Characterization of plasmacytoid dendritic cells in inflammatory arthritis synovial fluid
C. H. Van Krinks,
M. K. Matyszak and
J. S. Hill Gaston
Department of Rheumatology, University of Cambridge, Cambridge, UK.
Correspondence to: J. S. Hill Gaston, Box 157, Level 5 Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: jshg2{at}medschl.cam.ac.uk
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Abstract
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Objective. To examine the phenotype of dendritic cell subsets in synovial fluid and peripheral blood from patients with rheumatoid arthritis (RA) or spondyloarthropathy (SpA).
Methods. Multiparameter flow cytometry was used to identify and characterize dendritic cells in mononuclear cell populations isolated from synovial fluid and peripheral blood.
Results. Synovial fluid contained two subsets of dendritic cells (DC), myeloid and plasmacytoid. These subsets could also be identified in peripheral blood, but there were lower numbers of DC in peripheral blood compared with synovial fluid. Plasmacytoid DC were distinguished from the myeloid subset by high expression of CD123 and lack of expression of CD11c. In comparison with myeloid dendritic cells, the plasmacytoid subset were less mature, similar to those in peripheral blood. They failed to express CD83 and DC-LAMP, and had relatively low levels of CD40 and CD86. Comparison of dendritic cells in synovial fluid from RA and SpA patients showed increased numbers of the plasmacytoid subset in SpA.
Conclusions. This is the first demonstration of the plasmacytoid subset of dendritic cells in synovial fluid. Since these cells are major producers of type I interferons, their increased numbers in SpA might be relevant to pathogenesis, but the immature phenotype in SpA synovial fluid may also indicate that conditions for maturation of this subset do not pertain in SpA synovium.
KEY WORDS: Dendritic cells, Plasmacytoid, Spondyloarthropathy, Rheumatoid arthritis, Chemokine receptors, Trafficking.
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Introduction
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Dendritic cells (DC) have been recognized as the pre-eminent antigen-processing and antigen-presenting cells; they are necessary for the activation of naïve CD4+ and CD8+ T cells and are able to determine the nature of the immune response they elicit through the production of cytokines which affect T-cell differentiation (reviewed by Banchereau and Steinman [1]). Increased numbers of DC have been reported in the synovium and synovial fluid in inflammatory arthropathies where they are well placed to direct local immune responses and inflammation [24].
Recently it has been possible to identify subsets within dendritic cell populations through their differential expression of surface markers. One particular subset, the plasmacytoid DC (PDC), was originally recognized on morphological grounds in tissue sections [5], but it is now possible to identify these cells and their precursors in peripheral blood and to examine their growth requirements and their effects on immune responses. Unlike myeloid DC (MDC), so called because they can be derived in vitro from CD14+ monocytes by culture with interleukin-4 (IL-4) and granulocytemacrophage colony-stimulating factor (GM-CSF), PDC respond poorly to these cytokines but respond instead to IL-3 and express high levels of CD123, the
chain of the IL-3 receptor [6]. Their principal functional characteristic is the ability to make large quantities of type I interferons (
and ß) [7], and they are likely therefore to play an important role in the immune response to viruses, recognizing viruses and their nucleic acids through Toll-like receptor (TLR) 9. In contrast, MDC respond best to bacterial infection, recognizing LPS via TLR4 and producing IL-12 and tumour necrosis factor-
(TNF
) [8], whereas PDC do not express TLR4.
PDC are present in increased numbers in psoriatic skin, and in contact dermatitis [9], and they are believed to be an important source of type I interferons in skin lesions of patients with systemic lupus erythematosus (SLE) [10]. However, the presence of PDC in inflamed joints has not to our knowledge been previously reported. We used multicolour flow cytometry to identify DC in peripheral blood and synovial fluid mononuclear cells (PBMC/SFMC) and noted two distinct populations, one of which was found to have a phenotype characteristic of PDC. This allowed us to investigate their phenotype in more detail and to determine their proportions in SFMC from patients with different forms of inflammatory arthritis.
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Materials and methods
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Patients
We analysed synovial fluid from 7 rheumatoid arthritis (RA) patients (4 seropositive for rheumatoid factor, 5 erosive) and 14 patients with spondyloarthropathy (SpA) (5 with psoriatic arthritis and 9 with reactive arthritis or undifferentiated SpA). By definition all had active synovial inflammation requiring therapeutic aspiration. We also analysed peripheral blood from 10 RA patients and 7 patients with SpA. All patients gave informed consent and the work was approved by Addenbrooke's Hospital Local Research Ethics Committee.
