Rheumatoid arthritis synovium contains plasmacytoid dendritic cells
© Cavanagh et al.; licensee BioMed Central Ltd. 2004
Received: 11 June 2004
Accepted: 26 October 2004
Published: 11 January 2005
We have previously described enrichment of antigen-presenting HLA-DR+ nuclear RelB+ dendritic cells (DCs) in rheumatoid arthritis (RA) synovium. CD123+HLA-DR+ plasmacytoid DCs (pDCs) and their precursors have been identified in human peripheral blood (PB), lymphoid tissue, and some inflamed tissues. We hypothesized recruitment of pDCs into the inflamed RA synovial environment and their contribution as antigen-presenting cells (APCs) and inflammatory cells in RA. CD11c+ myeloid DCs and CD123+ pDCs were compared in normal and RA PB, synovial fluid (SF), and synovial tissue by flow cytometry, immunohistochemistry, and electron microscopy and were sorted for functional studies. Nuclear RelB-CD123+ DCs were located in perivascular regions of RA, in a similar frequency to nuclear RelB+CD123- DCs, but not normal synovial tissue sublining. Apart from higher expression of HLA-DR, the numbers and phenotypes of SF pDCs were similar to those of normal PB pDCs. While the APC function of PB pDCs was less efficient than that of PB myeloid DCs, RA SF pDCs efficiently activated resting allogeneic PB T cells, and high levels of IFN-γ, IL-10, and tumor necrosis factor α were produced in response to incubation of allogeneic T cells with either type of SF DCs. Thus, pDCs are recruited to RA synovial tissue and comprise an APC population distinct from the previously described nuclear RelB+ synovial DCs. pDCs may contribute significantly to the local inflammatory environment.
Keywordsdendritic cells plasmacytoid rheumatoid arthritis TNF
Plasmacytoid dendritic cells (pDCs) are a distinct population of antigen-presenting cells (APCs) with the capacity for potent antigen-presenting function and production of large amounts of cytokines, including tumor necrosis factor (TNF)-α and IFN-α. Human pDCs can be identified by cell-surface expression of MHC molecules, the α-chain of the IL-3 receptor (CD123), and the presence of blood dendritic-cell (DC) antigens known as BDCA2 and BDCA4 in a proportion of cells . In comparison with CD11c+ myeloid DCs, pDCs display a distinct set of chemokine and Toll-like receptors [2–4]. In response to viruses and CpG DNA, pDCs become activated to produce IFN-α and their APC function is enhanced [5–8]. While pDCs were first demonstrated in the T-cell areas of lymph nodes [5, 9], precursors of this DC population have been isolated from several sources, including normal peripheral blood (PB), thymus, fetal liver, and bone marrow . Although they do not reside in normal peripheral tissues, pDCs have been shown to infiltrate certain inflamed tissues and tumor sites, including the skin in psoriasis and lupus, the cerebrospinal fluid in multiple sclerosis, and melanoma and ovarian carcinoma [11–15]. While pDCs play an important effector role in viral disease, being the major producers of IFN-α and having a primary role in innate immunity, there is also evidence that they may play an immunoregulatory role, through the induction of Th2 (T helper 2)-type cytokines [9, 16–18].
The synovial autoimmune reaction of rheumatoid arthritis (RA) is characterized by lymphocyte, macrophage, and DC infiltration that can progress to the development of lymphoid tissue in established disease [19–21]. DCs are likely to contribute to the formation and maintenance of such organized lymphoid tissue and antigen presentation in RA and other autoimmune lesions [22–24]. We have previously shown that the effector site in RA synovial tissue is enriched in differentiated myeloid DCs, which express CD33, CD11c, MHC and costimulatory molecules, and nuclear RelB [21, 25]. Translocation of RelB to the nucleus of myeloid DCs is associated with APC function, particularly through increased expression of MHC molecules CD86 and CD40 .
The proinflammatory cytokines TNF-α and IL-1β are key contributors to the inflammatory cytokine cascade in RA [27, 28]. This relates to a number of actions, but activation of the endothelium by TNF-α is particularly important in cellular recruitment to the synovium [29–31]. Since RA is characterized by endothelial activation, leukocyte recruitment, and the development of high endothelial venules, we hypothesized that pDCs would be enriched in inflamed but not normal synovium. Since the functional role of pDCs in disease pathogenesis is only partly understood, we also wished to address whether these cells represent a population distinct from the described nuclear RelB+ synovial DCs, and whether they may contribute as APCs or inflammatory cells in RA .
