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Response of Th17 cells to a citrullinated arthritogenic aggrecan peptide in patients with rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 62, No. 1, January 2010, pp 143–149
DOI 10.1002/art.25064
© 2010, American College of Rheumatology
Response of Th17 Cells to a Citrullinated Arthritogenic
Aggrecan Peptide in Patients With Rheumatoid Arthritis
Alexei von Delwig, James Locke, John H. Robinson, and Wan-Fai Ng
Objective. Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disease. However,
the autoantigens that play an important role in the
development of RA remain unclear. The aim of this
study was to investigate whether T cells specific for
citrullinated epitopes from self proteins are present in
patients with RA.
Methods. Peripheral blood mononuclear cells
(PBMCs) from 28 RA patients and 18 healthy controls
were stimulated with citrullinated or noncitrullinated
aggrecan peptide Agg84–103, and proliferative and cytokine responses were assessed using 3H-thymidine incorporation assay, enzyme-linked immunosorbent assay,
and intracellular cytokine analysis.
Results. A proliferative response to the citrullinated aggrecan peptide was detected in >60% of RA
patients but not in healthy controls. Furthermore, citrullinated aggrecan peptide–stimulated PBMCs from
RA patients produced high levels of the proinflammatory cytokine interleukin-17 (IL-17), accompanied by an
induction of IL-17ⴙCD4ⴙ T cells. In contrast, PBMCs
from RA patients and healthy controls exhibited no
response to stimulation with the noncitrullinated aggrecan peptide.
Conclusion. Proinflammatory T cell responses to
stimulation with a citrullinated arthritogenic aggrecan
peptide were detected in RA patients but not in healthy
individuals, suggesting a role for these autoantigenspecific T cells in the pathogenesis of RA. Our results
suggest that the lack of response to the noncitrullinated
analog peptide not only implicates the citrulline residue
in T cell recognition but also highlights the potential
value of citrullinated aggrecan peptide–specific responses as biomarkers of RA. To our knowledge, this is
the first study to demonstrate the presence of citrullinated antigen–specific T cells in human RA.
Rheumatoid arthritis (RA) is considered a prototypical autoimmune disease. However, the autoantigens that play a key role in the development of RA
remain undetermined. There is an increasing body of
evidence suggesting that posttranslational modifications
of proteins by processes such as citrullination can generate novel epitopes and that these new epitopes may in
turn trigger autoimmunity (1). Indeed, recent studies
have shown that anti–cyclic citrullinated peptide (antiCCP) antibodies are not only highly specific for RA (2)
but may also be pathogenic (3). Furthermore, B cell
depletion resulting from the use of biologic therapies
effectively suppresses synovial inflammation (4,5). These
observations implicate citrullinated autoantigen–specific
B cells in mediating joint inflammation in RA. However,
the underlying immune processes that drive the development of these autoantigen-specific B cells are poorly
understood.
Immunogenetic studies have shown that ⬎90%
of RA patients have a similar amino acid sequence,
commonly known as the RA “shared epitope,” at positions 70–74 of the HLA–DR ␤-chain (6). Since
HLA–DR is a class II major histocompatibility complex
(MHC) molecule, the key function of which is antigen
presentation to CD4⫹ T cells, the strong association
between the shared epitope and the development of RA
suggests that CD4⫹ T cells play an important role in
mediating the disease process. More recently, the results
of genome-wide association studies have implicated
other T cell–associated genes in the development of RA,
reinforcing the importance of T cells in the pathogenesis
Mr. Locke and Dr. Ng’s work was supported by grants from
the Arthritis Research Campaign (grants 17864 and 14912, respectively).
Alexei von Delwig, DSc, PhD, James Locke, BSc, John H.
Robinson, PhD, Wan-Fai Ng, MRCP, PhD: Newcastle University,
Newcastle upon Tyne, UK.
Address correspondence and reprint requests to Wan-Fai Ng,
MRCP, PhD, Musculoskeletal Research Group, Institute of Cellular
Medicine, 4th Floor, Catherine Cookson Building, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. E-mail: Wan-Fai.Ng@
ncl.ac.uk.
Submitted for publication July 6, 2009; accepted in revised
form September 25, 2009.
143
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VON DELWIG ET AL
of the disease (7). However, the antigens that drive T
cell activation in RA remain unknown, and the mechanisms by which T cells may mediate the pathologic
process are not fully understood. Since anti-CCP antibodies are strongly correlated with shared epitope alleles (2) and since anti-CCP antibodies of the IgG
subclass (implying that class switching has taken place)
are present in RA patients (8), one possible role of
CD4⫹ T cells in RA pathogenesis is to provide T cell
help for citrullinated antigen–specific B cells. Alternatively, CD4⫹ T cells may be directly involved in the
pathologic process through the production of proinflammatory cytokines. It is noteworthy, therefore, that citrullination may increase the affinity of peptide binding to
class II MHC molecules expressing the shared epitope
(9), thus enhancing the efficiency of antigen presentation.