Peripheral blood (PB) and synovial fluid (SF) samples were placed in universal tubes containing 10 U/ml preservative-free heparin. Synovial fluid was incubated for 30 min with 10 U/ml hyaluronidase (Sigma, Poole, UK) prior to isolation of mononuclear cells. Mononuclear cells were isolated from both SF and PB by density gradient centrifugation over Ficoll-Hypaque (Amersham Biosciences, Amersham, UK), washed and resuspended in heat-inactivated foetal calf serum (First Link, UK) containing 10% dimethyl sulphoxide (Sigma), and stored in liquid nitrogen at a density no greater than 107 cells/1 ml vial.
For analysis cells were retrieved from cryopreservation by rapid thawing followed by drop-wise addition of 10 ml pre-warmed tissue culture medium per vial over 10 min. The cells were then washed twice, counted and then stained with monoclonal antibodies.
Characterization of DC phenotype in peripheral blood and synovial fluid
Four-colour flow cytometry was used to detect DC in mononuclear cells from SF samples. The antibodies used are listed in Table 1. All incubations and washes were carried out in FACS buffer [phosphate-buffered saline (PBS)/0.1% bovine serum albumin (BSA)/0.01% sodium azide]. Cells were incubated with the appropriate concentration of antibody (see Table 1) in 100 µl FACS buffer for 20 min, on ice and in the dark unless otherwise stated. After each staining step, cells were washed twice. Before staining, cells were incubated in 10% mouse serum for 15 min on ice, where appropriate, to block non-specific binding of antibodies to Fc receptors. PBMC and SFMC were first stained with a cocktail of fluorescein isothiocyanate (FITC)-conjugated antibodies to visualize T cells, monocytes, B cells, natural killer (NK) cells and 
T cells. These antibodies were as follows: anti-CD2, anti-CD3, anti-CD8, anti-CD14, anti-CD20 and anti-CD94. Next cells were stained with allophycocyanin (APC)-conjugated anti-HLA-DR and CyChrome conjugated anti-CD4. DC were identified as the population which was FITC dim or negative, and positive for HLA-DR and CD4. Phycoerythrin (PE)-conjugated antibodies were used to analyse chemokine receptor and maturation marker expression on the DCthese were: anti-CCR5, anti-CCR7, anti-CD11c, anti-CD40, anti-CD80, anti-CD83, anti-CD86, anti-CD123 and anti-DC-LAMP. Finally, cells were fixed with 4% paraformaldehyde for 20 min on ice, then washed and resuspended in 300 µl FACS buffer in 5 ml tubes.
In order to analyse expression of DC-LAMP, which is an intracellular protein, cells were permeabilized with CytoFix/CytoPerm (Pharmingen), prior to staining with anti-DC-LAMP antibody. Subsequent washes and incubation with the antibody were carried out in PermWash buffer (Pharmingen).
As an alternative way of examining the phenotype of plasmacytoid dendritic cells, PBMC and SFMC were resuspended in PBS/0.5% BSA/2 mM EDTA and incubated with FITC-conjugated anti-BDCA-2 antibody for 15 min at 4°C, before staining with antibodies for chemokine receptors and antigens expressed by DC.
Staining was measured using a flow cytometer (FACSCalibur, BD Biosciences) and the results analysed using WinMDI version 2.8 software. Patient data were plotted and statistical analyses carried out using GraphPad Prism version 3.0. The MannWhitney U-test was used to test for statistically significant differences between patient subsets.
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Results
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Identification and characterization of DC subsets in PBMC and SFMC
Dendritic cells (DC) in PB and SF mononuclear cells were identified by three-colour flow cytometry as cells that were dim or negative for antigens expressed on T (CD2, CD3 and CD8), B (CD20) or NK cells (CD94), and on monocytes (CD14), but positive for CD4 and major histocompatibility complex (MHC) Class II. Using this technique, in several instances two distinct populations of DC were clearly visible in SF; the first expressed high levels of MHC Class II, and was dim for antigens expressed on T, B and NK cells and monocytes, whereas the second expressed somewhat lower levels of MHC Class II, but was completely negative for antigens expressed on the other cell types, as shown in Fig. 1A which presents data from SFMC of a patient with undifferentiated SpA. The second population also expressed higher levels of CD4. That these populations were indeed phenotypically different was shown by staining for expression of CD11c and CD123 (IL-3 receptor
chain). The first population was uniformly positive for CD11c, and expressed relatively low levels of CD123, whereas the second population was predominantly CD11c negative and stained brightly for CD123. This phenotype is similar to that reported for so-called plasmacytoid dendritic cells (PDC) [6], as compared with the classical myeloid DC (MDC) which are CD11c+ and CD123dim.

