Review TRENDS in Immunology
4 April 2006
A gut feeling for joint inflammation –
using coeliac disease to understand
rheumatoid arthritis
Øyvind Molberg and Ludvig M. Sollid
Institute of Immunology and Department of Rheumatology, Rikshospitalet University Hospital, University of Oslo,
N-0027 Oslo, Norway
Major advances have been made in the molecular
understanding of coeliac disease, initiated by the
identification of intestinal gluten-reactive T cells. It is
now clear that this common intestinal disorder, which is
precipitated by the ingestion of wheat gluten, is
mediated by DQ2-restricted T cells specific for gluten
peptides modified by transglutaminase 2, the same
enzyme that is targeted by disease-specific autoanti-
bodies. Interestingly, many of the important features
identified in coeliac disease, including HLA association,
target organ T-cell infiltration, disease-specific autoanti-
bodies and the distinct targeting of in vivo modified
antigens, are also present in rheumatoid arthritis. The
experiences from coeliac disease should therefore help
identify disease-relevant T-cell epitopes in rheumatoid
arthritis.
Introduction
The past few years have witnessed breakthroughs in our
understanding of the pathogenesis of the gluten-sensitive
enteropathy coeliac disease (CD; Box 1). A key to these
advances has been a multi-faceted approach combining
clinical, genetic, immunological and chemical studies. It
has become evident that CD is a prevalent disorder
characterized by disease-specific autoantibodies against
the enzyme transglutaminase 2 (TG2, also called tissue
transglutaminase) and driven by gluten-reactive T cells
resident within the coeliac lesions [1,2]. Mapping analyses
suggest that these interferon (IFN)-g-producing CD4C T
cells recognize epitopes that are present within naturally
digested gluten fragments and modified in vivo by TG2 [3–
10].
Interestingly, we and others have observed that some of
the crucial features of CD, including human leukocyte
antigen (HLA) association, target organ T-cell infiltration,
disease-specific autoantibodies and the importance of
in vivo modified antigens, are paralleled in the chronic
joint disorder rheumatoid arthritis (RA; Box 1) [2,11].
These observations suggest to us that it might be feasible
to use the molecular understanding of CD as a conceptual
framework to aid the identification of disease-relevant
Corresponding author: Molberg, Ø (oyvind.molberg@medisin.uio.no).
www.sciencedirect.com 1471-4906/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2006.02.006
Vol.27 No.
T-cell epitopes in RA. The purpose of this review is twofold:
first to give an updated overview of the features that are
shared between CD and RA; and second to discuss the
potential benefits and pitfalls of using the approach
developed for CD to understand RA.
Shared features of coeliac disease and rheumatoid
arthritis
CD and RA are typically classified together with diseases
such as type I diabetes and multiple sclerosis as complex
diseases because of their multifactorial aetiologies invol-
ving environmental and genetic factors (both HLA-linked
and non-HLA-linked genes) [2]. Complex diseases have
certain group characteristics but the available data
suggest that the similarities between CD and RA extend
beyond these. In particular, key enzymes that catalyse the
post-translational modification of distinct amino acid
residues within antigenic structures have a central role
in CD and RA. These enzymes are TG2 in CD [12,13] and
distinct peptidyl arginine deiminase (PAD) isoforms in RA
[14]. These enzymes and other shared features of CD and
RA, including HLA association, target organ T-cell
infiltration, autoimmune phenomena, immune targeting
of modified proteins and the importance of post-transla-
tional modification for peptide binding to the disease-
associated HLA molecules, will be the focus of this review.
Association to genes in the HLA complex
The HLA association in CD is clear; most (90-95%)
patients carry DQA1*05 and DQB1*02, which encode
the allelic HLA variant DQ2, whereas most of the
remaining patients carry DQA1*03 and DQB1*0302,
which encode DQ8 [15]. The CD-associated DQA1*05–
DQB1*02 dimer can be encoded by genes on the same
chromosome (in cis) or on two different chromosomes (in
trans) [15]. HLA molecules bind to antigenic peptides, and
in the HLA class II molecules there are pockets (P1, P4,
P6, P7 and P9) in the binding site that accommodate the
amino acid side chains of the peptides at corresponding
positions. DQ2 has a preference for binding to peptides
with negatively charged residues at position P4, P6 and/or
P7. This preference is mainly determined by the positively
charged lysine residue at position 71 in DQb [16]. DQ8 has
a preference for binding peptides with negatively charged
residues at position P1 and/or P9 [2].
