afnity/avidity than other ligands to both LILRB2 (77) and KIR3DL2 (78). The KIR3DL2/B27
interaction can have proinammatory effects on both NK (79) and T cells (78) and is associated
with a Th17 phenotype in AS (80). This model is shown in Figure 3.
Although these observations have led us to propose that cell surface B272 contributes to the
pathogenesis of AS/SpA, there was until recently little direct evidence in human disease, in part
because of the lack of reagents specic for B272 . Increased HLA class 1 heavy chain expression
on peripheral blood monocytes of AS patients had been demonstrated using the HC10 antibody
(81, 82). HC10 binds B272 and FHC but also recognizes other B27 heavy chain structures and
binds to other HLA-B, -C and some -A allele heavy chains (83). Using a phage display library,
novel antibodies with specicity for B27 heavy chains including B272 have been generated (84;
O. Marroquin, C. Renner, P. Bowness, unpublished data). One of these, HD6, binds to recom-
binant B272 complexes but not to HLA-B27 heterotrimers or HLA-A2, HLA-A3, HLA-A24, or
HLA-B7 complexes (84). HD6 also stains some but not all HLA-B27-transfected B lymphoblas-
toid cell lines, including the LBL721.220B27, LBL721.221B27, and C1RB27 lines. The binding
pattern to recombinant and cell-expressed molecules is thus different from that seen with HC10.
HD6 expression is signicantly higher on monocytes from AS patients than on monocytes from
B27+ or B27 healthy control individuals (84). Lastly, HD6 also inhibits binding of recombinant
and cell-expressed B272 to immunoreceptors, raising the possibility of future therapeutic use (84).
Nevertheless a number of questions regarding the homodimer hypothesis of B27 pathogenesis
remain unanswered. What are the cellular requirements for B272 formation? Does B272 formation
in patients with AS correlate with disease activity and/or tissue specicity? Does blockade of B27
FHC interaction with immunoreceptors ameliorate disease in B27 transgenic animals? Addressing
these questions will determine the validity of the B27 FHC hypothesis of SpA pathogenesis.
Other Theories of HLA-B27 Pathogenesis

Microbial dysbiosis and increased gut inflammation. Studies from several groups have demon-
strated subclinical gastrointestinal inammation, both acute and chronic, in approximately half of
AS patients (85). This is in addition to the well-recognized co-occurrence of AS and Crohn disease
and ulcerative colitis. Although I favor the concept that other genetic (and environmental) factors
predispose individuals to gastrointestinal inammation in combination with AS, it remains a clear
and testable possibility that the presence of HLA-B27 does itself alter the gut microbiome or local
inammatory response. This is strongly supported by recent data from HLA-B27-transgenic rats
(86). It is noteworthy that from the available GWAS data (which are less comprehensive in AS
than inammatory bowel disease), AS does not share autophagy-related genetic associations (e.g.,
ATG6) with Crohn disease.
Thymic selection. Alternatively, HLA-B27 may act during T cell development in the thymus
to facilitate generation of a proarthritic T cell repertoire (this is assumed in the arthritogenic
peptide model). It is also possible that HLA-B27 itself presents a portion of its own structure to
the immune system (87) or acts as a receptor for a pathogen that triggers disease. Because of the
tight linkage disequilibrium within the MHC region of chromosome 6, it has been suggested that
B27 is a marker of a distinct but genetically linked pathogenic gene. However, this possibility is
now almost certainly excluded by the latest GWAS data (together with the transgenic rat data).
Amyloid generation. It has been proposed that HLA-B27 complexes might be predisposed to
shed 2 m in certain anatomical sites, which might then go on to form amyloid deposits (88).
Lessons from HLA-B27 Transgenic Mice and Rats

HLA-B27 transgenic mice remain healthy and are able to use HLA-B27 as a restriction element
to generate immune responses (25, 89). However, an SpA-like disease was reported to occur in
HLA-B27 transgenic mice when murine 2 m was replaced with human 2 m, and this disease
can be ameliorated by treatment with the heavy-chain-specic antibody HC10 (90), arguing for a
direct role of cell surface B27 heavy chains in disease pathogenesis. It should be pointed out that
SpA-like disease has subsequently been reported in mice lacking murine 2 m in the absence of
B27 (91). These data both raise the possibility that murine free heavy chains are also pathogenic
and emphasize the complex effects of background strain on disease expression. Indeed, further
reevaluation with attention to the gut microbiome may now be required in light of the nding
that B27 can have effects on the rat gut microbiome (86).
40 Bowness
HLA-B27 transgenic rats have proved to be a valuable model of B27-associated disease. Male
Lewis rats with multiple copies of HLA-B27 (and human 2 m) develop an SpA-like disease with
arthritis (including tail inammation), psoriasis, gut inammation, and orchitis (testicular inam-
mation) (92). Expression of HLA-B27 in bone marrowderived cells is sufcient to cause disease
(93). HLA-B27 misfolding and the unfolded protein response have been demonstrated and can
increase IL-23 production (64). However, introduction of additional human 2 m reduces both
UPR and arthritis, arguing against misfolding of B27 as a primary pathogenic event (70). A
minigene construct that introduced a B27-binding peptide epitope, the inuenza nucleoprotein
NP383-391 (SRYWAIRTR), into the ER also reduced the prevalence of arthritis (94). This may
have been due to displacement of lower-afnity arthritogenic peptides, or to effects on B27 fold-
ing or cell surface heavy chain expression (which was not examined). Disease causation through
presentation of arthritogenic peptide(s) to CTLs is perhaps less likely given the nding that CD8
depletion or knockout does not ameliorate disease (58). I would interpret the B27TG animal data,
whilst complex and inconclusive, to be most compatible with a role for cell surface B27 FHC in
disease pathogenesis, perhaps through interaction with rodent PIR expressed on immune cells.
The latter has, however, not been addressed experimentally. Nevertheless, it is clear that the
effects of HLA-B27 are protean, with abnormalities in dendritic cell populations (65) and osteo-
clasts also described in B27TG rats (66). Lastly, differences in the cecal microbiome of Lewis rats
transgenic for HLA-B27 and human 2 m (including increases in Prevotella spp. and reductions in
Rikenellaceae) have recently been described, supporting the hypothesis that HLA-B27 has direct
or indirect effects on the gut microbiome (86).
Interaction of HLA-B27 with ERAP1 and Other Peptidases in AS Pathogenesis

