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* Department of Immunology and Rheumatology and Institut National de la Sante et de la Recherche Médicale Unité 403, Hôpital Edouard Herriot, Lyon, France; and
Schering-Plough Laboratory for Immunological Research, Dardilly, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DC are found in the rheumatoid arthritis (RA) synovium and are likely to play an important role in its pathogenesis. This conclusion is supported by the histological observations demonstrating MHC class II+ APC clustered with T cells around blood vessels, sometimes in germinal center (GC) structures, and the association of HLA-DR alleles with disease severity (2, 3, 4, 5, 6). However, the function of DC according to phenotype and subset in RA synovium remains to be clarified, in particular regarding their mode of migration and accumulation (7, 8, 9, 10). Recently, differentiated DC expressing nuclear RelB have been detected in RA synovium, predominantly located in perivascular mononuclear cell aggregates (11).
RA synovium has several, but not all, of the characteristics of lymphoid organs with regard to cellular composition and organization (12), but it is unknown whether DC reach the synovium as mature cells or undergo local maturation. In particular, an accumulation of immature DC could be secondary to inflammation. Such studies are difficult to perform because of the low frequency of DC in such tissue. In addition, synovium dissociation with enzymes may affect phenotypes and functions with a difficult recovery of such rare cells. Accordingly, we have selected immunohistochemical techniques to investigate the different DC subsets found in RA synovium. We used several newly defined markers of the immature and mature DC subsets. CD1a, first described as a marker of Langerhans cells (LC) in skin epithelium, was later described as a marker of immature DC (13). Conversely, DC-lysosome-associated membrane protein (LAMP) and CD83 have been associated with more mature DC subsets. In vitro studies of DC differentiation have shown that CD83 expression appears before that of DC-LAMP, suggesting that CD83+ DC are less mature than DC-LAMP+ DC (14, 15). We selected tonsils, an active lymphoid organ, as a control. We analyzed DC frequency and localization with the aim of studying the respective immature/mature DC compartmentalization pattern in RA synovium. Such compartmentalization has been observed in breast carcinoma tissue where immature DC were detected within the tumor and mature DC in peritumoral areas (16).
To study the mode of migration of DC, we also looked at the expression
of several chemokines and their associated receptors.
Macrophage-inflammatory protein-3
, a CC chemokine, recently renamed
CCL20 (17), and its receptor CCR6 (18) are
critical for the recruitment of immature DC (19). CCL20
plays a major role in epithelial colonization by LC in response to
inflammation (20). Macrophage-inflammatory
protein-3
/CCL19 and 6-chemokine/CCL21 contribute through their
associated receptor CCR7 to the accumulation of Ag-loaded mature DC in
T cell-rich areas of lymphoid organs (19). These
chemokines attract in vitro-derived DC following CCR7 induction by CD40
ligand, TNF-, or LPS stimulation (19, 21). In situ
detection of CCL19 showed its expression within the T cell areas of
secondary lymphoid organs (22), with CCL21 having a wider
distribution.
In this work we report the coexistence of both immature and mature DC subsets in RA synovium. The close association between immature CD1a+ DC and CCL20-producing cells suggests the contribution of CCL20 to the homing of immature CCR6+ cells into RA synovium. Conversely, the colocalization of CCL21/CCL19, CCR7, and mature DC in perivascular infiltrates suggests a role for these chemokines in the homing of mature CCR7+ DC in lymphocytic infiltrates.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Synovial samples were obtained from 12 patients with RA, defined according to the revised criteria of the American College of Rheumatology (formerly the American Rheumatism Association) (23). To assess inflammatory synovium, samples were obtained from patients undergoing knee or wrist synovectomy, and not at a late stage, such as for joint replacement. Tonsils were obtained from children undergoing tonsillectomy.