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FIG. 1. Identification of DC subsets in synovial fluid and peripheral blood. A: Top left shows two gated subsets of dendritic cells (DC) based on the degree of expression of MHC Class II antigens and whether they showed dim, or a complete lack of, expression of antigens characteristic of other cell lineages. Upper panels show that one subset was CD11c+ (myeloid DC) and CD123dim, whilst the other (lower panels) was CD11c CD123hi (plasmacytoid DC). B: Similar analysis of the total DC populations in paired PB shows the existence of two subsets based on CD11c and CD123 expression. Quadrants were set using isotype-matched control antibodies.
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Fig. 1B presents data from PBMC from the same patient. As noted in previous studies [2, 3], the numbers of DC in PB are much lower than in SF, and for this reason two populations cannot readily be discerned. However, as with the SFMC, when expression of CD11c and CD123 was examined, two populations were again clearly present, both CD11c+ and CD11c, and CD123hi and CD123dim.
The phenotype of the PDC in SFMC is shown in more detail in Figs 2A and 2B; these data are also from a patient with undifferentiated SpA. In Fig. 2A, PDC were identified by gating on cells negative for antigens expressed on other cell lineages, positive for MHC Class II and expressing high levels of CD4, and analysed for expression of markers of dendritic cell maturation and chemokine receptors. In Fig. 2B, PDC in the same sample of SFMC were positively identified by staining with an antibody to BDCA-2, a Type II C-type lectin which has recently been shown to be expressed specifically by PDC. The analysis showed that both gated and BDCA-2+ cells had the same CD11c,CD123hi phenotype characteristic of PDC, and did not express CD83 or DC-LAMP, two markers of DC maturation. There were low levels of expression of CD40 and CD86, but both CCR5 and CCR7 were clearly expressed. For comparison, PDC in PBMC from the same patient (Fig. 2C) could also be identified by staining with BDCA-2, and again had a phenotype identical to the PDC in SF. Thus PDC from both PBMC and SFMC have phenotypic properties consistent with immaturity.

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FIG. 2. Analysis of the surface phenotype of plasmacytoid DC in synovial fluid and peripheral blood. PDC, identified by high CD4 expression, moderate MHC Class II expression, and lack of expression of other lineage markers (A), or by staining with an antibody to BDCA-2 (B) were analysed by flow cytometry for their expression of additional cell surface antigens. PDC in paired PBMC were also analysed following identification by staining with an antibody to BDCA-2 (C). Quadrants were set using isotype-matched control antibodies.
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This pattern of expression of surface markers by SF PDC was consistently seen in other patients, and contrasts with that seen when MDC within the same SFMC samples were analysed. This comparison is shown in Fig. 3; a median of 87% of MDC expressed CD40 compared with 8% of PDC (P = 0.0079), and whilst PDC did not express any CD83 or DC-LAMP, around 25% of myeloid DC expressed these proteins. Expression of CCR5 and CCR7 also varied in the two subsets (Fig. 4); CCR5 expression was higher on PDC than on MDC (91% vs. 65%), whilst CCR7 expression was also higher on PDC than on MDC (80% vs. 42%). Although these differences were large, statistical significance was not achieved due to the relatively small number of cases examined. Note that previous studies have shown that PDC in PB are CCR5+,CCR7+ whereas MDC are CCR5+,CCR7 [11], so that the changes seen in SF represent up-regulation of CCR7 and the beginning of down-regulation of CCR5 by MDC, as compared with an unchanged level of expression of both CCR5 and CCR7 by PDC, consistent with a lack of maturation of these cells.

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FIG. 3. Expression of maturation markers by myeloid DC (MDC) and plasmacytoid DC (PDC) in synovial fluid. DC subsets were gated as described in Fig. 2A, and examined for their surface expression of CD40, CD83 and DC-LAMP. Median values are indicated by horizontal lines. Statistically significant differences between groups are indicated by brackets and asterisks: *P<0.05, **P<0.01.
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FIG. 4. Expression of chemokine receptors by myeloid DC (MDC) and plasmacytoid DC (PDC) in synovial fluid DC subsets was defined as described in Fig. 2A, and examined for their surface expression of CCR5 and CCR7. Median values are indicated by horizontal lines.