The genetic associations with AS of three ER aminopeptidases, ERAP1 (34), ERAP2, and LNPEP,
and with the cytoplasmic zinc aminopeptidase NPEPPS (35), have refocused attention on the
central role of HLA-B27 and peptide binding in disease pathogenesis. Of particular note, the
ERAP1 associationwhich is the second strongest, after HLA-B27, and contributes approximately
15% of the population attributable riskis only found in B27-positive AS patients (34). A similar
epistatic interaction with ERAP1 has also been described in psoriasis for HLA Cw3 (95), and for
Behcet disease and HLA-B 51 (96), suggesting the possibility of similar HLA-driven pathogenic
mechanisms operating in these diseases, even if precise ERAP1 allelic associations may differ in
different conditions.
There remains some uncertainty about the exact genetic mechanism operating in the ERAP1
region to cause AS, in part because of the presence of multiple single nucleotide polymorphisms
(SNPs) in linkage disequilibrium. However, it is clear that the SNPs at rs30187 alter disease
risk and are associated with a coding amino acid substitution at position 528 (34). The disease-
associated variant at this position (Lys528) is more active enzymatically than the protective allele
carrying an arginine at position 528 (97). Notably, AS patients may also have quantitatively more
ERAP1 (98), and an additional effect on gene expression levels seems likely. ERAP2 has been
studied less than ERAP1. The disease association does not appear to be conned to HLA-B27-
positive AS cases; and the disease-protective SNP appears to be associated with loss of function
(34, 35). How do HLA-B27 and ERAP1 interact to cause AS? The only conrmed function of
ERAP1 is to trim peptides for binding to HLA class 1 molecules. ERAP1 acts as a molecular ruler
to trim the N terminus of peptides within the ER (99). ERAP1 allelic variants may thus play a key
role in AS pathogenesiseither directly, through alteration of the repertoire of peptides bound to
HLA-B27 (100), or indirectly, from the generation of abnormal intracellular or extracellular forms
of HLA-B27, due to altered (peptide-mediated) stability or trafcking. Altered MHC stability and
immunogenicity have been demonstrated in ERAAP-decient murine cells (101).
The crystal structure of ERAP1 has recently been solved, in both open and closed
conformationsthe latter with the protease inhibitor ubenimex in the active site (97). ERAP1
has a nonredundant role in shaping the repertoire of peptides bound to HLA-B27 (102), and the
AS-protective K528R allele has reduced function in trimming extended peptides containing known
HLA-B27 epitopes (97). ERAP1 polymorphisms may alter the repertoire of peptides loaded onto
HLA-B27 and modulate subsequent immune recognition of bound peptides by CTLs and/or NK
cells. Alternatively, ERAP1 polymorphisms might promote AS by affecting either ER misfolding
or the export of proinammatory B27 forms to the cell surface. Several questions arise and are
under active investigation. First, it is not entirely clear that HLA-B27 misfolding increases in the
presence of disease-associated ERAP1 variants (and decreases with ERAP1-protective variants);
a recent study argues against such a mechanism (103). Second, are more surface HLA-B27 heavy
chains expressed in the presence of disease-associated ERAP1 variants, as suggested by Haroon

and colleagues (104)? Finally, it is not known whether ERAP1 interacts directly with HLA-B27
and/or the peptide-loading complex or whether this is altered for ERAP1 variants. None of these
studies has yet been carried out in the context of ERAP2, LNPEP, or the cytoplasmic peptidase
NPEPPS, although all might be expected to have effects on the peptide repertoire available to
bind HLA-B27.
Although incomplete, these data provide strong support for a key role of antigen presentation
and peptide generation in AS pathogenesis, conceptually placing HLA-B27 at the very center.
They also suggest that inhibition of ERAP1 might be a valid therapeutic strategy for treatment of
AS and SpA. Indeed ERAP1 inhibitors are already in preclinical development (105).
SUMMARY
AS is a largely inherited disease, almost certainly with a ubiquitous environmental trigger. Many
genes contribute to AS pathogenesis, with HLA-B27 by far the most important. HLA-B27 may
cause AS by presenting arthritogenic peptides to cytotoxic T cells (or to NK cells through peptide-
sensitive NK receptor recognition). B27 may behave badly to misfold within the ER and trigger
stress or autophagy responses. Alternatively, B27 may cause pathology through cell surface expres-
sion of aberrant FHC forms. The latter forms of HLA-B27 have been shown capable of driving
proinammatory Type 17 responses through interaction with KIR receptors expressed on T and
NK cells.
SUMMARY POINTS
1. HLA-B27 is the strongest risk factor for development of AS, which is a largely inherited
disease.
2. HLA-B27 is an HLA class 1 molecule that efciently binds and presents immunodomi-
nant peptide epitopes to cytotoxic T cells in several important viral infections, including
inuenza, HIV, EBV, and hepatitis C.
3. HLA-B27 may cause AS by presenting arthritogenic peptides to cytotoxic T cells.
4. B27 misfolds within the ER and is capable of triggering stress and autophagy responses.
The former can result in IL-23 production.
42 Bowness
5. Aberrant FHC forms of HLA-B27, including homodimers, are expressed at the cell
surface in cell lines and AS patient monocytes.
6. FHC forms of HLA-B27 bind KIR receptors expressed on T and NK cells and LILR
receptors on myeloid cells.
7. Interaction of HLA-B27 FHC forms with KIR3DL2-expressing T cells can drive type
17 immune responses.
FUTURE ISSUES
1. Are HLA-B27-restricted T cells with novel specicity present in the joints of
SpA patients?
2. Does HLA-B27 misfolding increase in the presence of disease-associated ERAP1