These observations strongly suggest that citrullinated autoantigen–specific T cells play a role in the
pathogenesis of RA. Indeed, data from a recent mouse
model of inflammatory arthritis, in which naive mice
were immunized with citrullinated fibrinogen, revealed
a strong citrullinated fibrinogen–specific T cell response
in the arthritic mice (10). However, citrullinated
autoantigen–specific T cell responses have not been
reported in human RA to date.
The findings of studies using mouse models and
human RA patients have implicated aggrecan as a
candidate autoantigen (11,12). Furthermore, the immunodominant, arthritogenic epitopes of aggrecan have
been identified (13). In the current study, we showed
that T cells specific for a citrullinated arthritogenic
aggrecan peptide are present in RA patients but not in
healthy controls, providing the first evidence that citrullinated autoantigen–specific T cells may play a key role
in the pathogenesis of RA in humans.
PATIENTS AND METHODS
Study population. All cases in the study (n ⫽ 28) were
patients at the rheumatology clinic of a regional teaching
hospital, and all were diagnosed according to the American
College of Rheumatology (formerly, the American Rheumatism Association) revised classification criteria for RA (14).
Anti-CCP antibody levels were assessed at a clinical immunology laboratory (Royal Victoria Infirmary, Newcastle upon
Tyne, UK) using the Diastat assay (Axis-Shield, Dundee, UK).
Control samples were obtained from healthy volunteers at
Newcastle University (n ⫽ 15) or from buffy coats stored at the
Newcastle Blood Transfusion Centre (n ⫽ 3). The study was
approved by the Newcastle and North Tyneside Local Research Ethics Committee, and all participants provided written
informed consent before samples were collected. Data on
clinical characteristics of the patients are available from the
author upon request.
Culture medium and reagents. RPMI 1640 medium
supplemented with 3 mM L -glutamine, 50 ␮ M
2-mercaptoethanol, 30 ␮g/ml gentamicin, and 5% human
antibody serum was used (all from Sigma-Aldrich, Gillingham,
UK). All cells were incubated at 37°C in a humidified incubator containing 95% air and 5% CO2.
Antigens. Citrullinated and noncitrullinated peptides
were synthesized according to the peptide sequence of the
human aggrecan Agg84-103, using a commercially available
synthesis service (GenScript, Piscataway, NJ). (The arginine/
citrulline substitution is underlined in the following:
VVLLVATEGR/CitVRVNSAYQDK.) Heat-inactivated Candida hyphae (1.1 ␮g/ml protein equivalent of 1 ⫻ 105 colonyforming units/ml), a gift from Dr. Desa Lilic (Newcastle
University), was used as a positive control antigen for stimulating interleukin-17 (IL-17) and interferon-␥ (IFN␥) production.
Proliferation assays. Peripheral blood mononuclear
cells (PBMCs) were isolated from whole blood samples using
density-gradient centrifugation. PBMCs (2 ⫻ 105/well, in triplicate) were incubated in 96-well plates with 10 ␮g/ml of
citrullinated or noncitrullinated aggrecan peptide for 9 days.
During the final 18 hours of culture, supernatant to be used in
measuring cytokine production was collected and stored at
⫺40°C. To the remaining culture, medium containing 3Hthymidine was added (final concentration 14.8 kBq/well). Cells
were harvested on glass fiber membranes after 12–16 hours,
and radioactivity was quantified using a Microbeta TriLux
scintillation counter (PerkinElmer, Emeryville, CA). The stimulation index was calculated as counts per minute with antigen/
counts per minute without antigen. Response to phytohemagglutinin (5 ␮g/ml) (Sigma-Aldrich), measured on day 3, was
used as a positive control. A stimulation index of ⬎2 was
considered a positive response.
Intracellular cytokine analysis. PBMCs were stimulated either with R/Cit93-substituted Agg84-103 peptides or with
Candida hyphae. Then, cells were treated with phorbol myristate acetate (50 ng/ml) and ionomycin (1 ␮g/ml) for 5 hours,
the last 4 of which were in the presence of 5 ␮g/ml brefeldin A
(all from Sigma-Aldrich). Nonspecific Fc␥ receptor–mediated
binding was blocked by incubation with human IgG. Cells were
incubated with peridinin chlorophyll A protein–Cy5.5–
conjugated anti-human CD4 (BD Biosciences, Oxford, UK).