The study was first initiated with frozen sections. However, immunostaining using frozen specimens, despite good Ag preservation, was not sufficient to clearly define the morphology of DC and to allow their quantification. Accordingly, an effort was made to develop immunostaining in paraffin-embedded sections, which allows a better preservation of histological patterns. Samples were fixed in 4% phosphate-buffered paraformaldehyde and then embedded in paraffin. Four-micrometer sections were cut and mounted on glass slides (adhesive slides, SuperFrost; CML, Nemours, France). To detect Ag expression in paraffin-embedded sections, Ag retrieval procedures were performed, including incubation in either citrate buffer (10 mM, pH 6) or EDTA buffer (1 mM, pH 8), followed by microwave oven incubation (three times for 3 min each time).
Following staining with hematoxylin, samples were classified according to the following criteria (24): diffuse infiltration of T cells and B cells and absence of lymphoid organization (n = 4), T cell-B cell aggregates without GC (n = 5), and presence of GC (n = 3).
Detection of DC subsets
For single staining, an immunoperoxidase technique using 3-amino
9-ethylcarbazole (AEC; red color; DAKO, Glostrup, Denmark) or
3,3'-diaminobenzidine tetrahydrochloride (DAKO) as chromogen was
performed. Briefly, endogenous peroxidase activity was blocked with 3%
hydrogen peroxide. Sections were incubated with several mouse mAbs
recognizing the following molecules (see also Table I
): CD1a (IgG2b; BD Biosciences, Pont de
Claix, France), CD11c (IgG2b; CamFolio, San Jose, CA), Langerin
(IgG1; Schering-Plough, Dardilly, France), CD40 (IgG1;
Schering-Plough), HLA-DR (IgG2b; BioSource, Camarillo, CA), CD83
(IgG2a; Immunotech, Marseilles, France), and DC-LAMP (IgG1;
Immunotech). (Refs. 13, 14, 15, 25, 26, 27, 28 , see Table I for details). After
overnight incubation at 4°C and washing, the sections were
incubated with biotinylated anti-mouse IgG, followed by
streptavidin-peroxidase (DAKO). The peroxidase was developed by AEC,
and Mayer hematoxylin (DAKO) was used as the counterstain. In negative
control sections the primary Abs were omitted, or irrelevant Ab was
applied at the same concentration as the primary Ab.
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Detection of chemokines and their associated receptors
For detection of chemokines, goat polyclonal Abs to CCL19, CCL20, or CCL21 (R&D Systems, Abingdon, U.K.) were used, followed by biotinylated rabbit anti-goat IgG (DAKO), and was developed using streptavidin-peroxidase. CCR6 and CCR7 were detected using anti-CCR6 (R&D Systems) and anti-CCR7 (BD Biosciences) mouse mAbs.
In double-step immunohistochemical staining, after an initial blocking with rabbit serum, avidin-biotin, and BSA, primary Ab to CCL20 was added, followed by rabbit biotinylated anti-goat IgG and streptavidin-peroxidase. Peroxidase was developed by AEC. Mouse mAb to CD1a (IgG2b) was followed by rat anti-mouse IgG2a/2b (BD Biosciences) and mouse alkaline phosphatase anti-alkaline phosphatase (DAKO). Alkaline phosphatase was revealed using Fast Blue as chromogen (blue color; Vector Laboratories).
Quantification of positive cells
Because of the high heterogeneity of RA synovium and the low frequency of DC subsets, quantification was performed with a method first used for the estimation of new blood vessel formation in breast tumor (29). This method allows quantification of cells in hot spots, defined in this study as synovium areas containing the highest density of positive cells. Accordingly, two hot spots per rheumatoid synovium section were selected. In each spot positive cells were counted in 10 consecutive high-power fields (x500). One field corresponded to 0.3 mm2, and thus one spot to 3 mm2. The number of positive cells per two hot spots was averaged, and results are expressed as the number of positive cells per square millimeter.