variants?
3. Are more surface HLA-B27 heavy chains expressed in the presence of disease-associated
ERAP1 variants?
4. Does blockade of B27 FHC interaction with immunoreceptors ameliorate disease in B27
transgenic models of disease?
5. What, if any, are the effects of HLA-B27 on the gut microbiome or local inammatory
response?
6. What are the roles of ERAP2, LNPEP, and the cytoplasmic peptidase NPEPPS in
disease?
DISCLOSURE STATEMENT
The author is not aware of any afliations, memberships, funding, or nancial holdings that might
be perceived as affecting the objectivity of this review.
LITERATURE CITED
1. Zinkernagel RM, Doherty PC. 1973. Cytotoxic thymus-derived lymphocytes in cerebrospinal uid of
mice with lymphocytic choriomeningitis. J. Exp. Med. 138(5):126669
2. Zinkernagel RM, Doherty PC. 1974. Restriction of in vitro T cellmediated cytotoxicity in lymphocytic
choriomeningitis within a syngeneic or semiallogeneic system. Nature 248(5450):7012
3. Townsend AR, Rothbard J, Gotch FM, Bahadur G, Wraith D, McMichael AJ. 1986. The epitopes of
inuenza nucleoprotein recognized by cytotoxic T lymphocytes can be dened with short synthetic
peptides. Cell 44(6):95968
4. Nixon DF, Townsend AR, Elvin JG, Rizza CR, Gallwey J, McMichael AJ. 1988. HIV-1 gag-specic
cytotoxic T lymphocytes dened with recombinant vaccinia virus and synthetic peptides. Nature
336(6198):48487
5. Huet S, Nixon DF, Rothbard JB, Townsend A, Ellis SA, McMichael AJ. 1990. Structural homologies
between two HLA B27restricted peptides suggest residues important for interaction with HLA B27.
Int. Immunol. 2(4):31116
6. Madden DR, Gorga JC, Strominger JL, Wiley DC. 1991. The structure of HLA-B27 reveals nonamer
self-peptides bound in an extended conformation. Nature 353(6342):32125
7. Madden DR, Gorga JC, Strominger JL, Wiley DC. 1992. The three-dimensional structure of HLA-B27
at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell 70(6):103548
8. Jardetzky TS, Lane WS, Robinson RA, Madden DR, Wiley DC. 1991. Identication of self peptides
bound to puried HLA-B27. Nature 353(6342):32629
9. Brooks JM, Murray RJ, Thomas WA, Kurilla MG, Rickinson AB. 1993. Different HLA-B27 subtypes
present the same immunodominant Epstein-Barr virus peptide. J. Exp. Med. 178(3):87987
10. Raghavan M, Lebron JA, Johnson JL, Bjorkman PJ. 1996. Extended repertoire of permissible peptide
ligands for HLA-B 2702. Protein Sci. 5(10):208088
11. Blum JS, Wearsch PA, Cresswell P. 2013. Pathways of antigen processing. Annu. Rev. Immunol. 31:443
73
12. Peh CA, Burrows SR, Barnden M, Khanna R, Cresswell P, et al. 1998. HLA-B27-restricted antigen
presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide
loading. Immunity 8(5):53142
13. Goulder PJ, Phillips RE, Colbert RA, McAdam S, Ogg G, et al. 1997. Late escape from an immunodom-
inant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3(2):21217
14. den Uyl D, van der Horst-Bruinsma IE, van Agtmael M. 2004. Progression of HIV to AIDS: a protective
role for HLA-B27? AIDS Rev. 6(2):8996
15. Dazert E, Neumann-Haefelin C, Bressanelli S, Fitzmaurice K, Kort J, et al. 2009. Loss of viral tness
and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human
immune response. J. Clin. Investig. 119(2):37686
16. Bowness P. 2002. HLA B27 in health and disease: a double-edged sword? Rheumatology 41(8):85768
17. Peruzzi M, Wagtmann N, Long EO. 1996. A p70 killer cell inhibitory receptor specic for several
HLA-B allotypes discriminates among peptides bound to HLA-B 2705. J. Exp. Med. 184(4):158590
18. Malnati MS, Peruzzi M, Parker KC, Biddison WE, Ciccone E, et al. 1995. Peptide specicity in the
recognition of MHC class I by natural killer cell clones. Science 267(5200):101618
19. Stewart-Jones GBE, di Gleria K, Kollnberger S, McMichael AJ, Jones EY, Bowness P. 2005. Crystal
structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA-
B 2705. Eur. J. Immunol. 35(2):34151
20. Colonna M, Samaridis J, Cella M, Angman L, Allen RL, et al. 1998. Cutting edge: Human myelomono-
cytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J. Immunol.
160(7):3096100
21. Bashirova AA, Martin-Gayo E, Jones DC, Qi Y, Apps R, et al. 2014. LILRB2 interaction with HLA class
I correlates with control of HIV-1 infection. PLOS Genet. 10(3):e1004196
22. Urban RG, Chicz RM, Lane WS, Strominger JL, Rehm A, et al. 1994. A subset of HLA-B27 molecules
contains peptides much longer than nonamers. PNAS 91(4):153438
23. Malik P, Klimovitsky P, Deng L-W, Boyson JE, Strominger JL. 2002. Uniquely conformed peptide-
containing 2 -microglobulin-free heavy chains of HLA-B2705 on the cell surface. J. Immunol. Baltim.
Md 1950 169(8):437987
24. Boyle LH, Goodall JC, Opat SS, Gaston JS. 2001. The recognition of HLA-B27 by human CD4+ T
lymphocytes. J. Immunol. 1950 167(5):261924
25. Roddis M, Carter RW, Sun M-Y, Weissensteiner T, McMichael AJ, et al. 2004. Fully functional HLA
B27-restricted CD4+ as well as CD8+ T cell responses in TCR transgenic mice. J. Immunol. 1950
172(1):15561
26. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, et al. 2012. Immune self-reactivity triggered by
drug-modied HLA-peptide repertoire. Nature 486(7404):55458
27. Schnabl E, Stockinger H, Majdic O, Gaugitsch H, Lindley IJ, et al. 1990. Activated human T lymphocytes
express MHC class I heavy chains not associated with 2 -microglobulin. J. Exp. Med. 171(5):143142
28. Pickl WF, Majdic O, Fae I, Reuschel R, Holter W, Knapp W. 1993. The soluble pool of beta 2
microglobulin free HLA class I alpha-chains: qualitative and quantitative characterization. J. Immunol.
151(5):261322
29. Lee H, Brott BK, Kirkby LA, Adelson JD, Cheng S, et al. 2014. Synapse elimination and learning rules
co-regulated by MHC class I H2-Db . Nature 509(7499):195200
44 Bowness
30. Winternitz JC, Minchey SG, Garamszegi LZ, Huang S, Stephens PR, Altizer S. 2013. Sexual selection
explains more functional variation in the mammalian major histocompatibility complex than parasitism.
Proc. R. Soc. B 280(1769):20131605
31. Costantino F, Talpin A, Said-Nahal R, Goldberg M, Henny J, et al. 2013. Prevalence of spondyloarthritis
in reference to HLA-B27 in the French population: results of the GAZEL cohort. Ann. Rheum. Dis. In
press. doi: 10.1136/annrheumdis-2013-204436
32. Reveille JD. 2011. Epidemiology of spondyloarthritis in North America. Am. J. Med. Sci. 341(4):28486
33. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. 2014. Global preva-
lence of ankylosing spondylitis. Rheumatology. 53(4):65057
34. Evans DM, Spencer CCA, Pointon JJ, Su Z, Harvey D, et al. 2011. Interaction between ERAP1 and
HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in
disease susceptibility. Nat. Genet. 43(8):76167
35. Int. Genet. Ankyl. Spondylitis Consort. (IGAS), Cortes A, Hadler J, Pointon JP, Robinson PC, et al.
2013. Identication of multiple risk variants for ankylosing spondylitis through high-density genotyping
of immune-related loci. Nat. Genet. 45(7):73038