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Differences in the proportions of different DC subsets in PBMC and SFMC from patients with different forms of inflammatory arthritis
Fig. 5 presents analysis of DC from healthy controls and RA or SpA patients, together with paired SF from RA and SpA patients. Fig. 5a and b compare the proportions of DC that express CD11c and high levels of CD123 respectively. Whereas the majority of DC in PB or SF from RA patients were CD11c+, SF DC in SpA patients showed a much wider range of proportions of CD11c+ cells, with only
50% of DC being positive in some cases. Since CD11c is characteristic of MDC, this suggests that a higher proportion of these cells are present in RA SF as compared with SpA SF. Likewise, examination of the proportions of CD123hi cells showed a larger proportion in SpA SF (P = 0.017), consistent with over-representation of PDC in SpA (although in some cases there were too few mononuclear cells for reanalysis of CD123 expression after the results for CD11c had been obtained). The proportions of CD11c+ and CD123hi DC in control PB varied over a wider range than that seen in PB DC from either RA or SpA patients.

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FIG. 5. Proportions of DC from peripheral blood of healthy controls, and peripheral blood and synovial fluid of patients with RA and SpA, which express CD11c or high levels of CD123. The total DC population, identified by expression of CD4 and MHC Class II together with dim or negative expression of other lineage markers, was then analysed for expression of (a) CD11c and (b) CD123. Median values are indicated by horizontal lines. Statistically significant differences between groups are indicated by brackets and asterisks: *P<0.05.
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Finally, Fig. 6 shows the percentages of CD11-negative DC (i.e. PDC) within the total PB or SF mononuclear cell population from controls, and from RA or SpA patients. Whilst these percentages were comparable in control and SpA PB, the percentage was much higher in SpA SF. In contrast, SF and PB from RA patients contained comparable numbers of PDC, similar to those found in control PB. Together these results suggest that PDC are substantially enriched in the SF of patients with SpA, but not in the SF of RA patients.

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FIG. 6. Proportions of mononuclear cells identified as PDC in blood and synovial fluid from patients with RA or SpA. Numbers of PDC, identified by expression of CD4 and MHC Class II together with dim or negative expression of other lineage markers, and their lack of expression of CD11c, were plotted as a percentage of total mononuclear cells. Median values are indicated by horizontal lines.
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Discussion
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In this paper we have identified two populations of DC in SF. One population was shown to be the myeloid subset of DC, which expresses CD11c, whereas the other was the more recently described plasmacytoid subset, which does not express CD11c but expresses high levels of CD123. Whilst several previous investigators have commented on the increased numbers of DC in SF and synovial tissue in inflammatory arthritis [24] those observations were confined to the myeloid subset (or failed to distinguish between subsets), so that this is to our knowledge the first report on the presence and phenotype of the plasmacytoid subset of dendritic cells in SF. Several questions arise in relation to our findings: why are PDC more numerous in SpA SF as compared with RA SF; why do SF PDC fail to mature in SF (unlike MDC); and what are the implications of these findings for our understanding of the pathogenesis of joint inflammation in SpA and RA?
Increased numbers of PDC in SpA SF might reflect increased recruitment to the joint. Recruitment of DC to the joint is influenced primarily by available chemokines and expression of appropriate chemokine receptors by DC. Although immature PDC express both CCR5 and CCR7 (unlike MDC which express only CCR5), neither of these receptors is functional, and it is only upon maturation that CCR7 is further up-regulated and becomes functional, whilst CCR5 is down-regulated [11]. Indeed, the only chemokine to which blood PDC respond by chemotaxis is CXCL12, which acts through CXCR4 [11], although in patients with neurological inflammation, blood PDC have also been shown to respond to MCP-1 (CCL2) [12]. Since CXCL12 (SDF-1) is known to be produced by the synovium, this is the most likely chemokine to be involved in recruiting PDC into the joint. Indeed, in preliminary studies we have shown that SF PDC populations do express CXCR4, consistent with their immature phenotype. However, CXCL12 is expressed in the synovium of both RA [13, 14] and SpA patients [15], so production of this chemokine cannot account for the higher numbers of PDC observed in SF from SpA patients. Very recently it has been shown that the response to SDF-1 is greatly enhanced by chemokines which bind to CXCR3 including CXCL9 (Mig) and CXCL11 (I-tac) [16], so differential expression of these chemokines could also play a role in recruitment to the SpA joint. Once recruited, PDC require IL-3 to survive, and undergo rapid apoptosis in culture if no IL-3 is present [6]; IL-3 has been shown to be present in SF of both reactive arthritis (ReA) and RA patients, but levels have been found to be higher in RA so that the availability of this growth factor also does not account for the increased numbers of PDC in SpA SF.