 Review TRENDS in Immunology
Box 1. Clinical characteristics
CD is characterized by alterations in the architecture of the small-
intestinal mucosa induced by wheat gluten and similar rye and
barley proteins. The disease is common with a prevalence of 1:100–
1:300 in North America and Europe. It has a female-to-male ratio of
2:1. CD is precipitated by dietary exposure to gluten. Patients go into
complete remission when put on a gluten-free diet and they relapse
when gluten is reintroduced into their diet. CD can present in early
childhood with malabsorption, diarrhoea and failure to thrive but
often presents later in life with extra-intestinal manifestations such
as anaemia, fatigue and osteoporosis. The disease is associated with
type I diabetes and some other auto-immune disorders, but not with
RA. Currently, the only treatment for CD is a lifelong adherence to a
strict gluten-free diet [1,2,10,15].
RA affects w1% of the population worldwide. The disease has a
female-to-male ratio of 3:1 and a peak onset at 40–60 years of age. RA
is a clinical syndrome defined by a constellation of symptoms and
findings but the characteristic feature is a chronic and destructive
inflammation that is primarily localized to the synovial lining of
diarthrodial joints. RA can also cause inflammation in other organs,
including the heart, lungs, skin and peripheral nerves, often with
serious and even fatal consequences. The current treatment options
for RA include cytotoxic drugs such as Methotrexate and biological
agents such as the anti-tumour necrosis factor agents [17,30,33,34].
RA is not associated with one allelic HLA variant, but
with several DRB1* alleles, the most common being
DRB1*0401, DRB1*0404 and DRB1*0101 [17]. More
than two thirds of RA patients express at least one of
these three alleles. All the RA-associated DRB1* alleles
encode similar amino acids in the 67–74-position of the
DRb chain. Originally, the shared sequence in this DR
region was referred to as a ‘shared epitope’ [18]. The
common DRb-chain position 67–74 sequence gives RA-
associated DR alleles common peptide-binding properties.
Particularly important is the arginine or lysine at position
71 in DRb that, owing to charge interactions, repels
binding of peptides with positively charged residues at the
P4 position [17,19,20].
It seems that the HLA genes exert a gene dosage effect
because having more than one disease-associated HLA
allele confers a greater than expected disease risk, both in
CD and in RA [15,17]. Notably, the total genetic
contribution to CD and RA involves more than HLA
genes alone: O50% of the total disease risk in these
diseases is contributed by multiple disease genes located
outside the HLA complex [15,21].
Infiltration of CD4C T cells in the target organ
All complex inflammation disorders are characterized by
destructive organ inflammation involving CD4C or CD8C
T cells, B cells, plasma cells, macrophages and dendritic
cells (DCs). In general, little is known about the factors
inducing and maintaining inflammation but CD might
represent an exception. Although the mechanisms are not
entirely clear, it seems that the destructive inflammation
of the small intestinal mucosa is orchestrated by resident
CD4C T cells specific for modified wheat gluten peptides.
Following activation in vivo by DQ2C Cd11cC DCs, these
T cells secrete pro-inflammatory cytokines that drive
inflammation and contribute to the flattening of intestinal
villi [1,2].