36. Caffrey MF, James DC. 1973. Human lymphocyte antigen association in ankylosing spondylitis. Nature
242(5393):121
37. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. 1973. High association of AN HL-A antigen,
W27, with ankylosing spondylitis. N. Engl. J. Med. 288(14):7046
38. Brewerton DA, Caffrey M, Nicholls A, Walters D, Oates JK, James DC. 1973. Reiters disease and HL-A
27. Lancet 302(7836):99698
39. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A. 2015. Prevalence of extra-articular manifes-
tations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Ann. Rheum. Dis.
74(1):6573
40. Brewerton DA, Caffrey M, Nicholls A, Walters D, James DC. 1973. Acute anterior uveitis and HL-A
27. Lancet 302(7836):99496
41. Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, et al. 1996. HLA class I associations of ankylosing
spondylitis in the white population in the United Kingdom. Ann. Rheum. Dis. 55(4):26870
42. Khan MA. 2013. Polymorphism of HLA-B27: 105 subtypes currently known. Curr. Rheumatol. Rep.
15(10):362
43. Liu Y, Jiang L, Cai Q, Danoy P, Barnardo MCNM, et al. 2010. Predominant association of HLA-B 2704
with ankylosing spondylitis in Chinese Han patients. Tissue Antigens 75(1):6164
44. Lopez-Larrea C, Sujirachato K, Mehra NK, Chiewsilp P, Isarangkura D, et al. 1995. HLA-B27 subtypes
in Asian patients with ankylosing spondylitis: Evidence for new associations. Tissue Antigens 45(3):16976
45. DAmato M, Fiorillo MT, Carcassi C, Mathieu A, Zuccarelli A, et al. 1995. Relevance of residue 116 of
HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur. J. Immunol. 25(11):3199201
46. Fiorillo MT, Meadows L, DAmato M, Shabanowitz J, Hunt DF, et al. 1997. Susceptibility to ankylosing
spondylitis correlates with the C-terminal residue of peptides presented by various HLA-B27 subtypes.
Eur. J. Immunol. 27(2):36873
47. Garca-Peydro M, Mart M, Lopez de Castro JA. 1999. High T cell epitope sharing between two
HLA-B27 subtypes (B 2705 and B 2709) differentially associated to ankylosing spondylitis. J. Immunol.
163(4):2299305
48. Hulsmeyer M, Fiorillo MT, Bettosini F, Sorrentino R, Saenger W, et al. 2004. Dual, HLA-B27 subtype-
dependent conformation of a self-peptide. J. Exp. Med. 199(2):27181
49. Benjamin R, Parham P. 1990. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol. Today
11(4):13742
50. Benjamin RJ, Madrigal JA, Parham P. 1991. Peptide binding to empty HLA-B27 molecules of viable
human cells. Nature 351(6321):7477
51. Hermann E, Yu DT, Meyer zum Buschenfelde KH, Fleischer B. 1993. HLA-B27-restricted CD8 T
cells derived from synovial uids of patients with reactive arthritis and ankylosing spondylitis. Lancet
342(8872):64650
52. Appel H, Kuon W, Kuhne M, Wu P, Kuhlmann S, et al. 2004. Use of HLA-B27 tetramers to identify low-
frequency antigen-specic T cells in Chlamydia-triggered reactive arthritis. Arthritis Res. Ther. 6(6):R521
34
53. Fiorillo MT, Maragno M, Butler R, Dupuis ML, Sorrentino R. 2000. CD8+ T-cell autoreactivity to an
HLA-B27-restricted self-epitope correlates with ankylosing spondylitis. J. Clin. Investig. 106(1):4753
54. Allen RL, Gillespie GM, Hall F, Edmonds S, Hall MA, et al. 1997. Multiple T cell expansions are found
in the blood and synovial uid of patients with reactive arthritis. J. Rheumatol. 24(9):175057
55. May E, Dulphy N, Frauendorf E, Duchmann R, Bowness P, et al. 2002. Conserved TCR chain usage
in reactive arthritis; evidence for selection by a putative HLA-B27-associated autoantigen. Tissue Antigens
60(4):299308
56. Mamedov IZ, Britanova OV, Chkalina AV, Staroverov DB, Amosova AL, et al. 2009. Individual charac-
terization of stably expanded T cell clones in ankylosing spondylitis patients. Autoimmunity 42(6):52536
57. May E, Dorris ML, Satumtira N, Iqbal I, Rehman MI, et al. 2003. CD8 T cells are not essential to
the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats. J. Immunol. 170(2):1099105
58. Taurog JD, Dorris ML, Satumtira N, Tran TM, Sharma R, et al. 2009. Spondylarthritis in HLA-
B27/human 2 -microglobulin-transgenic rats is not prevented by lack of CD8. Arthritis Rheumatol.