Differences in treatment, or disease duration, between patient groups might affect the relative proportions of different DC subsets in SF. Although SpA patients had a shorter duration of arthritis than those with RA, we mainly studied patients with chronic undifferentiated SpA or chronic ReA, rather than those with acute disease, so our findings do not reflect differences between acute and chronic arthritis. Shodell and Siegal [17] showed that prednisolone reduced the number of PDC present in the blood of healthy individuals and patients (and hence the amount of interferon-
(IFN
) produced upon stimulation of PBMC with virus, PDC being the main source of IFN
, although high doses (30 mg/day prednisolone) were used in that study. In our study none of the patients received more than 10 mg/day prednisolone. Disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate or leflunomide might also have an effect on particular DC subsets; in our study there were examples of SpA patients treated with these drugs who had high numbers of PDC in SF, and we could also identify PDC in the peripheral blood of both RA and SpA patients, so it is unlikely that differential exposure to DMARDs accounts for the difference between RA and SpA patients.
As noted, one of the principal characteristics of PDC is their ability to produce large amounts of IFN
and IFNß in response to viral and bacterial infection [7]. Kadowaki et al. [18] demonstrated that addition of neutralizing antibody to IFN
or IFNß decreased the viability of the PDC, suggesting that the Type I interferons they produce may act as an autocrine survival signal. In this case the presence of bacterial products in the joint, as is known to be the case in ReA, could lead to activation of PDC, release of IFN
and increased survival, possibly accounting for the higher numbers of PDC in SpA, and particularly in ReA where the highest numbers of PDC were observed. In addition to Type I interferons, PDC also make TNF
in response to infection, and this acts to increase expression of co-stimulatory molecules. However, we found that PDC in the joint expressed low levels of CD80 and CD86 (data not shown), arguing against the notion that they had responded to bacterial products in the joint by producing TNF
since this would have resulted in up-regulation of CD80 and CD86. It is possible that low-level exposure to bacteria or bacterial products might induce survival of PDC through production of Type I interferon, but fail to produce TNF
and consequent up-regulation of co-stimulatory molecules.
Finally, PDC might actually be recruited to RA joints in the same way as to SpA joints, but be retained in synovium and induced to mature there, rather than trafficking through the tissue into SF. Expression of functional CCR7, which occurs on PDC maturation, would allow PDC to remain in the synovial tissue or migrate to draining lymph nodes, so that they would not be present in the SF. Indeed, in contrast to the CD83, DC-LAMP PDC which we noted in SF, Page et al. [19] observed a subset of CD83+ DC-LAMP+ cells in rheumatoid synovial tissue with a plasmacytoid-like appearance, and a remote nucleus in a large cytoplasm, although these authors did not further characterize these cells. Also, in a review article Cavanagh and Von Andrian [20] mentioned unpublished observations of PDC in rheumatoid synovial tissue. These observations suggest that mature PDC may be present in the rheumatoid synovium, and that conditions in the tissue are conducive to their maturation. In contrast PDC would be recruited to the SpA synovium, fail to mature, and pass through in an immature state into SF. A major signal for PDC maturation is CD40 ligand (CD40L), expressed by T cells, and the organized lymphoid aggregates of the chronic RA synovium could provide more opportunities for PDC contact with CD40L+ T cells and subsequent maturation. IL-3 induces up-regulation of CD40 on PDC, and cells which respond in this way to IL-3 in synovium would then be able to receive signals from T cells expressing CD40L, and mature. Cells failing to up-regulate CD40 would not respond to CD40L and move into SF, consistent with our finding of relatively low CD40 expression by the SF population of PDC. To answer these questions, immunohistochemical studies of synovial tissue should be carried out, in order to detect the presence of PDC, identified by expression of high levels of CD123 and BDCA-2, and determine their expression of CD40, and whether they are associated with T cells.
PDC have been reported at other peripheral non-lymphoid sites of inflammation, where they may contribute to disease pathogenesis. Both MDC and PDC were shown to be enriched in the cerebrospinal fluid (CSF) of patients with inflammatory neurological diseases such as multiple sclerosis and optic neuritis. PDC numbers were especially high in the CSF of patients with neuroborreliosis, caused by the spirochaete Borrelia burgdorferi, and patients with bacterial meningitis [12, 21]. These PDC were of a similar phenotype to those found in the blood and those we have studied in the synovial fluid, i.e. expressing low levels of CD40 and CD86, and moderate levels of MHC Class II and CCR5 [22, 23]. These findings may suggest that PDC tend to accumulate in tissues affected by inflammatory disorders secondary to microbial infection.
