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The Journal of Immunology, 2004, 172: 5063-5068.
Copyright © 2004 by The American Association of Immunologists

Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis1

Jolanda H. M. van Bilsen2, Josée P. A. Wagenaar-Hilbers, Mayken C. J. T. Grosfeld-Stulemeijer, Maarten J. F. van der Cammen, Mariska E. A. van Dijk, Willem van Eden and Marca H. M. Wauben3

Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA)4 is considered to be an autoimmune disease resulting from a complex interplay of factors. Its etiology remains unknown, but genetic factors and data from animal models support the idea that autoreactive T cells play a central role in the autodestructive process (1, 2). Autoreactive T cells are part of a normal immune repertoire and because of their strict regulation, do not normally induce autoimmune diseases. However, such autoreactive T cells can become activated and clonally expanded by, e.g., bacterial or viral superantigens (3, 4, 5) or by viral or bacterial peptides that have similarity with a self-epitope (molecular mimicry) (6). To better understand the role of autoreactive T cells during the arthritis process and to develop T cell modulatory immunotherapies, it is important to identify the Ags driving these T cell responses.

Adjuvant arthritis (AA), a T cell-mediated experimental arthritis model induced by immunization of Lewis rats with heat-killed Mycobacterium tuberculosis (Mt) in oil (7), can be passively transferred into naive irradiated rats by a CD4+ T cell clone obtained from AA rats (8). This arthritogenic T cell clone (A2b) is specific for amino acids 178–186 of the Mt 65kDa heat shock protein (hsp60 family) (9, 10), and shows cross-reactivity with a to be defined self-epitope present in crude and chondroitin sulfate-enriched preparations of cartilage proteoglycans (11). These findings led to the hypothesis of molecular mimicry between the mycobacterial epitope and a cartilage-associated component.

Recently, we tried to identify this cartilage-associated epitope by searching the Swiss-Prot database with a search profile based on MHC binding and TCR contact residues of the mycobacterial T cell epitope recognized by the A2b T cell clone (12). However, none of the predicted arthritis-associated self-epitopes appeared to be the mimicry epitope for A2b.

One the selection criteria for the prediction of arthritis-associated self-epitopes was binding to the MHC class II molecule RT1.BL. In the present study, we investigated whether the selected epitopes were recognized by T cells during experimental arthritis (AA and avridine arthritis), and investigated the arthritogenic capacity of a subset of peptides upon immunization. Furthermore, self-peptide-specific T cells were generated and analyzed for their capacity to passively transfer arthritis. Interestingly, several matrix metalloproteinase (MMP)-derived epitopes were recognized by arthritogenic T cells. Because T cell responses to MMP-3 were most pronounced, B cell responses to MMP-3 were also analyzed during the course of AA.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Peptides

Mt hsp65178–186 (SNTFGLQLE) and OVA323–339 (ISQAVHAAHAEINEAGR) peptides were obtained from Isogen (Maarn, The Netherlands). All other peptides used in this study were synthesized via automated simultaneous multiple peptide synthesis (13). Peptides were obtained as C-terminal amides after cleavage with 90–95% TFA/scavenger mixtures. Peptides were analyzed by reversed-phase HPLC, and checked via electrospray ionization mass spectrometry (LCQ; Thermoquest, Breda, The Netherlands). Peptides MBP72–85 (QKSQRSQDENPV) and MBP87–99 (VHFFKNIVTPRTP) were biotinylated during synthesis and used as marker peptides in respectively the RT1.BL and the RT1.DL MHC peptide-binding assays. We used nonamer peptides for initial screening of the entire panel of predicted self-epitopes (12) in AA. Subsequently, we used 15-mer for a second screening in AA, avridine arthritis, and the in vivo experiments, by extending the 9-mer core peptides by adding three naturally flanking residues at either the N or the C terminus.

Induction of experimental arthritis

AA and avridine arthritis were induced in 6- to 8-wk-old male Lewis rats (Maastricht University, Maastricht, The Netherlands) by intradermal injection at the base of the tail with 0.1 ml of, respectively, 10 mg/ml heat-killed Mt H37RA in IFA (Difco, Detroit, MI) or 20 mg/ml avridine (CP20961; Pfizer, Groton, CT) in light mineral oil (Sigma-Aldrich, Zwijndrecht, The Netherlands).