After permeabilization and blocking of nonspecific binding
with mouse IgG and rat serum, cells were incubated with Alexa
Fluor 647–conjugated anti-human IL-17 and Pacific Blue–
conjugated anti-human IFN␥ according to the instructions of
the manufacturer (eBioscience, San Diego, CA). Cells were
analyzed using an LSR II 18-color flow cytometer (BD Biosciences), and 10,000 events in the CD4⫹ T cell gate were
collected for each sample. Analysis was performed using
FACSDiva software, version 5 (BD Biosciences).
Measurement of cytokine production in culture supernatant. Concentrations of IL-17A and IL-22 were determined
using a Ready Set Go kit (eBiosciences) and enzyme-linked
immunosorbent assay (Emelca Bioscience, Breda, The Netherlands), respectively, according to the manufacturers’ instructions. Cytokine concentrations in individual samples were
assessed by the 4-parameter Boltzmann sigmoidal curve-fitting
method using GraphPad Prism, version 5.01 (GraphPad Soft-
HUMAN T CELL RESPONSES TO CITRULLINATED AGGRECAN PEPTIDE
ware, San Diego, CA). Th1/Th2 cytokines (IFN␥, IL-2, IL-4,
IL-5, IL-10, IL-12, and IL-13) were quantified simultaneously
using electrochemiluminescence multiplex technology according to the instructions of the manufacturer (Meso Scale
Discovery, Gaithersburg, MD). Signal was detected using a
Sector Imager 2400 (Meso Scale Discovery).
Statistical analysis. Statistical analysis (descriptive statistics, linear regression, and correlation analysis) was performed using GraphPad Prism, and paired and unpaired
2-tailed t-tests were performed using Excel 2002, Service Pack
3 (Microsoft, Redmond, WA). P values less than or equal to
0.01 were considered significant.
RESULTS
A proliferative response to a citrullinated arthritogenic aggrecan peptide was detected in the
majority of RA patients but not in healthy controls. In
order to determine the optimal culture duration for
the detection of proliferative responses to citrullinated and noncitrullinated aggrecan peptides, we
measured the proliferation of PBMCs from 10 RA
patients in response to citrullinated and noncitrullinated aggrecan peptide Agg84-103 over a period of
6–12 days. Throughout the culture period, none of the
patient samples exhibited a response to the noncitrul-
145
linated aggrecan peptide. Strikingly, however, 7 of 10
samples exhibited a response to the citrullinated
aggrecan peptide, with maximal response observed on
day 9 (data available from the author upon request).
We therefore extended our investigation to include a
total of 28 RA patients and 18 healthy controls.
Consistently, PBMCs from 17 of the 28 RA patients
(60.7%) proliferated in response to the citrullinated
aggrecan peptide. In contrast, none of the RA samples
proliferated in response to the noncitrullinated aggrecan peptide. Furthermore, PBMCs from healthy controls did not proliferate in response to either the
citrullinated or the noncitrullinated aggrecan peptide
(Figure 1). The responses to phytohemagglutinin, a
polyclonal T cell mitogen, were similar in RA patients
and in healthy controls (data not shown).
Responses to the citrullinated aggrecan peptide
are biased toward proinflammatory cytokines. Using
PBMCs from RA patients, we also examined cytokine
production in response to the aggrecan peptide. The
level of IL-17 in the culture supernatant of PBMCs that
had proliferated in response to the citrullinated aggrecan peptide was significantly increased compared with
Figure 1. Proliferative and cytokine responses in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis (RA) patients (n ⫽ 28)
and normal subjects (n ⫽ 18). PBMCs were pulsed with the aggrecan84–103 peptide (R-Agg) or the citrullinated analog of the same peptide (Cit-Agg)
for 9 days. A, Proliferative responses, measured as the mean 3H-thymidine incorporation in triplicate cultures. Horizontal bars show the mean;
vertical bars show the 95% confidence interval. Differences between groups were compared by 2-tailed t-test. B and C, Concentrations of
interleukin-17 (IL-17) (B) and interferon-␥ (IFN␥) (C) in cell cultures that were stimulated with the citrullinated or noncitrullinated aggrecan
peptide or were left unstimulated. Concentrations of IL-17 and IFN␥ in supernatants were assessed using enzyme-linked immunosorbent assay.
Horizontal bars show the median. RA patients classified as responders were those in whom the proliferative response (i.e., stimulation index) to the
citrullinated aggrecan peptide was ⬎2, and patients classified as nonresponders were those in whom the proliferative response was ⱕ2.