Materials and methods
Patients and controls
Thirty patients who fulfilled the American College of Rheumatology criteria for RA were included . Of these, 10 provided synovial fluid (SF) samples and 27 provided PB samples. Of the 30 patients, 80% were seropositive, 62% were female, and 73% were taking at least one disease-modifying antirheumatic drug or low-dose prednisone or both. Synovial tissue was obtained at arthroscopy from seven patients with RA, of whom three were untreated and four were taking at least one disease-modifying antirheumatic drug and low-dose prednisone. The duration of disease ranged from 0.5 to 18 years. In addition, we studied synovial tissue from four healthy individuals with nonspecific knee pain undergoing arthroscopy, one patient who had had psoriatic arthritis for 8 years, and one patient who had had ankylosing spondylitis for 30 years. Each patient with spondyloarthropathy was taking sulfasalazine. No patient in the study was taking biologics. Synovial tissue was provided by Dr Malcolm Smith (Repatriation Hospital, Adelaide, Australia). PB buffy coats prepared from 30 healthy donors were obtained from the Red Cross Blood Transfusion Service (Brisbane, QLD, Australia). The study was approved by the Research Ethics Committee of the Princess Alexandra Hospital.
Culture medium and cell isolation
All cells were cultured in RPMI 1640 (Gibco, Life Technologies, Mulgrave, VIC, Australia) supplemented with 10% FCS (CSL Ltd, Parkville, VIC, Australia), 0.3 mg/ml L-glutamine (Trace Biosciences, Castle Hill, NSW, Australia), 0.12 mg/ml benzylpenicillin (CSL), and 10 μg/ml gentamicin (Delta West, Pharmacia and Upjohn, Spring Hill, QLD, Australia). The monoclonal antibodies used in this study include FITC, phycoerythrin (PE), and purified anti-CD11c, CD14-PerCP, PE, biotinylated and purified anti-CD123, CD86-FITC (all from BD Pharmingen, San Diego, CA, USA), BDCA2-FITC (Miltenyi Biotech, San Francisco, CA, USA), HLA-DR-biotin (Coulter Immunotech, Fullerton, CA, USA), CD40-FITC (Biolegend, San Diego, CA, USA), CD80-FITC (Cymbus Biotech, Chandlers Ford, Hants, UK), CD68 (Kp-1, DAKO, Carpinteria, CA, USA), RelB (C-19, Santa Cruz Biotech, Santa Cruz, CA, USA), and biotinylated Ulex europaeus agglutinin I (Vector Laboratories, Burlingame, CA, USA).
Mononuclear cells were prepared from normal or RA PB or RA SF by density gradient centrifugation over Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) as described elsewhere . T cells were purified from PB mononuclear cells by passing the cells over a nylon wool column, followed by immunomagnetic depletion of remaining monocytes, DCs, B cells, and NK (natural killer) cells using monoclonal antibodies against CD14, CD16, CD19, CD56, and HLA-DR (all from BD Pharmingen), followed by goat antimouse immunoglobulin magnetic beads, then passage through a strong magnetic field (MACS, Miltenyi Biotech), and collection of the unbound fraction. On analysis by flow cytometry, the unbound fraction routinely contained 95–98% CD3+ T cells. DC-enriched non-T cells were produced by immunomagnetic depletion of T, B, and NK cells from non-T cells, by incubation with monoclonal antibodies against CD19, CD16, CD56, and CD3.
Flow cytometric analysis and selection of cells by cell sorting
To enumerate CD123+ and CD11c+ subsets of DCs, mononuclear cells from normal PB or RA SF were stained for four-colour flow cytometry as described elsewhere , using monoclonal antibodies against CD14-PECy5, CD11c-FITC, CD123-PE, and HLA-DR-APC. Live CD14-HLA-DR+ mononuclear cells were gated for analysis. Subset percentages are expressed as percentage of total mononuclear cells. Listmode data were analyzed using Winlist 2.0 software (Verity Software House, Topsham, ME, USA). For sorting, PB or SF DC-enriched non-T cells stained with the same four markers were sorted using the Moflo flow cytometer (DAKO), gating on CD14-HLA-DR+ and either CD123+CD11c- or CD11c+CD123- cells, respectively. For phenotypic analysis, mononuclear cells from PB or SF were stained with CD14-PECy5, CD123-PE or CD11c-PE, HLA-DR-APC, and either a fourth monoclonal antibody or isotype control monoclonal antibody conjugated with FITC. DCs were gated as described above.