Ex vivo proliferation assays

At consecutive time points after experimental arthritis induction, spleen, popliteal, and inguinal lymph node (INLC) cells and PBMC were isolated and cultured (2 x 105 cells/well in triplicate) in the absence or presence of peptide (1 or 10 µg/ml). After 3 days of culturing, proliferation was determined by overnight incorporation of [3H]thymidine (14). Proliferation was considered positive at a stimulation index (SI) >= 2. Peptides were selected for further study if they induced proliferation in >=50% of a specified organ (e.g., spleen) tested at one time point. If only two spleens or lymph nodes were tested at a certain time point, an additional time point or organ should be positive as well for a peptide to be selected.

Competitive MHC class II-peptide binding assays

Lewis rat MHC class II molecules RT1.BL and RT1.DL were purified from the Z1a T cell clone as described previously (15). The MHC class II-peptide binding studies were performed using a competitive binding assay as described previously (15). Binding to RT1.BL and RT1.DL was tested with the 15-mer peptides. As marker peptides, the peptides MBP72–85 (QKSQRSQDENPV) and MBP87–99 (VHFFKNIVTPRTP) were used in, respectively, the RT1.BL and RT1.DL MHC class II-peptide binding assays.

Peptide-induced arthritis

Rats were immunized s.c. in one hind footpad with 100 µl of a 1:1 emulsion of peptide (100 µg) mixed with the adjuvant dimethyl dioctadecyl ammonium bromide-suspension (DDA; Phase Separations, Waddinxveen, The Netherlands; 20 mg/ml in PBS) (16). Rats were examined for clinical signs of arthritis for at least 60 days in a blinded set-up, by grading each paw from 0 to 4 based on erythema, swelling, and deformity of the joints resulting in a maximum score of 16.

Passive transfer of arthritis

Rats were injected with a 1:1 emulsion of peptide in DDA suspension as described above. At day 11, popliteal lymph nodes were isolated and labeled with FITC-conjugated mouse anti-CD4 (OX35; BD PharMingen, San Diego, CA). CD4+ cells were positively selected by cell sorting using the FACS-Vantage (BD Biosciences, Brussels, Belgium) and restimulated in vitro (2 x 106 cells/ml) with 10 µg/ml peptide in the presence of irradiated (3000 rad) syngeneic thymocytes (107/ml) as APCs. After 3 days, viable cells were isolated by Ficoll-Isopaque gradient and transferred i.v. into naive rats (8.0–10 x 106 CD4+ cells/rat). After 11–26 days, rats were injected s.c. with 50 µl of DDA suspension into one hind footpad to promote inflammation (17). Rats were monitored for clinical signs of arthritis as described above.

Histologic analysis

Joints were fixed in 4% phosphate-buffered paraformaldehyde, decalcified with a 10% EDTA solution, pH 7.0 (Merck, Darmstadt, Germany), and embedded in paraffin wax. Joint sections were stained with H&E, and analyzed by light microscopy.

Determination of IgG Abs to MMP-3 in serum

Serum samples were collected from arthritic rats 35 days after AA induction, and sera from n = 5 rats were pooled. As serum control, a pool of n = 5 age- and sex-matched healthy rats were used. To detect Abs against MMP-3 in serum, recombinant human pro-MMP-3 (R&D Systems/ITK Diagnostics, Uithoorn, The Netherlands) was applied to a 12% SDS-polyacrylamide gel under reducing conditions and blotted to nitrocellulose membranes as described above. After blocking, the membranes were cut into strips, and subsequently incubated for 1 h in the different serum pools which were diluted in blocking reagent (Boehringer Mannheim, Almere, The Netherlands) and 0.05% Tween 20 in PBS. Binding of the serum Abs was followed by an incubation with peroxidase-conjugated F(ab')2 rabbit-anti-rat IgG (Jackson ImmunoResearch/Sanbio, Uden, The Netherlands). Next, the strips were incubated with biotinylated goat anti-rabbit polyclonal Ab (Dakocytomation, Heverlee, Belgium) which was detected by incubation with peroxidase-conjugated streptavidin and visualized on preflashed films (Hyperfilm; Amersham Pharmacia Biotech, Roosendaal, The Netherlands) through ECL (Western blot ECL kit; Amersham Pharmacia Biotech). As control for the MMP-3 blotting, we used a monoclonal mouse Ab against human MMP-3 (Neomarkers Immunologic, Duiven, The Netherlands), which was detected with peroxidase-conjugated monoclonal goat-anti-mouse IgG (Nordic Immunological Laboratories, Tilburg, The Netherlands). As negative control, we incubated membranes without rMMP-3 with the different serum pools and second and third step conjugates. Spots on the films were analyzed by Molecular Analyst Software version 1.5 (Bio-Rad Laboratories, Veenendaal, The Netherlands).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
T cell recognition of self-peptides during experimental arthritis