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Vol.27 No.4 April 2006 189
The area immediately beneath the lining layer of the
inflamed rheumatoid joint is heavily infiltrated by CD4C
T cells. Several lines of evidence indicate that these
infiltrating T cells are antigen driven and have a central
role in RA pathogenesis: (i) they are clonally expanded,
probably because of previous encounters with local
peptide–HLA-class-II complexes [22]; (ii) they have an
activated phenotype [17,23]; (iii) they cluster with
putative antigen-presenting cells (synovial macrophages
and DCs) [23]; and (iv) recent data suggest that the
rheumatoid synovia in the initial phase is dominated by
T-cell-derived cytokines [24]. Despite extensive efforts,
little is known about the antigen specificity of the synovial
T cells (see next section). Another unresolved issue is how
the synovial T cells interact with other inflammatory cells,
in particular, the invasive tumor necrosis factor (TNF)-a-
secreting macrophages and fibroblast-like cells of the
multilayered synovial lining [17].
Autoimmune features
Serum antibodies specific for self proteins are a hallmark
of human complex disorders. Some of them are distinctly
disease-specific and are therefore useful as diagnostic
tools. The immunoglobulin (Ig)A anti-TG2 antibodies in
untreated coeliac patients are a good example. These
antibodies, which recognize the Ca2C-activated form of
TG2, are sensitive markers of CD (they are present in O
95% of untreated coeliac patients) [12]. Although much
has been learned about the crucial role of TG2 enzymatic
activity in CD, little is known about its role as a B-cell
auto-antigen. Moreover, it is unclear how anti-TG2
antibodies affect TG2 function [1,2,25].
Several self-reactive antibodies have been described in
RA but antibodies combining exquisite specificity with
reasonable sensitivity were only recently identified. These
disease-specific antibodies predominantly reacted with
self proteins in which some of the native arginine residues
were deiminated to citrulline [26,27]. Detailed analyses of
these polyclonal anti-citrullinated protein antibodies
(ACPAs) showed that a citrulline residue was a crucial
constituent in all recognized epitopes [28]. In the clinic,
the presence of ACPAs is evaluated using the cyclic
citrullinated peptide (CCP) assay. This assay is highly
specific for RA with a sensitivity of up to 80% [29]. The
ACPAs have some interesting features: they occur most
frequently in patients carrying RA-associated DR alleles,
particularly DRB1*0401 [30], and their presence seems to
predict the later development of RA [31,32].
RA is often regarded as a bona fide autoimmune
disorder because it is characterized by disease-specific
autoantibodies, infiltrating T cells and HLA association
[33,34]. It has also been claimed that the ACPA response
in RA fulfils the Witebsky criteria for autoimmune
disorders [34,35]. In our opinion, the similarity of RA to
CD gives sufficient reason to question these statements. If
the specificity of the coeliac lesion T cells had not been
defined, CD would probably have been described as an
autoimmune disorder driven by reactivity to TG2.
However, we are not stating that RA is caused by an
environmental factor, although valid candidates exist [36],
190 Review TRENDS in Immunology Vol.27 No.4 April 2006

but warning against using the lack of evidence to exclude

this possibility. (a) Coeliac disease
H O H O
CD and RA have other autoimmune features in
addition to auto-reactive B cells. A feature that is unique N C H2O N C
R C R R C R
to CD is the presence of auto-reactive intra-epithelial
CH22 TG2 CH22
lymphocytes (IELs) expressing NKG2D, one of the NK-cell
C C
family receptors [37–39]. NKG2D, the expression level of NH3
H2N O HO O
which is regulated by interleukin (IL)-15, mediates killing
by the binding of MHC class I chain-related molecule Glutamine Glutamatic acid
(MIC) to epithelial cells. No association has yet been (deamidated
glutamine)
established between the DQ2-restricted gluten-specific T