Functional characterization of PDC from the inflamed joint has not yet been carried out. Isolation of DC from synovial fluid has, in the past, relied on sorting, by flow cytometry, cells that were negative for antigens expressed on other cell lineages. Therefore, it is likely that both MDC and PDC were present in the sorted population. It would be important to determine if synovial PDC produce Type I interferons, and to compare their ability to stimulate T cells with that of SF MDC.
The authors have declared no conflicts of interest.
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Acknowledgments
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This work was supported by the UK MRC.
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References
|
---|
- Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:24552.[CrossRef][ISI][Medline]
- Thomas R, Davis LS, Lipsky PE. Rheumatoid synovium is enriched in mature antigen-presenting dendritic cells. J Immunol 1994;152:261323.[Abstract/Free Full Text]
- Zvaifler NJ, Steinman RM, Kaplan G, Lau LL, Rivelis M. Identification of immunostimulatory dendritic cells in the synovial effusions of patients with rheumatoid arthritis. J Clin Invest 1985;76:789800.[ISI][Medline]
- Stagg AJ, Harding B, Hughes RA, Keat A, Knight SC. The distribution and functional properties of dendritic cells in patients with seronegative arthritis. Clin Exp Immunol 1991;84:6671.[ISI][Medline]
- Facchetti F, De Wolf-Peeters C, van den Oord JJ, De vos R, Desmet VJ. Plasmacytoid T cells: a cell population normally present in the reactive lymph node. An immunohistochemical and electron microscopic study. Hum Pathol 1988;19:108592.[ISI][Medline]
- Grouard G, Rissoan MC, Filgueira L et al. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med 1997;185:110111.[Abstract/Free Full Text]
- Siegal FP, Kadowaki N, Shodell M et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999;284:18357.[Abstract/Free Full Text]
- Kadowaki N, Ho S, Antonenko S et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001;194:8639.[Abstract/Free Full Text]
- Wollenberg A, Wagner M, Gunther S et al. Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 2002;119:1096102.[Abstract/Free Full Text]
- Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 2001;159:23743.[Abstract/Free Full Text]
- Penna G, Sozzani S, Adorini L. Cutting edge: selective usage of chemokine receptors by plasmacytoid dendritic cells. J Immunol 2001;167:18626.[Abstract/Free Full Text]
- Pashenkov M, Teleshova N, Kouwenhoven M et al. Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J Neuroimmunol 2002;122:10616.[CrossRef][ISI][Medline]
- Nanki T, Hayashida K, El-Gabalawy HS et al. Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol 2000;165:65908.[Abstract/Free Full Text]
- Buckley CD, Amft N, Bradfield PF et al. Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol 2000;165:34239.[Abstract/Free Full Text]
- Gu J, Marker-Hermann E, Baeten D et al. A 588-gene microarray analysis of the peripheral blood mononuclear cells of spondyloarthropathy patients. Rheumatology 2002;41:75966.[Abstract/Free Full Text]
- Vanbervliet B, Bendriss-Vermare N, Massacrier C et al. The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. J Exp Med 2003;198:82330.[Abstract/Free Full Text]
- Shodell M, Siegal FP. Corticosteroids depress IFN-alpha-producing plasmacytoid dendritic cells in human blood. J Allergy Clin Immunol 2001;108:4468.[CrossRef][ISI][Medline]
- Kadowaki N, Antonenko S, Lau JY, Liu YJ. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J Exp Med 2000;192:21926.[Abstract/Free Full Text]
- Page G, Lebecque S, Miossec P. Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium. J Immunol 2002;168:533341.[Abstract/Free Full Text]
- Cavanagh LL, Von Andrian UH. Travellers in many guises: the origins and destinations of dendritic cells. Immunol Cell Biol 2002; 80:44862.[CrossRef][ISI][Medline]
- Pashenkov M, Huang YM, Kostulas V et al. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 2001;124:48092.[Abstract/Free Full Text]
- Dzionek A, Fuchs A, Schmidt P et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 2000;65:603746.
- Cella M, Jarrossay D, Facchetti F et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nature Med 1999;5:91923.[CrossRef][ISI][Medline]
Submitted 3 September 2003;
Accepted 25 November 2003