Statistical analysis
Results were expressed as the mean ± SD. Levels of marker expression were compared using the nonparametric Mann-Whitney U test between RA synovium and tonsils and between subsets of RA synovium.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We investigated DC subsets in sections obtained from 12 RA
patients and used tonsils, an active secondary lymphoid organ as a
control. We used several mAbs against specific and nonspecific DC
markers (Table I
). HLA-DR, CD11c, and CD40, known to be expressed by
DC, were detected in all RA synovium samples. HLA-DR, CD11c, and CD40
were highly expressed in every sample (44 ± 11, 32 ± 11,
and 35 ± 12 positive cells/mm2, using the
hot spot analysis, respectively; Table II). Similar expression was observed in
tonsils (not significantly different vs RA synovium). These markers
were detected in many cell types other than DC, such as T cells, B
cells, and synoviocytes, and localized in the lining and sublining
layers as well as in infiltrates.
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We then focused on more DC-specific markers. Immature DC were
defined by CD1a expression. Immature CD1a+ DC
were detected in 10 of 12 RA synovium samples. The number of
CD1a+ cells per square millimeter in RA synovium
ranged from 1 to 26 cells (mean ± SD, 7 ± 7; Table II). In
tonsils, that number was 
2-fold higher (15 ± 2 positive
cells/mm2), but without reaching significance
(not significantly different vs RA synovium).
The LC subset, also expressing CD1a marker in skin epithelium (13), has been characterized by the specific expression of langerin/DCGM4. This represents a marker of epithelial tissue. As expected, no LC were found in RA synovium. Conversely, LC in tonsils (14 ± 2 positive cells/mm2; p < 0.001 vs RA synovium) were exclusively present in the epithelium. Such finding excludes the migration of epithelial-derived DC to the synovium.
In RA synovium immature CD1a+ DC were
preferentially localized in the lining (inset of Fig. 1A) or sublining layer as well
as at the periphery of perivascular infiltrates (Fig. 1A).
CD1a+ cells were detected in the lining layer of
all 10 CD1a+ samples, whereas immature DC in
perivascular infiltrates were present in only 4 of 12 samples (patients
4, 8, 10, and 12). In tonsils, CD1a+ DC were
detected in the T cell zone and the epithelium (Fig. 1B).
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A). Mature DC are preferentially localized in the perivascular or lymphocytic infiltrates
Mature DC were analyzed for the expression of CD83 and DC-LAMP. In
vitro studies of DC differentiation have shown that CD83 expression
appears before that of DC-LAMP, suggesting that
CD83+ DC are less mature than
DC-LAMP+ DC (15).
CD83+ cells were detected in 9 of 12 samples, and
DC-LAMP+ cells were found in 11 of 12 samples.
The mean numbers of CD83+ cells and
DC-LAMP+ cells per square millimeter in RA
synovium were 5 ± 6 and 8 ± 5, respectively (Table II). In
tonsils the expression of CD83 and DC-LAMP was 7-fold higher (35
± 7 positive cells/mm2; p <
0.001 vs RA synovium) and 10-fold higher (79 ± 3 positive
cells/mm2; p < 0.001 vs RA
synovium) compared with RA synovium, and the DC-LAMP/CD83 ratio was
79/35 = 2.3, indicating a relative accumulation of the most mature
subset. In RA synovium, that ratio was 8/5 = 1.6 (not significant
vs tonsils).
Mature CD83+ cells were mainly detected at the
periphery of the perivascular or lymphocytic infiltrates (Fig. 1C). In contrast, DC-LAMP+ DC were not
observed at the periphery, but inside the lymphocytic infiltrates (Fig. 1E), the site of interactions between mature DC and
lymphocytes. In tonsils, DC-LAMP+ DC were
exclusively detected in the T cell zone (Fig. 1F), whereas
CD83+ cells were found in both T cell and GC
zones (Fig. 1D).
In synovium, most of the mature DC also had a dendritic-like morphology
(inset of Fig. 1, C and E). Some of the
DC-LAMP+ or CD83+ cells had
a less common aspect, with a plasmacytoid-like appearance and a remote
nucleus in a large cytoplasm (Fig. 1E, inset).