We analyzed whether the previously predicted T cell self-epitopes (12) were recognized during AA. To this end, proliferative T cell responses were monitored during the course of AA in three lymphoid organs: the spleen, to represent the systemic immune response; the ILNC draining the immunization site; and the popliteal lymph nodes (PLNC) draining the arthritic joints. T cell responses were analyzed in lymphocyte proliferation assays at days 10 (before clinical onset of disease), 14 (onset of disease), 21 (overt disease), and 35 (no or limited clinical disease) after disease induction with Mt/IFA. Of the n = 51 previously predicted T cell self-epitopes (12), n = 14 peptides induced proliferation (Table I, AA section). The T cell epitopes OVA323–339 and MBP72–85 were used as negative control and did not induce proliferation (data not shown), while Mt hsp65 and the Mt hsp65178–186 epitope were used as positive controls (Table I). Furthermore, lymph nodes and spleens derived from naive rats (n = 5 tested) or rats immunized with OVA323–339/DDA (n = 8 tested) did not show specific proliferation to the peptides recognized during AA (our unpublished data).


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  		Table I. Monitoring of proliferation to arthritis/cartilage-associated epitopes in experimental arthritisa

 
To extend the relevance of T cell recognition of these "novel" self-epitopes beyond the AA model, we tested whether the same T cell reactivity could be found in another arthritis model in Lewis rats, i.e., avridine arthritis. Interestingly, 11 of the 14 peptides recognized during AA also induced proliferation during avridine arthritis (Table I, Avridine Arthritis section). The Mt. hsp65 178–186 epitope (positive control) showed proliferation in both experimental arthritis models indicating that the recognition of this epitope is not restricted to the AA model (Table I). The properties of the n = 14 peptides recognized during experimental arthritis are depicted in Table II.


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  		Table II. Characteristics of the self-peptides recognized during AA

 
MHC binding affinity of peptides recognized during experimental arthritis

The search profile used for the selection of arthritis-associated self-epitopes was based on binding to MHC class II RT1.BL. The MHC class II binding affinities of the n = 14 peptides recognized during experimental arthritis, were tested in a competitive MHC peptide binding assay (15). As shown in Table III, the MHC class II RT1.BL binding affinities ranged from low to high, indicating that there is no clear correlation between the MHC binding affinity of the peptides and T cell recognition. Furthermore, all peptides were poor MHC class II RT1.DL binders (IC50 values >256 µM) confirming the selectivity of our search profile for RT1.BL binders.


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  		Table III. Peptide-MHC binding affinity to purified RT1.BL and RT1.DL molecules

 
Peptide-induced arthritis

To study the arthritogenic capacity of the self-epitopes that induced specific proliferation in the experimental arthritis models (n = 14), rats were immunized with the selected peptides in DDA (n >= 5 rats/peptide), and observed for clinical signs of arthritis. The arthritogenic capacity of these peptides was compared with predicted self-epitopes (n = 5 rats/peptide) that did not induce T cell reactivity in experimental arthritis (n = 14 peptides). Of the latter panel (Table IV, self peptides not recognized during AA), none of the immunized rats developed arthritis while of the former panel (Table IV, self peptides recognized during AA) 6 of 14 peptides induced arthritis (Table IV). Interestingly, three of the six arthritogenic peptides appeared to be MMP-derived epitopes. The clinical arthritic manifestations were further confirmed by histology (data not shown).