146
VON DELWIG ET AL
Figure 2. A and B, Intracellular production of IL-17 (A) and IFN␥ (B) measured using flow cytometry. Horizontal bars show the median. C,
Representative flow cytometric plots from a responder (top) and a nonresponder (bottom). Cells were gated on CD4⫹ lymphocytes. Differences
between groups were compared by 2-tailed t-test. See Figure 1 for explanations and definitions.
levels in unstimulated cultures (Figure 1B). This was
accompanied by an induction of IL-17⫹CD4⫹ cells,
as detected using flow cytometry (Figures 2A and C).
In contrast, in the culture supernatant of PBMCs that
had not proliferated in response to the citrullinated
aggrecan peptide, there was only a modest increase in
IL-17 levels and no increase in IFN␥ levels, compared
with levels in unstimulated cultures (Figure 1), and
there was no induction of either IL-17⫹CD4⫹ cells or
IFN␥⫹CD4⫹ cells (Figure 2). Furthermore, there
was no significant increase in the production of IL-17
or IFN␥ in PBMCs that did or those that did not
respond to stimulation with the noncitrullinated aggrecan peptide. Production of IL-17 and IFN␥ in
response to Candida, a control antigen, was similar in
PBMCs that did and those that did not respond to the
citrullinated aggrecan peptide (data available from
the author upon request). Furthermore, the production of IL-22 was increased in PBMCs that responded
to the citrullinated aggrecan peptide (Figure 3A). The
levels of other cytokines (IL-2, IL-4, IL-5, IL-10,
IL-12, and IL-13) in PBMC cultures did not change
significantly after stimulation with either the citrulli-
nated or the noncitrullinated aggrecan peptide (data
not shown).
Correlation of citrullinated aggrecan peptide–
specific proliferative responses with IL-17 production
and anti-CCP titer. Since our data showed that the
production of IL-17 in PBMCs from RA patients was more
prominent in those that exhibited a response to the citrullinated aggrecan peptide, we performed linear regression
and correlation analysis to clarify the relationship between
the proliferative response and the IL-17 response. We
found that proliferation in response to the citrullinated
aggrecan peptide strongly correlated with production of
IL-17 (r ⫽ 0.724, P ⫽ 0.001) (Figure 3B). Taken together,
our data suggest that Th17 cells were the cellular subset in
PBMCs that were responsible for the citrullinated aggrecan peptide–specific responses in RA patients.
We also investigated whether proliferation was
correlated with other clinical parameters, including antiCCP titer, C-reactive protein level, erythrocyte sedimentation rate, disease duration, and age. Only anti-CCP
titer was found to be moderately correlated with the
proliferative response (r ⫽ 0.512, P ⫽ 0.009) (data not
shown).
HUMAN T CELL RESPONSES TO CITRULLINATED AGGRECAN PEPTIDE
147
Figure 3. A, IL-22 production by PBMCs from RA patients. PBMCs were incubated for 9 days in the presence of the aggrecan84–103 peptide or the
citrullinated analog of the same peptide. Concentrations of IL-22 in the cell culture supernatants were assessed using enzyme-linked immunosorbent
assay. Horizontal bars show the median. Differences between groups were compared by 2-tailed t-test. B, IL-17 production in response to stimulation
with the citrullinated aggrecan peptide. In RA patients, production of IL-17 in response to stimulation with the citrullinated aggrecan peptide was
strongly correlated with proliferative responses of the PBMCs. Concentrations of IL-17 were modeled as functions of the proliferative responses of
the PBMC samples from RA patients to the citrullinated aggrecan peptide. The diagonal solid line indicates linear regression lines, and curved
broken lines indicate the 95% confidence interval. NS ⫽ not significant; SI ⫽ stimulation index (see Figure 1 for other definitions).
DISCUSSION
In the current study, we have demonstrated that
PBMCs from ⬃60% of RA patients proliferated in
response to the citrullinated analog of a major arthritogenic epitope of aggrecan, which was accompanied by
increased production of IL-17 in the culture supernatant
and by the induction of IL-17⫹CD4⫹ T cells. The lack
of response to the corresponding noncitrullinated aggrecan peptide indicated that the citrulline residue is integral to the antigen specificity of the observed immune
response. Although purified T cells were not used in our
experiments, the use of a 20-mer peptide in these assays,
together with our observation that CD4⫹IL-17⫹ T cells
were induced following stimulation with the citrullinated
aggrecan peptide, strongly suggests that the citrullinated
aggrecan peptide–specific responses were driven by T
cells. To our knowledge, this is the first study demonstrating the presence of citrullinated autoantigen–
specific T cells in patients with RA.