60(7):197784
59. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, et al. 2012. Il-23 induces spondy-
loarthropathy by acting on ROR-t+ CD3+ CD4 CD8 entheseal resident T cells. Nat. Med.
18(7):106976
60. Allen RL, OCallaghan CA, McMichael AJ, Bowness P. 1999. Cutting edge: HLA-B27 can form a novel
2 -microglobulin-free heavy chain homodimer structure. J. Immunol. 162(9):504548
61. Mear JP, Schreiber KL, Munz C, Zhu X, Stevanovic S, et al. 1999. Misfolding of HLA-B27 as a re-
sult of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies.
J. Immunol. 163(12):666570
62. Antoniou AN, Ford S, Taurog JD, Butcher GW, Powis SJ. 2004. Formation of HLA-B27 homodimers
and their relationship to assembly kinetics. J. Biol. Chem. 279(10):8895902
63. Turner MJ, Delay ML, Bai S, Klenk E, Colbert RA. 2007. HLA-B27 up-regulation causes accumula-
tion of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in
transgenic rats: implications for the pathogenesis of spondylarthritis-like disease. Arthritis Rheumatol.
56(1):21523
64. DeLay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA. 2009. HLA-B27 misfolding and
the unfolded protein response augment interleukin-23 production and are associated with th17 activation
in transgenic rats. Arthritis Rheumatol. 60(9):263343
65. Utriainen L, Firmin D, Wright P, Cerovic V, Breban M, et al. 2012. Expression of HLA-B27 causes
loss of migratory dendritic cells in a rat model of spondylarthritis. Arthritis Rheumatol. 64(10):3199209
66. Layh-Schmitt G, Yang EY, Kwon G, Colbert RA. 2013. HLA-B27 alters the response to tumor necrosis
factor and promotes osteoclastogenesis in bone marrow monocytes from HLA-B27-transgenic rats.
Arthritis Rheumatol. 65(8):212331
67. Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L, et al. 2010. Endoplasmic reticulum stress-induced
transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. PNAS 107(41):17698703
68. Sahlberg AS, Ruuska M, Granfors K, Penttinen MA. 2013. Altered regulation of ELAVL1/HuR in
HLA-B27-expressing U937 monocytic cells. PLOS ONE 8(7):e70377
69. Colbert RA, DeLay ML, Klenk EI, Layh-Schmitt G. 2010. From HLA-B27 to spondyloarthritis: a
journey through the ER. Immunol. Rev. 233(1):181202
70. Tran TM, Dorris ML, Satumtira N, Richardson JA, Hammer RE, et al. 2006. Additional human 2 -
microglobulin curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male
HLA-B27-transgenic rats. Arthritis Rheumatol. 54(4):131727
71. Campbell EC, Fettke F, Bhat S, Morley KD, Powis SJ. 2011. Expression of MHC class I dimers and
ERAP1 in an ankylosing spondylitis patient cohort. Immunology 133(3):37985
72. Ciccia F, Accardo-Palumbo A, Rizzo A, Guggino G, Raimondo S, et al. 2013. Evidence that autophagy,
but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with
ankylosing spondylitis and subclinical gut inammation. Ann. Rheum. Dis. 73:156674
46 Bowness
73. Dong W, Zhang Y, Yan M, Liu H, Chen Z, Zhu P. 2008. Upregulation of 78-kDa glucose-regulated pro-
tein in macrophages in peripheral joints of active ankylosing spondylitis. Scand. J. Rheumatol. 37(6):42734
74. Bird LA, Peh CA, Kollnberger S, Elliott T, McMichael AJ, Bowness P. 2003. Lymphoblastoid cells
express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling.
Eur. J. Immunol. 33(3):74859
75. Kollnberger S, Bird L, Sun M-Y, Retiere C, Braud VM, et al. 2002. Cell-surface expression and immune
receptor recognition of HLA-B27 homodimers. Arthritis Rheumatol. 46(11):297282
76. Kollnberger S, Bird LA, Roddis M, Hacquard-Bouder C, Kubagawa H, et al. 2004. HLA-B27 heavy
chain homodimers are expressed in HLA-B27 transgenic rodent models of spondyloarthritis and are
ligands for paired Ig-like receptors. J. Immunol. 173(3):1699710
77. Giles J, Shaw J, Piper C, Wong-Baeza I, McHugh K, et al. 2012. HLA-B27 homodimers and free H
chains are stronger ligands for leukocyte Ig-like receptor B2 than classical HLA class I. J. Immunol.
188(12):618493
78. Wong-Baeza I, Ridley A, Shaw J, Hatano H, Rysnik O, et al. 2013. KIR3DL2 binds to HLA-B27 dimers
and free H chains more strongly than other HLA class I and promotes the expansion of T cells in
ankylosing spondylitis. J. Immunol. 190(7):321624

