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*
Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Department of Pathology, Slotervaart Hospital, Amsterdam, The Netherlands; and
Jan van Breemen Institute for Rheumatology, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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to express the FDC phenotype,
irrespective of their RA or non-RA background. By contrast, the FDC
function, i.e., stable binding of GC B cells and switching off the
apoptotic machinery in B cells, appeared to be the prerogative of
RA-derived FLS only. The present data indicate that FDC function of FLS
in RA patients is intrinsic and support the idea that synovial
fibroblast-like cells have undergone some differentiation process that
is unique for this disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The precise origin of FDCs has not been elucidated completely. FDCs
show phenotypic overlap with fibroblasts and proliferate poorly (13).
Also, ontogenetic studies have indicated that FDCs originate from
stromal cells (14). Moreover, in animals that are recovering from
immune suppression, it has been shown that the local presence of B
cells is a prerequisite for the induction of FDCs from stromal
precursors (15). Recent studies with knockout mice support these
findings and demonstrate an important role for lymphotoxin- and
lymphotoxin-ß from bone marrow-derived cells and the involvement of
the TNF-receptor 1 (TNFR1;p55) and the lymphotoxin-ßR on stromal
cells in the formation of GCs and FDC networks (16, 17, 18, 19, 20, 21, 22, 23).
It is tempting to suppose that RA patients have synovial fibroblasts
that are more prone to differentiate into FDC-like cells than patients
that do not develop RA. Since TNF- production is a common feature of
the synovium in active RA (24, 25, 26), and also TNFR1 (p55) is highly
expressed in synovial tissues of RA patients (27), it is well
conceivable that the basic conditions that lead to induction of FDCs in
lymphoid organs are fulfilled in the rheumatoid synovium as well.
In this study, we have investigated whether the presence of cells with an FDC phenotype and FDC function (i.e., the capacity to bind GC B cells and to switch off their apoptotic machinery) is a specific feature of the synovium in RA patients or is a common phenomenon that rather reflects the inflammatory situation of the synovium. In addition, we have looked if and under what conditions cultured fibroblast-like synoviocytes (FLS) from RA and non-RA arthritic patients may express the phenotype and function of FDCs. Our data show that RA-derived FLS display intrinsic FDC function, whereas non-RA FLS do not.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Biopsies were taken from the inflamed synovium of the knee joint
of patients summarized in Table I
using
direct vision, low pressure arthroscopy. All patients suffered from
arthritis of the knee. RA patients fulfilled the American College of
Rheumatology criteria of RA (28). From each patient, two to three
biopsies were used for pathology to confirm the diagnosis. Three to
five additional biopsies were used for the studies described below,
isolation of synovial cells, and the generation of FLS cell lines.
Researchers were blind for the diagnosis during their studies. All
procedures were done following a protocol agreed upon by the AMC
Medical Ethical Committee.
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Freshly obtained biopsies were frozen in liquid nitrogen and cut into 5-µm sections according to routine histopathologic procedures. For pathology, sections were stained with hematoxylin and eosin. Additional sections of the same biopsies were immunophenotyped, as described below.
Isolation of synovial cells
Biopsies were incubated twice for 60 min at 37°C under continuous shaking in 5 ml IMDM + 90 µg/ml gentamicin (IMDM/g) containing 800 U/ml collagenase type IV (Worthington, Freehold, NJ). This procedure led to virtually complete digestion of visible tissue fragments. Only blood vessels remained intact. These could readily be recognized and excluded from counting. The liberated cells were washed twice, resuspended in IMDM/g + 10% FCS (HyClone, Logan, Utah), and stored on ice until further testing. A total of 105–106 synovial cells was obtained from each biopsy.
Immunophenotyping of synovial biopsies and synovial cells
Immunophenotyping was done by indirect staining of cryosections,
cytospin preparations, or chamber slide cultures. Preparations were
incubated for 60 min with mAbs (Table II)
or isotype-matched control Igs, followed by horseradish
peroxidase-conjugated rabbit anti-mouse Ig (Dakopatts, Glostrup,
Denmark). Isotype-matched control Igs used were MOPC21 (IgG1), UPC10
(IgG2a), and MOPC141 (IgG2b) (all from Sigma, St. Louis, MO), or normal
mouse serum (Dako). No staining was found with any of these control
Igs. Peroxidase activity was visualized by incubation with the
substrate 3-amino-9-ethyl-carbazole (Sigma) in acetate buffer, pH 4.9,
for 60 min at room temperature. Sections and cells were counterstained
with hematoxylin.