Aggrecan is a proteoglycan which forms a major
structural component of articular cartilage. Data from
animal models have implicated aggrecan in the pathogenesis of RA, since immunization with aggrecan elicited aggrecan-specific T cell and B cell responses and
induced inflammatory arthritis in susceptible mouse
strains (11). However, although immune responses directed against aggrecan peptides have been reported in
RA patients (12), similar responses were also observed
in patients with other forms of arthritis, such as ankylosing spondylitis and osteoarthritis (15). Indeed, in one
study, the immune response to aggrecan peptides was
more readily detectable in healthy controls than in
patients with RA (16). In contrast, in our study, a
citrullinated aggrecan peptide–specific response was detected exclusively in patients with RA. Therefore, we
have identified not only a novel candidate, RA-specific
autoantigen that could play an important role in the
pathogenesis of RA, but also a potentially useful biomarker of RA.
Although it is tempting to speculate on a pathogenic role for citrullinated aggrecan peptide–specific T
cells, further investigations are needed to define their
148
role and clinical significance in RA. In the current study,
we found that citrullinated aggrecan peptide–specific T
cells produced proinflammatory cytokines IL-17 and
IL-22, raising the possibility that these cells may be
directly involved in joint and cartilage inflammation and
damage. Indeed, synovial fluid mononuclear cells from 2
of 3 RA patients also proliferated in response to stimulation with the citrullinated aggrecan peptide (von Delwig A, Ng W-F: unpublished observations). Another
possible role for the citrullinated aggrecan peptide–
specific T cells could be to provide help for citrullinated
aggrecan–specific B cells. In this regard, we found that
anti-CCP titer was modestly correlated with the magnitude of citrullinated aggrecan peptide–specific proliferative responses, although citrullinated aggrecan
peptide–specific responses were observed in some antiCCP–negative patients and were not observed in some
anti-CCP–positive patients. Additionally, it is unclear
whether the commercially available assay that we used to
measure anti-CCP antibodies was capable of detecting
anti–citrullinated aggrecan antibodies. Direct measurement of anti–citrullinated aggrecan antibodies in the
sera of these patients would be more informative for
addressing whether citrullinated aggrecan peptide–
specific T cells provide help for citrullinated aggrecan
peptide–specific B cell responses.
The reason for the lack of observable responses
to the citrullinated aggrecan peptide in ⬃40% of RA
patients and in all the healthy controls is unclear, but
there are several nonmutually exclusive possibilities.
First, the affinity of peptide binding to different class II
MHC molecules differs; therefore, it is possible that the
class II MHC molecules in patients who did not respond
to the citrullinated aggrecan peptide failed to efficiently
present the citrullinated aggrecan peptide, in favor of
another aggrecan peptide or different autoantigens.
Therefore, future studies will need to determine whether
responses to the citrullinated aggrecan peptide are restricted to particular class II MHC alleles and to investigate the responses to other candidate citrullinated
peptides. Second, the frequency of the citrullinated
aggrecan peptide–specific T cells might be too low to be
detected using the methods we employed in the current
study. Third, response to the citrullinated aggrecan
peptide may be suppressed (e.g., by Treg cells), which
may be particularly relevant in healthy controls.
In conclusion, we have shown that citrullinated
aggrecan peptide–specific Th17 cells are present in the
peripheral blood of RA patients. Further investigation
of the clinical significance of these autoimmune T cells
and their role in mediating the inflammatory process in
VON DELWIG ET AL
RA may advance our understanding of the pathogenesis
of RA, inform the development of novel antigen–
specific therapeutic strategies, and identify useful biomarkers of RA.
ACKNOWLEDGMENTS
We thank all the patients and volunteers for donating
blood samples, and all the medical and nursing staff in the
musculoskeletal department for assisting with sample collection.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Ng had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Von Delwig, Robinson, Ng.
Acquisition of data. Von Delwig, Locke.
Analysis and interpretation of data. Von Delwig, Robinson, Ng.
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DOI 10.1002/art.27320
Arthritis & Rheumatism 2009 Abstract Supplement Available Online
The abstracts presented at the ACR/ARHP 2009 Annual Scientific Meeting were published in a supplement
to the October 2009 issue of Arthritis & Rheumatism. The paper supplement was distributed on-site at the
2009 meeting in Philadelphia, and the full content of the supplement is available electronically at
http://acrmeeting.wiley.com. From there, abstracts can be searched by topic or author, or browsed. The
correct reference citation information is shown at the bottom of each abstract.
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