To further clarify the dichotomy between immature and mature DC subsets
in RA synovium, double staining using anti-DC-LAMP and
anti-CD1a Abs was performed. The lack of coexpression of DC-LAMP
and CD1a confirms the presence of independent immature and mature DC
subsets (Fig. 1, G and H). The DC-LAMP/CD1a ratio
was 8/7 = 1.1 in RA synovium vs 79/15 = 5.3 in tonsils
(p < 0.001 vs RA synovium), suggesting the
relative accumulation of immature DC in RA synovium.
CCL20 is expressed in RA synovium
To study the mode of migration of DC in response to chemokines, we
first analyzed the expression pattern of CCL20 and its receptor CCR6,
which is known to control the migration of immature DC. In RA synovium
CCL20 was mainly expressed in the lining layer (Fig. 2A), but also in the
perivascular infiltrates (Fig. 2C). CCL20 expression showed
a large degree of heterogeneity between the different RA synovium
samples. In 4 of 12 samples no CCL20 expression was detected. In the
eight CCL20+ RA synovium, the densities of
CCL20+ cells per square millimeter in the lining
layer and/or perivascular infiltrates were 9 ± 9 and 9 ±
11, respectively, with a large degree of heterogeneity (Table III). In samples 11 and 12, CCL20 was
only expressed in the lining layer. In tonsils, CCL20-producing cells
were more common (38 ± 5 positive
cells/mm2; p < 0.001 vs RA
synovium) and were exclusively detected in the epithelial crypts (Fig. 2E).
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CCR6, the receptor for CCL20, is highly expressed in RA synovium
CCR6 expression was detected in all RA synovium samples. CCR6 was
highly expressed (39 ± 20 positive
cells/mm2) in lymphocytic infiltrates and at the
periphery of blood vessels (Fig. 2D). In some cases CCR6 was
also observed in the lining layer where CCL20 was highly expressed
(Fig. 2B). In tonsils, CCR6 was highly detected (66 ±
6 positive cells/mm2; not significant vs RA
synovium) in the T cell zone, and accumulation of
CCR6+ cells was directly adjacent to
CCL20-expressing epithelial cells (Fig. 2F). In both RA
synovium and tonsils, CCR6-expressing cells had various morphotypes,
including cells with a dendritic morphology.
Close association between CCL20-producing cells and immature CD1a+ DC
As observed in Table II, the lack of CCL20 expression was
associated with the absence (samples 3 and 9) or low number (patients 6
and 7) of CD1a+ cells. This suggested a link
between the accumulation of immature CD1a+ DC and
the expression of CCL20 in RA synovium. This observation was extended
by double staining with anti-CCL20 and anti-CD1a Abs.
In both RA synovium and tonsils we observed a close association between
immature CD1a+ DC and CCL20-producing cells. In
tonsils, CCL20+ cells in epithelial crypts
localized near, but not in close contact with,
CD1a+ cells (Fig. 2I). In RA synovium
this association was mainly detected in the lining layer (Fig. 2G) and to a lesser degree in perivascular infiltrates (Fig. 2H).
CCL19 and CCL21 are mainly localized in perivascular infiltrates
We then looked at CCL19 and CCL21 expression, the CCR7 ligands
known to control the migration of mature DC. In RA synovium the
frequencies of CCL21+ and
CCL19+ cells were 13 ± 14 and 7 ±
10/mm2, respectively (Table III). Staining of
CCL21+ cells was more intense than that of
CCL19+ cells. As observed for CCL20, the
expression of CCL21 and CCL19 revealed a large degree of heterogeneity
between samples. No expression of CCL21 and CCL19 was detected in
samples characterized by a diffuse infiltrate without organization of
the lymphocytic aggregates (patients 3, 6, 7, and 9). All samples with
such features (patients 1, 2, 5, 8, and 11) showed the expression of
CCL21, whereas CCL19 was only detected in two of those samples
(patients 1 and 2). Both chemokines were detected in samples showing
lymphocytic infiltrates with GC (patients 4, 10, and 12). More
CCL21+ and CCL19+ cells
were found in samples with GC (33 ± 8 and 22 ± 3 positive
cells/mm2, respectively) than in samples without
GC (11 ± 3 and 3 ± 5 positive
cells/mm2, respectively; p <
0.001 and p < 0.001 vs samples with GC).