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Biopsies were cut into small pieces, placed into six-well culture plates (Costar, Cambridge, MA), and cultured in IMDM/g + 10% FCS. After 3 wk, FLS were harvested by incubating with 0.25% trypsin solution (Life Technologies, Paisley, Scotland) for 5–10 min at 37°C and transferred to 75-cm2 culture flasks (Costar). Upon confluence, cultures were passaged (1:5). Cultured FLS were used for experiments between passages 2 and 8. All FLS cell lines expressed the enzyme prolyl 4-hydroxylase (EC 1.14.11.2) and stained positive with the fibroblast-specific mAbs MAS516 and ASO2.
Stimulation of FLS in vitro
FLS were harvested and cultured for 3 days in 16-well chamber
slides (Nunc, Naperville, IL) in the presence or absence of human
rTNF- (rhuTNF-; Chiron, Emeryvile, CA) and IL-1ß (rhuIL-1ß;
CLB, Amsterdam, The Netherlands). Cytokines were added at 50 U/ml final
concentration. After stimulation, the cells were fixed in acetone and
immunophenotyped, as described above.
Purification of GC B cells
Tonsillar B lymphocytes were isolated according to the method described by Falkoff et al. (29). Briefly, tonsillar cell suspensions were depleted of T cells by rosetting with 2-aminoethylisothiouroniumbromide (AET; Sigma)-treated SRBC. The rosetted cells were removed by centrifugation on Lymphoprep (1077 mg/ml; Nycomed, Oslo, Norway). The final cell population contained >98% CD20-positive cells (B cells) and <1% CD3-positive cells (T cells), as analyzed by FACScan.
Low density B cell fractions were obtained according to the method described by Koopman et al. (30). Briefly, B cells were centrifugated (15 min, 1200 x g, 4°C) on a Percoll gradient, consisting of four layers (1077, 1067, 1056, and 1043 mg/ml). Cells at the 1043/1056 interface (low density B cells) were harvested. GC B cells were further purified by incubation of the LD B cell fraction with Abs against sIgD (JA11; Oxoid, London, U.K.) and anti-CD39 (AC2; Immunotech, Luminy, France), followed by depletion of the labeled cells using sheep anti-mouse Ig-coated Dynabeads (Dynal, Oslo, Norway). Purified GC B cell fractions consisted of >98% CD38+ cells and <2% CD39+ and sIgD+ cells.
Cocultures of FLS with GC B cells
Cultured FLS were seeded into six-well culture plates (Costar)
and activated for 3 days with rhuTNF-/rhuIL-1ß, as described
above. Next, the cultures were washed carefully and 2–4 x
106 freshly isolated GC B lymphocytes were added. To study
GC B cell apoptosis in FLS-B cell cocultures, the cultures were stained
supravitally with Hoechst 33342 (Sigma) for 15 min and examined
directly in their culture wells by fluorescence microscopy, as
previously described (31), using a Leitz Orthoplan fluorescence
microscope (Leitz, Wetzlar, Germany) with Ploem-Opak illumination. An
NPL 50x/1.00 oil immersion objective was routinely used. In each
individual coculture, 400–500 B lymphocytes were examined, and
classified as single cells or cells binding to FLS as well as being
apoptotic or not.
DNA fragmentation assay of isolated nuclei
To investigate the effect of FLS coculture on endonuclease activity in GC B cells, FLS-B cell clusters and single GC B cells were separated after 16 h of coculture. B cell nuclei were isolated according to Nieto et al. (32). Endonuclease activity in the nuclei of single and clustered B cells was assayed, as described previously (33).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Synovial biopsies taken from the inflamed knees of 10 RA patients
were compared with biopsies taken from 16 non-RA arthritic patients
(Table I
). Cryosections revealed lymphonodular infiltrates in the
deeper synovium containing B cells (CD20+, Fig. 1a), sometimes with clear GCs
(CD21+, Fig. 1b) in part of the RA patients, but
not in the non-RA group. FDC-specific staining (DRC-1+) was
difficult to detect with indirect labeling, but enhancement with
alkaline-phosphatase antialkaline-phosphatase (APAAP) revealed clear
FDC networks inside some of these GCs (Fig. 1c). However,
due to the limited size of the biopsies and the small size of these
GCs, the incidence of such FDC networks was difficult to quantify. Our
present data suggest that FDC networks are restricted to the RA
patients, but it cannot be ruled out that due to their small size they
have been missed in the non-RA group. Additional experiments, including
representative numbers of synovial biopsies from every patient, will be
more conclusive. In synovial tissues obtained from joint replacement
surgery, we have found DRC-1+ FDC networks in occasional
patients with osteoarthritis as well (not shown), indicating that the
expression of DRC-1 is not RA specific.