cells and the NKG2DC IELs. Interestingly, NKG2D-
expressing CD4C T cells, regulated by IL-15, have also
been identified in RA [40]. Their function in RA is unclear (b) Rheumatoid arthritis
but they might mediate the apoptosis of MIC-expressing H O H O
synoviocytes. The relationships between NKG2DC T cells, N C N C
R C R R C R
auto-reactive B cells and the other T-cell subsets in H2O
CH23 CH23
synovia require investigation. PAD
NH3 NH3
The hunt for RA-specific CD4C T-cell responses against
self peptide–HLA combinations is now in its third decade. C NH3 C
+H N
Several endogenous candidate antigens, in particular, 2 NH3 H2N O
proteins previously known to be expressed within the Arginine Citrulline
inflamed joint and targeted by the humoral immune (deiminated
system, have been tested [41]. Type II collagen (CII) is a arginine)
prime example; it is a cartilage-specific protein that is TRENDS in Immunology
targeted by RA-specific B cells [42,43]. Moreover, CII
induces T-cell-driven arthritis in various rodents, includ- Figure 1. The key enzymes involved in the pathogenesis of coeliac disease and
rheumatoid arthritis. (a) TG2 is an enzyme that catalyses distinct post-translational
ing mice transgenic for the RA-associated DRB*0101 and modifications of proteins by transamidation or deamidation. The enzyme targets
DRB*0401 molecules [44,45]. Despite these observations, selected glutamines in its substrate proteins. In the transamidation reaction, these
there is no evidence that native CII is a synovial T-cell glutamines become crosslinked to a protein-bound lysine residue or another
primary amine through an isopeptide bond. The deamidation reaction depicted
antigen in RA, with the possible exception of an early here uses water and, through removal of the amide (red), results in the
report [41,46,47]. transformation of glutamine to glutamic acid. TG2-mediated deamidation of gluten
proteins (e.g. wheat gliadin or glutenin) has a crucial role in coeliac disease because
it generates the major gluten epitopes recognized by coeliac lesion T cells. (b) The
PAD family contains the only enzymes that deiminate arginine residues in substrate
Involvement of distinct enzymes in pathogenesis proteins (e.g. fibrin, vimentin) to yield citrulline. The PAD-mediated generation of
TG2 is a multifunctional enzyme that has several roles in citrulline residues is important in the pathogenesis of rheumatoid arthritis because
it creates epitopes recognized by disease-specific ACPAs. The real in vivo targets of
CD [2,13,48]. The best characterized is the modification of ACPAs are unknown. PAD has five different isoforms; PAD2 and/or PAD4 are
selective glutamine residues in wheat gluten [49,50]. probably involved in rheumatoid arthritis.
These modifications result in either the formation of
deamidated gluten fragments (Figure 1a) or cross-linking Immune targeting of modified protein fragments
of gluten to TG2 and other lysine-containing proteins Rather than recognizing native gluten peptides, most
[51,52]. DQ2- and DQ8-restricted gluten-reactive T cells within
The crucial post-translational antigen modification in
the coeliac mucosa respond to in vivo peptides deamidated
RA is also an enzymatic, and therefore selective, side-
by TG2 [3,5,6,9] (Figure 2a). Several studies have
chain charge alteration of a distinct amino acid residue
demonstrated that the epitopes recognized by intestinal
(Figure 1b). The PAD family contains the only enzymes
T cells cluster in proline-rich regions of gluten proteins
that target protein-bound arginine residues [14] but it is
that are resistant to digestive processing [6–8,10]. The
still unclear which of the five PAD isoforms are operative
proline residues within the epitopes are crucial because
in RA. PAD2 and/or PAD4 are the best candidates. Both
isoforms are expressed by immune cells and co-localize they select for binding to DQ2 and govern the glutamine
with citrullinated proteins in inflamed tissues, including deamidation selectivity of TG2 [9].