79. Chan AT, Kollnberger SD, Wedderburn LR, Bowness P. 2005. Expansion and enhanced survival of
natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis.
80. Bowness P, Ridley A, Shaw J, Chan AT, Wong-Baeza I, et al. 2011. Th17 cells expressing KIR3DL2+ and
responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J. Immunol. 186(4):267280
81. Tsai WC, Chen CJ, Yen JH, Ou TT, Tsai JJ, et al. 2002. Free HLA class I heavy chain-carrying
monocytesa potential role in the pathogenesis of spondyloarthropathies. J. Rheumatol. 29(5):96672
82. Raine T, Brown D, Bowness P, Hill Gaston JS, Moffett A, et al. 2006. Consistent patterns of expression
of HLA class I free heavy chains in healthy individuals and raised expression in spondyloarthropathy
patients point to physiological and pathological roles. Rheumatology 45(11):133844
83. Stam NJ, Spits H, Ploegh HL. 1986. Monoclonal antibodies raised against denatured HLA-B locus heavy
chains permit biochemical characterization of certain HLA-C locus products. J. Immunol. 137(7):2299
306
84. Payeli SK, Kollnberger S, Marroquin Belaunzaran O, Thiel M, McHugh K, et al. 2012. Inhibiting HLA-
B27 homodimer-driven immune cell inammation in spondylarthritis. Arthritis Rheumatol. 64(10):3139
49
85. Van Praet L, Van den Bosch FE, Jacques P, Carron P, Jans L, et al. 2013. Microscopic gut inammation
in axial spondyloarthritis: a multiparametric predictive model. Ann. Rheum. Dis. 72(3):41417
86. Lin P, Bach M, Asquith M, Lee AY, Akileswaran L, et al. 2014. HLA-B27 and human 2 -microglobulin
affect the gut microbiota of transgenic rats. PLOS ONE 9(8):e105684
87. Luthra-Guptasarma M, Singh B. 2004. HLA-B27 lacking associated 2 -microglobulin rearranges to
auto-display or cross-display residues 169181: a novel molecular mechanism for spondyloarthropathies.
FEBS Lett. 575(13):18
88. Uchanska-Ziegler B, Ziegler A. 2003. Ankylosing spondylitis: a 2 m-deposition disease? Trends Immunol.
24(2):7376
89. Kievits F, Ivanyi P, Krimpenfort P, Berns A, Ploegh HL. 1987. HLA-restricted recognition of viral
antigens in HLA transgenic mice. Nature 329(6138):44749
90. Khare SD, Hansen J, Luthra HS, David CS. 1996. HLA-B27 heavy chains contribute to spontaneous
inammatory disease in B27/human 2 -microglobulin (2 m) double transgenic mice with disrupted
mouse 2 m. J. Clin. Investig. 98(12):274655
91. Kingsbury DJ, Mear JP, Witte DP, Taurog JD, Roopenian DC, Colbert RA. 2000. Development of
spontaneous arthritis in 2 -microglobulindecient mice without expression of HLA-B27: association
with deciency of endogenous major histocompatibility complex class I expression. Arthritis Rheumatol.
43(10):229096
92. Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD. 1990. Spontaneous inammatory disease
in transgenic rats expressing HLA-B27 and human 2 m: an animal model of HLA-B27-associated human
disorders. Cell 63(5):1099112
93. Breban M, Hammer RE, Richardson JA, Taurog JD. 1993. Transfer of the inammatory disease of
HLA-B27 transgenic rats by bone marrow engraftment. J. Exp. Med. 178(5):160716
94. Zhou M, Sayad A, Simmons WA, Jones RC, Maika SD, et al. 1998. The specicity of peptides bound to
human histocompatibility leukocyte antigen (HLA)-B27 inuences the prevalence of arthritis in HLA-
B27 transgenic rats. J. Exp. Med. 188(5):87786
95. Genet. Anal. Psoriasis Consort. Wellcome Trust Case Control Consort. 2, Strange A, Capon F, Spencer
CCA, Knight J, et al. 2010. A genome-wide association study identies new psoriasis susceptibility loci
and an interaction between HLA-C and ERAP1. Nat. Genet. 42(11):98590
96. Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, et al. 2013. Genome-wide association
analysis identies new susceptibility loci for Behcets disease and epistasis between HLA-B 51 and ERAP1.
Nat. Genet. 45(2):2027
97. Kochan G, Krojer T, Harvey D, Fischer R, Chen L, et al. 2011. Crystal structures of the endoplasmic
reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. PNAS
108(19):774550
98. Campbell EC, Fettke F, Bhat S, Morley KD, Powis SJ. 2011. Expression of MHC class I dimers and
ERAP1 in an ankylosing spondylitis patient cohort. Immunology 133(3):37985