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  		Table IV. Arthritogenic capacity of motif-containing self-peptides

 
Passive transfer of arthritis by peptide-specific CD4+ T cells

To investigate whether the peptide-induced arthritis was T cell-mediated, we performed T cell transfer studies. CD4+ T cells were isolated from peptide-immunized rats and restimulated once in vitro with the specific peptide before T cell transfer into naive Lewis rats. Only CD4+ cells derived from MMP-3-immunized rats could passively transfer arthritis (in one of five rats) without an additional inflammatory DDA stimulus (Table V). In the presence of DDA, CD4+ T cells from MMP-3, MMP-10, and MMP-16 immunized rats could transfer arthritis, while CD4+ T cells from aggrecan-1, lumican, and perlecan-murine were not arthritogenic. As control T cell lines, we transferred CD4+ T cells from rats immunized with two nonarthritogenic peptides, derived from our initial panel of n = 51 peptides: phospholipase A253–67 (n = 4 rats), laminin {alpha}-1 chain precursor2179–2193 (n = 4 rats), or with peptide OVA323–339 (n = 6 rats). None of the 14 control rats developed arthritis (Table V). Although, it has been published that under certain circumstances and at high concentrations, DDA can induce arthritis in Lewis rats (18), the low concentration of DDA used in our studies did not induce arthritis in our colony of Lewis rats (tested in > n = 100 rats (our unpublished data)). The clinical manifestations observed in the CD4+-transfer studies were further substantiated with histology. In the ankle joints of the clinically affected rats, alterations of the normal architecture, including synovial cell proliferation and perivascular and diffuse infiltrates of mononuclear and polymorphnuclear cells, were evident (Fig. 1, A–D). Although both bone and cartilage destruction were clearly present, no signs of new bone formation or ankylosis were observed. In contrast, in the OVA323–339-CD4+ transferred control rats, no (inflammatory) changes could be detected (Fig. 1, E and F).


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  		Table V. Passive arthritis induction by CD4+ T cell transfera

 


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  		FIGURE 1. Histologic presentation of passively transferred arthritis by CD4+ T cells from peptide-immunized rats. Ankle joints of rats that received CD4+ T cells from MMP-3444–458 (A and B), MMP-10329–343 (C and D), and OVA323–339 (E and F) immunized rats.

 
B cell recognition of MMP-3 during AA

In several rodent models of experiment arthritis and also in RA, the presence of autoantibodies has been described. Because arthritogenic T cell responses to the MMP-3-derived T cell epitope were most prominent, we addressed the question of whether MMP-3 also becomes a target for B cells during the course of AA. To this end, we evaluated the kinetics of the Ab response to the MMP-3 protein in naive rats and in rats that recovered from AA (35 days after AA induction). Because human and rat MMP-3 proteins have a high sequence homology, and no rat recombinant MMP-3 is available, purified human recombinant pro-MMP-3 (54/56 kDa; unglycosylated/glycosylated pro-MMP-3) was used to set-up a Western blot assay to detect serum Abs to MMP-3 in arthritic Lewis rats. As positive control, recombinant pro-MMP-3 was incubated with mouse anti-human MMP-3 (Fig. 2, lane 1). Naive rat serum already contains IgG autoantibodies against the glycosylated 56 kDa recombinant MMP-3 (Fig. 2, lane 4). However, at day 35 after AA induction the titer is increased (Fig. 2, lane 3). Moreover, serum from rats 35 days after disease induction also contains IgG autoantibodies against the unglycosylated 54-kDa recombinant MMP-3 (Fig. 2, lane 3).



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  		FIGURE 2. IgG Ab responses to recombinant pro-MMP-3 after AA induction. Ab titers in the serum pools to recombinant pro-MMP-3 were analyzed by Western blot analysis. Lane 1, Incubation with mouse anti-human MMP-3 (positive control); lane 2, incubation without serum (negative control); lane 3, incubation with serum from rats 35 days after disease induction (pool n = 5); lane 4, incubation with serum from naive rats (pool n = 5).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
To better understand the role of autoreactive T and B cell responses during the arthritis process and to develop immunomodulatory therapies, it is important to identify the Ags driving these responses. At present, T cell recognition of only a limited number of self-Ags has been described in RA, e.g., type II collagen (19, 20), human cartilage glycoprotein 39 (HC gp-39) (21), hsp60 (22, 23), chondrocyte Ag 65 (24), synovial fluid-derived p205 (25), and the endoplasmatic reticulum molecular chaperone BiP (26). In this study, we have identified several new targets for the immune system during the arthritis process.

Previously, the prediction of putative autoantigens in RA (e.g., within HC gp-39 (21) and aggrecan (27)), was based on high MHC binding affinity for the RA-associated HLA-DRB1*0401. However, it is still a matter of debate whether self-epitopes display high or low binding affinity for their MHC restriction element (15, 28, 29). Our present data demonstrate that self-epitopes recognized by T cells during experimental arthritis display a wide range of MHC class II binding affinities. Interestingly, although the original search profile was based on rat MHC class II RT1.BL binding peptides, almost 50% of the peptides recognized during experimental arthritis were also recognized by RA patients, suggesting a possible similarity in the pathophysiology in RA patients and the experimental arthritis models in the rat (30).