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As shown in Table III, the majority of
the liberated cells have a fibroblast phenotype (MAS516+),
but also considerable amounts of macrophages (CD14+) were
seen in all patients tested. T lymphocytes (CD3+) and B
cells (CD20+) were seen in synovial cell suspensions of
part of the patients. No obvious differences were seen between RA and
non-RA patients. Cells expressing markers associated with
activation/inflammation (HLA-DR, CD29, CD40, CD54, CD55, CD106)
were seen in high amounts in almost every patient (Table III). In
general, no differences were seen between both patient groups.
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The present data indicate that cells with an FDC phenotype are seen more often in single cell suspensions prepared from synovial biopsies from RA patients than from non-RA patients. However, in a number of non-RA patients, these markers were found as well, suggesting that the possibility to express the FDC phenotype is a rather common feature of synoviocytes that may correlate with local inflammatory conditions instead of being a specific hallmark of RA.
FLS may express FDC-specific markers in vitro, irrespective of their diagnostic background
In an attempt to identify putative precursors for FDCs, FLS were
cultured and their phenotypes were studied directly after culture or
after incubation with the proinflammatory cytokines IL-1ß and
TNF-.
FLS cell lines were established from most patients. In our hands, these cell lines grew slowly in comparison with, for example, primary skin fibroblasts or tonsil fibroblasts. Their average doubling time was in the order of 1 wk.
All FLS cell lines were positive for the fibroblast markers MAS516,
ASO-2 (34), and prolyl 4-hydroxylase, a key enzyme of collagen
synthesis (not shown). Both in RA-FLS and in non-RA FLS, the basal
expression of the tested markers was rather low (Table IV), except of ICAM-1 and VCAM-1, which
were definitely expressed on the majority of the cell lines (Fig. 2, a and b). The
same was seen in the non-RA FLS. CD55 expression was seen more often in
unstimulated non-RA FLS than in RA-FLS (Fig. 2c). The
expression of FDC-specific markers (DRC-1, 7D6) was virtually absent
(Fig. 2d). A minority of the FLS cell lines showed faint
DRC-1 staining in part of the cells.
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, increased expression
of ICAM-1, VCAM-1, and CD55 was seen in the vast majority of the FLS
cell lines (Fig. 2e–g). No differences were mentioned when
RA and non-RA FLS were compared (Table IV).
With the FDC-specific markers, it was seen that especially DRC-1 was
up-regulated after incubation with rhuIL-1ß and rhuTNF- in a
fraction of the FLS cell lines, irrespective of their diagnostic
background. Although the expression of DRC-1 in RA-FLS (Fig. 2h) seems higher than in non-RA FLS, it remains unclear
whether this difference must be considered as significant. The same
holds true for the occasional expressions of the other FDC-specific
marker, the 7D6 Ag (a long form of CD21 (35)).
To date, our data show that the FDC phenotype can be induced or up-regulated in a fraction of the synovial fibroblast-like cell lines from both RA and non-RA patients under conditions that mimick an inflammatory situation in vitro.
FLS from RA patients can block apoptosis in GC B lymphocytes; non-RA FLS cannot
To assess the capacity of FLS to display FDC function, we have
tested the binding and survival of purified tonsillar GC B lymphocytes
to FLS cell lines from RA and non-RA patients. All experiments were
conducted with FLS cell lines precultured with or without rhuIL-1ß
and rhuTNF- for 3 days. GC B cells readily bind to all FLS tested,
leading to roughly 50% binding within 4 h (Fig. 3). After that moment, a difference was
seen between RA and non-RA FLS. RA-FLS were capable of maintaining GC B
cells on their surface for at least 48 h (Fig. 4a), whereas non-RA FLS could
not (Fig. 4b). In addition to this, apoptosis was very low
in GC B cells bound to RA FLS (Figs. 3c and 4a).