Electron microscopy of freshly sorted cells was carried out as described elsewhere . After fixation in 2.5% glutaraldehyde in phosphate-buffered saline, the cells were post-fixed with an aqueous solution of 1% OsO4 containing 1.5% K4Fe(CN)6. Subsequently, the specimens were dehydrated in an alcohol series and embedded into epon. Ultrathin sections (50 nm) were contrasted with lead citrate and uranyl acetate and studied with a CM100 electron microscope (Philips, Eindhoven, The Netherlands).
Mixed lymphocyte reactions and cytokine analysis
Various numbers of sorted PB or RA SF DCs were incubated with 105 allogeneic PB T cells in triplicate wells for 5 days, as described elsewhere . Supernatants were removed from some cultures and [3H]thymidine (1 μCi/well, ICN Biochemicals) was added to the remainder for the final 18 h. Cells were harvested onto glass-fiber filter mats and the incorporation of [3H]thymidine was determined by liquid scintillation spectroscopy (Packard Topcount, Packard Instrument Co, Meriden, CT, USA). IFN-γ, IL-10, and TNF-α were measured in supernatants by ELISA using OptEIA ELISA kits (BD Pharmingen).
Frozen or paraffin-embedded sections of synovial tissue from patients with untreated active RA were obtained by arthroscopic biopsy and supplied by Malcolm Smith (Repatriation Hospital, Adelaide, Australia). Normal synovial tissue was obtained at arthroscopy from patients undergoing arthroscopy for nonspecific knee pain and in whom no abnormality was found. After fixation with acetone, sections were stained with anti-CD11c or anti-CD123 using an immunoperoxidase technique, and revealed with diaminobenzidine (brown). Frozen sections were double-stained with U. europaeus agglutinin I (Ulex), a lectin that specifically binds endothelial cells (fast red), and anti-CD123 (brown), using a double, immunoperoxidase–immunoalkaline phosphatase technique as described elsewhere . Formalin-fixed paraffin-embedded sections were antigen-retrieved in 10 mM citrate buffer at pH6 in an autoclave, then stained with anti-CD123 (diaminobenzidine, brown) alone, or in combination with anti-RelB (BCIP, DAKO, purple). Sections were counterstained with hematoxylin except when they had been double-stained for CD123 and RelB and were photographed using a transmitted-light microscope (Leitz Diaplan, Leica, Germany). To quantitate infiltration by CD123+ DCs, the number of CD123+Ulex- cells was counted in sections double-stained with CD123 and Ulex. Cells were counted in each of the entire sections from three patients and three normal controls at high power, and for each biopsy this number was corrected for the area of the section to obtain the number per mm2. To quantitate infiltration by CD11c+ cells, the number of these cells was counted in three high-power fields of the synovial sublining in sections from three patients and three normal controls.
Differences were analyzed using unpaired Student's t-tests.
CD123+ nuclear RelB-DCs are located in perivascular regions of RA synovial tissue
CD11c+ and CD123+DCs in RA SF
CD123+PB DCs are immature whereas SF pDCs show signs of activation
On four-color flow cytometric analysis, gated RA SF CD14-HLA-DR+CD123+ DCs expressed low levels of CD40, CD80, and CD86. All or the majority of SF CD123+ DCs expressed the BDCA2 marker of immature pDC precursors . This cell-surface phenotype closely resembles that of control PB CD123+ DC precursors, although BDCA2 was consistently expressed at high levels only by a subset of CD123+ HLA-DR+ cells in PB (Fig. 4b). No PB or SF cells expressed the DC differentiation marker CD83 (data not shown). However, SF CD123+ and CD11c+ DCs expressed higher levels of cell-surface HLA-DR than the corresponding cells in PB, suggesting some cellular activation within the SF environment [5, 10, 44]. Thus CD123+ pDCs comprise a small proportion of RA SF mononuclear cells, which are predominantly immature but show some evidence of activation in situ. These observations regarding phenotype and PB and SF numbers are consistent with findings in two recent studies [39, 45].
CD123+ and CD11c+SF DCs are efficient APCs
Ongoing inflammation in RA involves positive feedback loops between activated T cells, B cells, DCs, macrophages, and their products, with destructive consequences for parenchymal cells. Clinical and animal data indicate that effector-site DCs play an important proinflammatory role in the perpetuation of autoimmune disease and contribute to the lymph-node-like organization of that tissue [22, 46]. This role may be effected by local antigen presentation to CD4+ and CD8+ effector cells, but DC cytokine and chemokine secretion are also important [47, 48]. TNF-α and IL-1β are important downstream proinflammatory and destructive cytokines in RA for somatic cells, whose release is promoted by activation of macrophages. IL-10 is highly expressed in RA, and IFN-γ is an important T-cell effector cytokine [49, 50].