In this study, we report that three of the six newly identified arthritogenic self-peptides are derived from the MMPs: MMP-3, MMP-10, and MMP-16. Furthermore, CD4+ T cells isolated from MMP-3, MMP-10, and MMP-16 peptide-immunized rats could passively transfer arthritis into naive Lewis rats, thereby demonstrating the CD4+ T cell-mediated nature of the peptide-induced arthritis.

Because MMP-3-peptide-specific CD4+ T cells induced arthritis with the highest incidence and scores, we evaluated the B cell response against MMP-3 and demonstrated that MMP-3 also becomes a target for B cells during AA. The Ab response was analyzed under reducing conditions in a Western blot. Therefore, this response is probably even underestimated because only Abs directed to linear epitopes were detected. The occurrence of autoantibodies against MMP-3 might on one hand suggest that a counterregulatory mechanism exists that regulates the presence, and thereby the destructive action, of MMP-3. In contrast, the autoantibodies might enhance the arthritic process by forming immune complexes. The physiological role of the observed B cell response to MMP-3 in the disease process remains to be elucidated.

Previously, MMP-3, MMP-10, and MMP-16 have been implicated in cartilage degradation and their expression is initiated or up-regulated in joints of RA patients (31, 32, 33). They are involved in the activation cascade of other proteinases relevant to RA, such as MMP-1, -2, -7, -8, -9, and -13 (34). Besides cartilage degradation, MMPs play a role in the migration of macrophages and neutrophils during RA (35, 36) and can antagonize apoptosis of proliferating synovial cells, thereby exacerbating the inflammatory process (37). On the contrary, MMPs can suppress inflammation by degrading biologically active molecules such as cytokines, chemokines, and growth factor receptors (38, 39, 40, 41, 42). In the present study, we identified a novel role for MMPs in the arthritis process, as targets for the immune system. We propose that the enhanced expression of MMPs during synovial inflammation leads to a breach in peripheral tolerance of MMP-specific T and B cells, resulting in the activation of such cells. Furthermore, because MMPs are not joint- or cartilage-specific but instead are expressed throughout the body, we assume that not the absence or presence of particular self-Ags as such drives the arthritis process, but that the expression level of the Ags and the APCs involved in the presentation are of crucial importance. In this manner, the inflammation-driven local up-regulation of MMPs in synovial tissues can explain the joint-localized inflammatory response. MMP expression is down-regulated by cytokines such as IL-4 and IFN-{gamma}, and up-regulated by proinflammatory cytokines such as IL-1 and TNF-{alpha} (43, 44). Whether the immune response to MMPs is involved in the perpetuation or the down-regulation of MMP production and arthritis is currently under investigation, and will largely depend on the produced cytokines.

In conclusion, here we show for the first time that MMPs become a target for T and B cell recognition during arthritis. Because several MMP epitopes are also recognized in RA patients (30), and appeared to be useful for immunotherapy in experimental arthritis (45), MMPs are interesting novel candidates for Ag-specific immunotherapy and monitoring of T and B cell reactivity during RA.


   Acknowledgments
 
We thank A. Noordzij and R. van der Zee for peptide synthesis, M. H. van der Hage for assistance in histologic evaluation, M. Nolte for technical assistance, and C. Broeren (deceased) (Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands) for critically reviewing this manuscript.


   Footnotes
 
1 This study has been financially supported by Upither B.V. and Yamanouchi Pharmaceutical, Japan. Back

2 Current address: Department of Rheumatology, Leiden University Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Back

3 Address correspondence and reprint requests to Dr. Marca H. M. Wauben at the current address: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: M.H.M.Wauben{at}lumc.nl Back

4 Abbreviations used in this paper: RA, rheumatoid arthritis; AA, adjuvant arthritis; Mt, Mycobacterium tuberculosis; hsp, heat shock protein; MMP, matrix metalloproteinase; DDA, dimethyl dioctadecyl ammonium bromide; SI, stimulation index; ILNC, inguinal lymph node; PLNC, popliteal lymph node. Back

Received for publication August 8, 2003. Accepted for publication February 11, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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