With non-RA FLS, the percentage of apoptosis in the bound B cells was
significantly higher when compared with RA-FLS (Figs. 3d and
4b; p = 0.005 for unstimulated FLS;
p = 0.01 for FLS stimulated with rhuIL-1ß and
rhuTNF-). These data indicate that non-RA FLS do not rescue GC
B cells from apoptotic cell death. By contrast, RA FLS have clear
antiapoptotic function, and functionally behave as FDCs.
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did not
significantly influence this cellular behavior, suggesting that the
antiapoptotic action of RA FLS is an intrinsic property of these cells,
independent of the presence of the cytokines used.
To investigate whether RA FLS, like FDCs, were able to switch off the
apoptotic machinery in the nuclei of the bound GC B cells, an
endonuclease activity assay (ENAA) was performed on B cell nuclei
isolated from single B cells and from B cells harvested from the
fraction bound to the FLS. As shown in Fig. 5, the ladder pattern typical of
apoptotic DNA fragmentation was seen in nuclei of the cells that were
not attached to FLS (single cells). In nuclei of B cells that had been
bound to RA-FLS for 24 h, no sign of DNA-fragmentation activity
could be detected, implying that their endonuclease activity has been
switched off during contact with the FLS. Additional gel
electrophoresis of high m.w. DNA confirmed the isolation of
unfragmented DNA from these nuclei (not shown). By contrast, ENAA of
nuclei from GC B cells bound for 24 h to non-RA FLS showed
uninhibited DNA fragmentation in these nuclei.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, the studies published to date do not point out whether these phenomena are specific features of RA only, or that certain functions are common to synovial cells in general. Also, it remains unclear what cell type may provide the precursors of putative FDCs in the RA synovium and under what conditions the phenotypic and/or functional differentiation has occurred. Elucidation of these issues may yield important new insights in the pathogenesis of RA. We have addressed these issues by studying arthroscopic synovial biopsies (and isolated cells thereof) from RA patients and comparing these with a variety of arthritic patients with a non-RA diagnosis.
Since FDCs have phenotypic overlap with a number of other cell types (reviewed in 13), we have used mAbs recognizing a long splice variant of CD21 (mAb DRC-1 and 7D6). These Abs are considered highly specific for FDCs (35). Cryosections of synovial biopsies indicated that GCs containing DRC-1+ networks of FDCs are present in a number of patients, especially in the RA group. These cryosections did not display DRC-1+ FDCs in every patient, even within the RA group. One explanation for this is that synovial GCs are rather small and, consequently, may be easily missed. Even if a GC was found in one section, the DRC-1+ networks appeared in only few subsequent sections (not shown). Also, it should be mentioned that DRC-1 expression is generally much lower in synovial tissues than in lymphoid organs. Therefore, although our cryosection data suggest that FDCs are more often found in the RA group, they are far from conclusive.
To obtain more information about the incidence of the FDC phenotype in
synovial biopsies, we have made single cell suspensions by collagenase
digestion of these biopsies and prepared cytospin preparations of the
isolated cells. The incidence of cells with an FDC phenotype
(DRC-1+, 7D6+) was higher in RA patients when
compared with the non-RA group (Table III), but cells with the FDC
phenotype were seen in some of the non-RA patients as well. This was
not associated with any particular diagnosis (1 AS, 1 OA, and 1 ReA).
In these patients, the percentages of FDC-like cells were very similar
with those found in the RA group. The present data indicate that cells
with the phenotype of FDCs are more often found in the RA group, but
this may quite well reflect the higher inflammatory status in many of
these patients rather than being an intrinsic property of this
particular disease.
Recently, the group of Gay et al. has demonstrated that RA synovial fibroblasts after several passages of in vitro culture are autonomous and aggressive, i.e., tissue destructive toward human cartilage implanted in SCID mice (38). That study highlights the possibility that these cells may have undergone some RA-specific differentiation. Since it has been suggested that fibroblasts may serve as local precursors for FDCs, we have cultured FLS from each patient and searched for a putative abberant propensity of RA-derived FLS to display the FDC-like phenotype (DRC-1+ and 7D6+) and function (the ability to block apoptosis in adherent GC B cells).