the rheumatoid synovium [53–55]. Differences between Recent data show that any inflamed synovial tissue
PAD2 and PAD4 include cellular localization and sub- contains citrullinated proteins. This suggests that it is not
strate fine-specificity [14,56]. Importantly, genetic studies the citrullination per se but the synovial B-cell reactivity
have shown an association between RA and variants of the [61] against the citrullinated proteins that is specific for
gene encoding PAD4 [57,58]. Parallel to the anti-TG2 RA [62,63]. Ongoing efforts to map the real in vivo target
response in CD, there seems to be a B-cell response to protein(s) of the citrulline-specific antibodies have ident-
PAD2 and PAD4 in RA [59,60]. Although not conclusive, ified responses to in vitro PAD-treated variants of self
the two published reports indicate that the anti-PAD proteins such as fibrin, vimentin, CII, a-enolase and the
responses in RA might be less disease-specific (and Epstein–Barr virus protein EBNA-1 [64–68]. Although
sensitive) than the anti-TG2 response in CD. these reports suggest candidate antigen(s), they give no
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 Review TRENDS in Immunology Vol.27 No.4 April 2006 191

(a) (b)

Intestinal
epithelium

PAD
TG2
APC
T cell T cell T
APC

B B cell B cell
B
Anti-TG2
Anti-ACPA

T
HLA-DQ2 + HLA-DR4 +
deamidated citrullinated
gluten peptide peptide x

TRENDS in Immunology

Figure 2. Schematic models of the target organ immune reactions in coeliac disease and rheumatoid arthritis. (a) The small intestinal coeliac lesion. Peptide fragments of
wheat gluten (yellow circles) survive digestion with intestinal and brush border proteases (scissors) and traverse the intestinal epithelium. In the intestine, the peptides
become deamidated or transamidated by TG2, which is either located in the extracellular matrix or associated with antigen-presenting cells (APCs; in green). CD4C T cells
within the mucosa recognize deamidated gluten peptides (red triangles) presented by disease-associated DQ2 or DQ8 molecules. B cells specific for TG2 are characteristic of
coeliac disease. The production of anti-TG2 IgA by these B cells can be explained by a hapten-carrier model. First, the TG2-specific B cells take up complexes of TG2 and
gluten, which are formed in vivo by TG2-mediated transamidation. Second, the B cells present deamidated gluten peptides to specific T cells and receive cognate help in
return. This mechanism provides a simple explanation for the observation that anti-TG2 antibody formation is strictly dependent on in vivo gluten exposure. (b) The
rheumatoid synovium. B cells specific for distinct citrullinated proteins (orange balls) are present in the area beneath the synovial lining layer (grey). The citrullinated proteins
are probably formed in situ through selective, PAD-mediated deimination of native substrate proteins (yellow). It is possible that the ACPA-specific B cells receive cognate
help from DR4-restricted T cells present within the inflamed synovium, because the production of the anti-citrulline protein antibodies (ACPAs) is linked to the DR association
in RA. To enable cognate help, these T cells must be specific for an epitope associated with the citrullinated B-cell antigen. This T-cell epitope (peptide x) can be a citrullinated
peptide (orange square) but it can also be a native peptide or contain other post-translational modifications.

information about how, where or when ACPA generation
occurs in vivo.
In contrast to CD, there is no link between auto-
reactive B cells and disease-relevant T cells in RA. The
generation of ACPAs, like any other isotype-switched
antibodies, is dependent on cognate T-cell help, therefore
T cells specific for an epitope associated with the
citrullinated B-cell antigen must exist (Figure 2b). This
T-cell epitope is probably presented by a RA-associated DR
molecule but its origin and nature is completely unknown,
unless it is identical to the citrullinated B-cell epitope. It
might be a self or non-self peptide and it might be native or
contain modifications other than citrullination. The last
possibility is exemplified by the identification of citrulli-
nated CII as an ACPA target. The T-cell help in this
system might be provided by cells specific for post-
translationally glycosylated CII epitopes. Support for
this idea comes from one report that describes peripheral
blood T-cell responses in RA to the glycosylated CII
epitopes identified as dominant in the DR4 transgenic
variant of the collagen-induced arthritis model [44].
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Importance of post-translational modification for
peptide binding to HLA molecules
The alignment of different TG2-modified gluten T-cell
epitopes to the binding site of DQ2 demonstrates that the
glutamate residues formed by TG2 are localized at the P4,
P6 or P7 positions [9]. The crystal structure of DQ2 in
complex with the gluten T-cell epitope DQ2-aI-gliadin that
has the TG2-formed glutamate at the P6 position showed
that this glutamate is important for binding because it
participates in an extensive hydrogen-bonding network
involving the lysine residue at position 71 of DQb [16]. In
addition, the crystal structure also showed that the DQ2–
gluten-peptide complex retained crucial hydrogen bonds
between the HLA molecule and the peptide backbone,
despite the presence of many proline residues in the
peptide [16]. This emphasized the importance of the
spacing of proline residues within the DQ2-binding core
region [9].