99. Kanaseki T, Blanchard N, Hammer GE, Gonzalez F, Shastri N. 2006. ERAAP synergizes with MHC
class I molecules to make the nal cut in the antigenic peptide precursors in the endoplasmic reticulum.
Immunity 25(5):795806
100. Seregin SS, Rastall DPW, Evnouchidou I, Aylsworth CF, Quiroga D, et al. 2013. Endoplasmic reticu-
lum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27
mediated presentation of multiple antigens. Autoimmunity 46(8):497508
101. Hammer GE, Gonzalez F, James E, Nolla H, Shastri N. 2007. In the absence of aminopeptidase ERAAP,
MHC class I molecules present many unstable and highly immunogenic peptides. Nat. Immunol. 8(1):101
8
102. Chen L, Fischer R, Peng Y, Reeves E, McHugh K, et al. 2014. Critical role of endoplasmic reticulum
aminopeptidase 1 in determining the length and sequence of peptides bound and presented by HLA-B27.
103. Kenna TJ, Lau MC, Keith P, Ciccia F, Costello M-E, et al. 2015. Disease-associated polymorphisms in
ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis. Genes Immun.
16(1):3542
104. Haroon N, Tsui FW, Uchanska-Ziegler B, Ziegler A, Inman RD. 2012. Endoplasmic reticulum
aminopeptidase 1 (ERAP1) exhibits functionally signicant interaction with HLA-B27 and relates to
subtype specicity in ankylosing spondylitis. Ann. Rheum. Dis. 71(4):58995
105. Zervoudi E, Saridakis E, Birtley JR, Seregin SS, Reeves E, et al. 2013. Rationally designed inhibitor tar-
geting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses.
PNAS 110(49):1989095
106. Brewerton DA, Caffrey M, Nicholls A, Walters D, James DC. 1974. HL-A 27 and arthropathies asso-
ciated with ulcerative colitis and psoriasis. Lancet 1(7864):95658
107. Thomson W, Barrett JH, Donn R, Pepper L, Kennedy LJ, et al. 2002. Juvenile idiopathic arthritis
classied by the ILAR criteria: HLA associations in UK patients. Rheumatology 41(10):118389
108. Kanga U, Mehra NK, Larrea CL, Lardy NM, Kumar A, Feltkamp TE. 1996. Seronegative spondy-
loarthropathies and HLA-B27 subtypes: a study in Asian Indians. Clin. Rheumatol. 15(Suppl. 1):1318
109. Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Greenwood BM, McMichael AJ. 1991. HLA class I
typing by PCR: HLA-B27 and an African B27 subtype. Lancet 337(8742):64042
48 Bowness
IY33-Frontmatter ARI 23 March 2015 20:35
Annual Review of
Immunology
Contents Volume 33, 2015
Remembrance of Immunology Past: Conversations with Herman Eisen

Herman N. Eisen and Sondra Schlesinger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
HLA-B27
Paul Bowness p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p29
Inammasome-Independent Regulation of IL-1-Family Cytokines

Mihai G. Netea, Frank L. van de Veerdonk, Jos W.M. van der Meer,
Charles A. Dinarello, and Leo A.B. Joosten p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Programmed Necrosis in the Cross Talk of Cell Death and Inammation
Francis Ka-Ming Chan, Nivea Farias Luz, and Kenta Moriwaki p p p p p p p p p p p p p p p p p p p p p p p p p79
Endoplasmic Reticulum Stress in Immunity
Sarah E. Bettigole and Laurie H. Glimcher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107
Insights into CytokineReceptor Interactions from Cytokine Engineering
Jamie B. Spangler, Ignacio Moraga, Juan L. Mendoza, and K. Christopher Garcia p p p 139
T Cell Antigen Receptor Recognition of Antigen-Presenting Molecules
Jamie Rossjohn, Stephanie Gras, John J. Miles, Stephen J. Turner,
Dale I. Godfrey, and James McCluskey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 169
Immunity to Helminths: Resistance, Regulation, and Susceptibility to
Gastrointestinal Nematodes
Richard K. Grencis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 201
Microbiota-Mediated Inammation and Antimicrobial Defense in the
Intestine
Silvia Caballero and Eric G. Pamer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227
Innate Immune Pattern Recognition: A Cell Biological Perspective
Sky W. Brubaker, Kevin S. Bonham, Ivan Zanoni, and Jonathan C. Kagan p p p p p p p p p p p 257
Ion Channels in Innate and Adaptive Immunity
Stefan Feske, Heike Wulff, and Edward Y. Skolnik p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291
TAM Receptor Signaling in Immune Homeostasis
Carla V. Rothlin, Eugenio A. Carrera-Silva, Lidia Bosurgi, and Sourav Ghosh p p p p p p p 355
Structural Biology of Innate Immunity
Qian Yin, Tian-Min Fu, Jixi Li, and Hao Wu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 393
v
IY33-Frontmatter ARI 23 March 2015 20:35
The Immunobiology of Interleukin-27