On cultured FLS, basal expression of FDC-specific markers was absent or
marginal, both in the RA and in the non-RA group (Table IV). Incubation
with the proinflammatory cytokines IL-1ß and TNF- clearly enhanced
the expression of ICAM-1, VCAM-1, and CD55. In part of the FLS cell
lines, DRC-1 was induced or up-regulated. Highest DRC-1 expressions
were seen in RA-derived FLS, but it remains to be established whether
these differences in expression levels between RA and non-RA FLS are
meaningful, since it is difficult to compare the staining intensities
obtained in different experiments. Also, it is unclear whether these
differences are intrinsic or may result from yet suboptimal in vitro
stimulation conditions. Further studies with different cytokines,
combinations of cytokines, and different concentrations of
cytokines are necessary.
Remarkably, profound differences between RA and non-RA FLS were seen when these cells were tested for their functional FDC behavior, i.e., their capacity to bind purified GC B cells and to rescue them from apoptosis. Clearly, RA FLS can keep many GC B cells alive for at least 2 days; by contrast, non-RA FLS initially bind GC B lymphocytes, but start to lose these after 8 h, leading to unobstructed B cell death in the following period. The capacity of RA FLS to prevent apoptosis in GC B cells is associated with a virtually complete switch off of endonuclease activity in the B cell nuclei.
The present study has shown that even after several passages, in vitro FLS from RA patients have maintained the unique capacity to provide powerful survival signals to GC B cells. We have shown previously that this is a typical function of FDCs (31, 33, 39) and one of the key steps of memory B cell selection in the GC (4). B cell survival by RA FLS seems independent of additional cytokines, strongly suggesting that the FDC behavior of RA FLS is an intrinsic property of the cells from these patients. It should be emphasized that this FDC-like function of RA FLS does not correlate at all with the FDC phenotype, which is clearly cytokine dependent and can be induced in FLS from both RA and non-RA patients.
The molecular mechanisms by which RA FLS bind GC B cells may be different from those by which, for example, tonsillar FDCs bind BC B cells. Previously, we have shown that tonsillar FDCs and GC B cells interact in vitro mainly by LFA-1/ICAM-1 and VLA-4/VCAM-1 interactions (30, 31, 40). To date, preliminary studies with blocking Abs have not revealed significant prevention of B cell binding to FLS, suggesting a different, yet unknown, cellular interaction (data not shown).
Additional experiments are now in progress to estimate the role of other cytokines in the induction of the FDC phenotype in FLS, to explain the discrepancies that are found between the phenotypic and the functional data, and to reveal the precise molecular mechanisms that enable RA FLS to behave as FDCs.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Tumor Immunology, University Hospital Nijmegen, St. Radboud, Philips van Leydenlaan 25, 6525EX Nijmegen, The Netherlands.
3 Address correspondence and reprint requests to Dr. C. de Groot, Academic Medical Center, University of Amsterdam, Dept. of Cell Biology & Histology, Cellular Immunology Group, P. O. Box 22700, 1100DE Amsterdam, The Netherlands. E-mail address:
4 Abbreviations used in this paper: GC, germinal center; ENAA, endonuclease activity assay; FDC, follicular dendritic cell; FLS, fibroblast-like synoviocyte; RA, rheumatoid arthritis; rhu, recombinant human.
Received for publication September 30, 1998. Accepted for publication February 26, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 and ß1 integrins in lymphocyte aggregates in Sjögren’s syndrome and rheumatoid arthritis. Ann. Rheum. Dis. 52:806.-deficient mice: a critical requirement for TNF in the formation of primary B cell follicles, follicular dendritic cell networks, and in the maturation of the humoral immune response. J. Exp. Med. 184:1397. and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from bone-marrow derived dells. J. Exp. Med. 12:1997.
-dependent fashion. J. Exp. Med. 187:1009., tumor necrosis factor ß, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis Rheum. 39:1703.[Medline]
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E. Zanelli, F. C. Breedveld, and R. R. P. de Vries HLA association with autoimmune disease: a failure to protect? Rheumatology, October 1, 2000; 39(10): 1060 - 1066. [Abstract] [Full Text] [PDF]
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