In the current studies, we show that, in addition to the previously described population of nuclear RelB+ DCs, a further population of nuclear RelB-CD123+ pDCs is located in perivascular regions of RA but not normal synovial tissue sublining. Moreover, pDCs were located within blood vessels, and both DC populations were observed in perivascular areas in which cells producing TNF-α were colocated . Adherence of CD123+ and CD11c+ DCs to TNF-α-activated endothelium was higher than to resting endothelium in vitro (data not shown). TNF-α plays an important role in the recruitment of other leukocytes to RA synovial tissue , and this most likely pertains to the recruitment of pDCs to RA but not normal synovial tissue through expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, CD62-E, and CD62-P and interaction with their ligands on pDCs [9, 11, 51–54]. Furthermore, TNF-α up-regulates synthesis of chemokines by endothelial cells . During experimentally elicited allergic rhinitis, CD123+HLA-DR+ pDCs have been shown to be recruited to human nasal mucosa .
The gene for MxA is specifically induced by IFN-α and therefore identifies a population of activated pDCs. In contrast, BDCA2 is a marker of immature pDCs. MxA+ pDCs have previously been demonstrated in involved lupus skin and inflamed tonsil . In RA synovial tissue, BDCA2 was shown to stain fewer cells than CD123 or MxA, suggesting differentiation in situ of a large proportion of pDCs into cells with a capacity for production of IFN-α and other cytokines. Together, the current and previous studies demonstrate recruitment of pDCs to normal lymphoid organs as well as inflammatory sites, with local differentiation, but no recruitment to normal peripheral tissues. In contrast, CD11c+ myeloid precursors populate normal resting tissues, as shown here, but additional CD11c+ myeloid cellular recruitment takes place at inflammatory sites, where RelB nuclear translocation takes place [21, 56]. We have previously shown that, like synovial pDCs, CD123+ DCs in the T-cell area of human tonsil are also nuclear RelB- . The data suggest either that activation of pDCs is not associated with nuclear translocation and transcriptional activity of RelB or that conditions in tonsil and synovium do not induce sufficient RelB translocation for detection by immunohistochemistry [26, 57]. As preliminary studies in vitro demonstrate induction of RelB in PB pDCs after stimulation with lipopolysaccharide and CpG, and reduced production of IFN-α by pDCs in RelB-deficient mice, it is likely that RelB activation does accompany pDC activation. However, RelB translocation might be quantitatively reduced or RelB might be more rapidly degraded in the nucleus of pDCs than of myeloid DCs in inflamed tissues .
Of relevance to the RA inflammatory lesion, stimulation of blood pDC precursors with signals including CD154, influenza virus, or CpG oligonucleotides induces production of large amounts of cytokines, including IFN-α, IFN-β, and TNF-α; induction of DC differentiation; and stimulation of APC function [3, 39, 44, 59]. Although inhibitory effects of SF on DC function, and thus on T-cell proliferation and cytokine production, are confirmed here [21, 39, 60], factors in the RA SF environment, such as IL-3 and CD154, may be sufficient to precondition the SF pDCs for efficient APC function ex vivo [36, 44]. IFN-γ, IL-10, and TNF-α were produced in mixed lymphocyte reactions stimulated by myeloid or pDCs derived from SF but not PB, potentially by DCs or by T cells or both. In the tissue, as a result of antigen presentation by myeloid DCs or pDCs, key effector cytokines may be produced in perivascular areas in RA, located strategically close to endothelial cells, as well as incoming leukocytes. It is not known whether pDCs are capable, like myeloid DCs, of migration from synovial tissue to draining lymph nodes. However, it seems probable that pDCs conditioned by local IL-3 and CD154, or even viral or bacterial products transported to the synovium, predominantly play local proinflammatory and antigen-presenting roles, through secretion of cytokines such as IFN-α and possibly TNF-α [61, 62].
pDCs are recruited to RA synovial tissue and comprise an APC population distinct from the previously described nuclear RelB+ synovial DCs. The APC function of pDCs is greater in SF than in PB. Activated pDCs and interacting T cells may contribute significantly to the inflammatory environment in RA.
enzyme-linked immunosorbent assay
fetal calf serum
tumor necrosis factor.
We thank Malcolm Smith (Repatriation Hospital, Adelaide, South Australia) for providing synovial tissue. This research was supported by grant 210237 from the National Health and Medical Research Council of Australia and by a grant-in-aid from the Princess Alexandra Hospital Foundation. Dr Thomas and Ms Smith were supported by the Arthritis Foundation of Queensland.
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