In RA synovium CCL21 and CCL19 were mainly localized in perivascular or
lymphocytic infiltrates (Fig. 3, A and B). We also observed the expression of
CCL21 and CCL19 in endothelium cells (Fig. 3, C and
D). In tonsils, CCL21 (82 ± 5 positive
cells/mm2; p < 0.001 vs RA
synovium) and CCL19 (43 ± 5 positive
cells/mm2; p < 0.001 vs RA
synovium) were highly present and detected in T cell areas, with a
wider distribution for CCL21 (Fig. 3, G and H).
They were expressed around GC.
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CCR7, the receptor for CCL21 and CCL19, is expressed in lymphocytic infiltrates
CCR7 expression was detected in 8 of 12 RA synovium samples at a
frequency of 10 ± 11/mm2 and at 31 ±
4/mm2 in tonsils (p <
0.005 vs RA synovium). As observed for CCL19 and CCL21, CCR7 was only
detected in samples characterized by lymphocytic aggregates with or
without GC. In RA synovium, CCR7+ cells were
mainly detected in lymphocytic infiltrates and rarely near a vascular
endothelium without any infiltrate (Fig. 3E). Some of them
had a dendritic morphology (Fig. 3E, inset). In tonsils most
of the CCR7+ cells localized in GC and the T cell
zone (Fig. 3F), some also with a dendritic morphology (Fig. 3F, inset).
Staining of serial sections with anti-CCR7, anti-CCL21, and
anti-DC-LAMP indicated the close association between
CCL21+ cells (Fig. 3K),
CCR7+ cells (Fig. 3I), and mature DC
(Fig. 3J). This observation is in line with an interaction
between the presence of mature CCR7+ DC and that
of CCL21- and CCL19-producing cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Compared with tonsils, accumulation of DC in RA synovium was lower, with a relative accumulation of immature DC. In tonsils, the mature/immature ratios (DC-LAMP/CD1a) were 5.3 and 1.1 in RA synovium. Such a difference may lead to functional changes between a lymphoid organ in a normal position (in this study, the tonsils) or an ectopic position (in this study, the synovium). Immature DC are highly efficient in Ag uptake. In the context of RA, further clarification is difficult because the causative Ag remains unknown. Immature DC could take up Ag directly in synovium, as suggested by the presence of a long process from CD1a+ cells, but immature DC could have already loaded Ag before their entry into the synovium. Conversely, mature DC are highly efficient APC and were localized in lymphocytic infiltrates of the synovium, where they can interact with T and B cells. Such interaction could occur at various stages of the RA process (31).
Immature CD1a+ DC were localized in the lining or sublining layers, as well as in the perivascular infiltrates. Mature DC were mainly detected in perivascular infiltrates. In RA synovium, detection of both immature and mature DC subsets in perivascular infiltrates argues for the lack of compartmentalization, such as is observed for breast carcinoma tissue, where immature DC were found within the tumor and mature DC in peritumoral areas (16). However, in RA synovium different localization patterns were observed for DC-LAMP+ and CD83+ DC in these infiltrates. CD83+ cells, considered less mature than DC-LAMP+ cells, were exclusively detected at the periphery, whereas the fully mature DC-LAMP+ cells were also observed inside the lymphocytic infiltrates. Differential localization of CD83+ and DC-LAMP+ cells could reflect the effect of maturation on the response of DC to the chemokines that control their homing into infiltrates.