The crystal structures of the DRB1*0101- and
DRB1*0401-encoded molecules suggest that RA-associ-
ated DR molecules select for the binding of peptides
192 Review TRENDS in Immunology
B cell
APC
T cell
Figure 3. Unresolved issues regarding the role of citrullinated proteins in the pathogenesis of rheumatoid arthritis. The synovial lining layer is shown in grey; the citrullinated
epitopes and protein are depicted as orange squares and orange balls, respectively; native substrate protein is shown in yellow; PAD is shown in pink.
that have a negatively charged or neutral amino acid in
position P4 [19,20]. In accordance with this, it was
recently shown that synthetic peptides containing a
neutral citrulline in position P4 had increased binding
affinity to DRB1*0401 compared with those with a
positively charged arginine at the same position [69].
These data indicate that protein citrullination mediated
by PAD might generate peptides that can bind to the
RA-associated DR molecules and be recognized by T
cells. Notably, a comparison of the DR4-binding proper-
ties of peptides with a neutral glutamine or a
negatively charged glutamate would probably yield
similar results. Because the activity of TG2 in the
rheumatoid synovium is high [70], TG2-mediated
deamidation might contribute to the generation of DR-
binding peptides in RA.
What can coeliac disease teach us about rheumatoid
arthritis?
Experiences from CD studies have taught us that the
most important factor necessary for making progress in
understanding a complex human disorder is molecular-
level knowledge of the epitopes recognized by the T cells
resident within the inflamed target organ. Therefore,
future work on the pathogenesis of RA should be focused
on the identification of the antigens recognized by T cells
isolated from the rheumatoid synovium. Previous
attempts to characterize T-cell epitopes in RA have
mostly been unsuccessful [17,41]. One possible reason
for these failures might be technical, because many
studies have used T cells from peripheral blood to screen
for the recognition of native peptides. These studies did,
by design, miss T-cell responses that were tissue-
restricted and/or directed against modified antigens.
Of the many possible strategies for defining RA-
associated T-cell antigens, we favour one based on the
lessons learned from CD. This would (i) take advantage
of the HLA association and limit the focus to epitopes
restricted by the RA-associated DR molecules; and (ii)
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Vol.27 No.4 April 2006
What are the in vivo PAD substrates in RA?
Are the PAD substrates self-proteins?
Which isotype of PAD is involved?
Where is PAD located in the synovium?
What is the target of the ACPA?
What is the role of ACPAs?
Are the T-cell epitopes citrullinated?
How are they linked to the B-cell epitopes?
What is the role of the specific T cells?
What will be the effect of T-cell silencing?
TRENDS in Immunology
look for T-cell epitopes linked to RA-specific B-cell
antigens. The rationale for starting with B cells comes
from our model on how gluten-reactive T cells might
assist the production of anti-TG2 antibodies [2,52]
(Figure 1b). One possibility here is to look for complexes
of PAD and citrullinated proteins and another is to map
the citrullinated proteins present in the synovium. Our
proposed strategies will hopefully contribute to resolving
some of the key issues related to the role of citrullination
in RA (Figure 3). Although progress has been made in
the understanding of CD, several new questions have
emerged. Many of these relate to the autoimmune
aspects of the disease and are therefore relevant to RA
[39]. We are confident that an integrative approach in
which striving to co-develop the research on CD, RA and
the other complex disorders will help to answer these
challenging questions.
Acknowledgements
Studies in our research group at the Institute of Immunology are funded
by grants from the Research Council of Norway, the European
Commission (BMH4-CT98–3087, QLRT-1999–00037, QLRT-2000–
00657), the Norwegian Cancer Society, Medinnova, Freia Chokolade
Fabriks Medicinske Fond, the Jahre Foundation and EXTRA funds from
the Norwegian Foundation for Health and Rehabilitation.
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