Hiroki Yoshida and Christopher A. Hunter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417
Innate Immune Recognition of Cancer
Seng-Ryong Woo, Leticia Corrales, and Thomas F. Gajewski p p p p p p p p p p p p p p p p p p p p p p p p p p p p 445
Natural Antibody Repertoires: Development and Functional Role in
Inhibiting Allergic Airway Disease
John F. Kearney, Preeyam Patel, Emily K. Stefanov, and R. Glenn King p p p p p p p p p p p p p p p 475
Transcription Factor Networks Directing the Development, Function,
and Evolution of Innate Lymphoid Effectors
Joonsoo Kang and Nidhi Malhotra p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 505
Early T Cell Activation: Integrating Biochemical, Structural,

and Biophysical Cues

Bernard Malissen and Pierre Bongrand p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 539
The Varieties of Immunological Experience: Of Pathogens,
Stress, and Dendritic Cells
Bali Pulendran p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 563
Transcriptional Regulation of Innate and Adaptive Lymphocyte Lineages
Maria Elena De Obaldia and Avinash Bhandoola p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 607
Macrophages: Development and Tissue Specialization
Chen Varol, Alexander Mildner, and Steffen Jung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 643
Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms,
and Function
Zvi Grossman and William E. Paul p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 677
Stromal Cells in Chronic Inammation and Tertiary Lymphoid
Organ Formation
Christopher D. Buckley, Francesca Barone, Saba Nayar, Cecile Benezech,
and Jorge Caamano p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 715
Interleukin-22: Immunobiology and Pathology
Jarrod A. Dudakov, Alan M. Hanash, and Marcel R.M. van den Brink p p p p p p p p p p p p p p p 747
The Immunology of Epstein-Barr VirusInduced Disease
Graham S. Taylor, Heather M. Long, Jill M. Brooks, Alan B. Rickinson,
and Andrew D. Hislop p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 787
Molecular Mechanisms in Genetically Dened Autoinammatory Diseases:
Disorders of Amplied Danger Signaling
Adriana Almeida de Jesus, Scott W. Canna, Yin Liu,
and Raphaela Goldbach-Mansky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 823
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IY33CH02-Bowness ARI 25 February 2015 8:54

Our comprehensive search

Annu. Rev. Immunol. 2015. 33:2948 Keywords

THE NATURAL FUNCTIONS OF HLA-B27

Peptide Presentation by HLA-B27 to CD8+ Cytotoxic T Cells

Position of cell membrane

Peptide Presentation by HLA-B27 to NK Cells

Atypical Peptide Presentation by HLA-B27

Other Functions of HLA-B27 Heterotrimers and Free Heavy Chains

HLA-B27 AND SPONDYLOARTHRITIS

Table 1 HLA-B27-associated spondyloarthritidesa

Acute anterior uveitis Acute sterile inammation of the anterior chamber of 50 40

Abbreviation: OR, odds ratio.

HLA-B27 Disease Associations

Table 2 HLA-B27 subtypes in different populations and their disease associations

B 2706 is not disease associated and is likely protective.

HLA-B27 Subtypes and AS

HLA-B27 PATHOGENIC MECHANISMS

Presentation of Arthritogenic Peptides

Table 3 Theories explaining pathogenic role of HLA-B27 in AS

HLA-B27, the Unfolded Protein Response and the Endoplasmic

Cell Surface Expression of Free Heavy Chain Forms of HLA-B27

T cell expressing KIR3DL2 Inhibition of

Induction of B27 IL-17 HLA-B27

Other Theories of HLA-B27 Pathogenesis

Lessons from HLA-B27 Transgenic Mice and Rats

Interaction of HLA-B27 with ERAP1 and Other Peptidases in AS Pathogenesis

chains expressed in the presence of disease-associated ERAP1 variants, as suggested by Haroon

2. Does HLA-B27 misfolding increase in the presence of disease-associated ERAP1

of immune-related loci. Nat. Genet. 45(7):73038

B27/human 2 -microglobulin-transgenic rats is not prevented by lack of CD8. Arthritis Rheumatol.

ankylosing spondylitis. J. Immunol. 190(7):321624

ERAP1 in an ankylosing spondylitis patient cohort. Immunology 133(3):37985

Contents Volume 33, 2015

Remembrance of Immunology Past: Conversations with Herman Eisen

Inammasome-Independent Regulation of IL-1-Family Cytokines

The Immunobiology of Interleukin-27

Early T Cell Activation: Integrating Biochemical, Structural,

and Biophysical Cues

Now Available from Annual Reviews:

Editor: Lynn W. Enquist, Princeton University

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Editor: Lynn W. Enquist, Princeton University