Such differences in the mature/immature ratio suggest changes in the
chemokine contribution. Indeed, chemokines are nonspecific soluble
factors that control the migration of DC and many other cells into the
synovium. We analyzed the expression of CCL20, the ligand of CCR6, and
CCL19 and CCL21, the ligands of CCR7. These chemokines have been
classified as chemoattractant for in vitro-derived immature and mature
DC, respectively (19, 32). It was critical to demonstrate
whether such findings are in line with the in vivo situation. The close
association between CCL20-producing cells and
CD1a+ immature DC observed in this study was
indeed an in situ confirmation of these previous results obtained in
vitro. CCL20 was highly expressed in the lining layer, extending our
recent results where in vitro incubation of synoviocytes with IL-1,
IL-17, and TNF- was associated with an up-regulation of CCL20
production (30). Synoviocytes are predominant in the
lining layer and represent the leading CCL20-producing cells, similar
to keratinocytes in psoriasis skin and epithelial cells in tonsil
crypts, which are the sites of CCL20 production (19, 20, 33). The expression of CCR6 near the lining layer suggests that
it represents one site of entry of immature CCR6+
DC into the RA synovium. Indeed, such DC were observed inside the
lining layer. However, high endothelial venules should also be
considered a site of immature DC entry, as shown by the high expression
of CCR6 and the close association between CCL20-producing cells and
CD1a+ cells in the perivascular infiltrates.
Compared with tonsils, where mature DC represent the major DC subset,
the RA synovium was characterized by the relative accumulation of
immature DC. This suggests a relative defect in DC maturation in RA
synovium. When considering the various cytokines used for in vitro
generation of hemopoietic CD34+-derived DC
(GM-CSF and TNF-) and monocyte-derived DC (GM-CSF and IL-4)
(34, 35), the lack of IL-4 in RA synovium contrasts
with the high levels of GM-CSF and TNF- (36). The
defect in DC differentiation compared with tonsils could be linked to
the lack of IL-4 leading to defective Ag processing. In addition, T
cell-derived cytokines are characterized by high IL-17 and low IL-4
production, resulting in a proinflammatory cytokine pattern
(37). IL-10, another anti-inflammatory cytokine known
to inhibit the capacity of synovial macrophages to function as APC
(38), had no immunosuppressive effect on rheumatoid
synovial fluid DC compared with peripheral blood DC (39).
These results indicate the contribution of synovium cytokine
microenvironment that results in complex changes in DC recruitment and
function.
The potent local defect of maturation of mature DC in RA synovium
led to evaluation of the expression of CCR7 and its ligands, CCL19 and
CCL21, known chemoattractants for in vitro-derived mature DC. The
detection of both chemokines in vascular endothelium and
perivascular infiltrates suggests that migration of mature
CCR7+ DC occurs from blood to RA synovium through
vascular endothelium. The expression of CCL19 and CCL21 in RA samples
with GC and their absence in samples with diffuse infiltrates suggest
that these chemokines are implicated in GC formation and migration of
mature DC in these lymphocytic aggregates. A similar conclusion was
reached with the B cell-attracting chemokine-1 (40).
However, stronger expression of CCL21 compared with CCL19 in RA
synovium may indicate a greater contribution of CCL21 to the migration
of mature DC. In addition, CCL19 expression (5 of 12 samples) was less
common than that of CCL20 production (9 of 12). When considering the
quantification of their associated receptors, the CCR6/CCR7 ratio was
39/10 = 3.9 in RA synovium, suggesting a higher contribution of
CCL20/CCR6 to that of CCR7 and its ligands, CCL19 and CCL21, in the
homing of DC. Such differences could result in a reduced migration of
mature DC from blood. The combined results observed here are depicted
in Fig. 4, which represents a model of DC
subsets and migration patterns in RA synovium.
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cell; AEC, 3-amino 9-ethylcarbazole; GC, germinal center; LAMP, lysosome-associated membrane protein; LC, Langerhans cell; RA, rheumatoid arthritis.
Received for publication October 11, 2001. Accepted for publication February 25, 2002.
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 P Middel, D Raddatz, B Gunawan, F Haller, and H-J Radzun Increased number of mature dendritic cells in Crohn's disease: evidence for a chemokine mediated retention mechanism Gut, February 1, 2006; 55(2): 220 - 227. [Abstract] [Full Text] [PDF]
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J G Walker, M J Ahern, M Coleman, H Weedon, V Papangelis, D Beroukas, P J Roberts-Thomson, and M D Smith Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis Ann Rheum Dis, February 1, 2006; 65(2): 149 - 156. [Abstract] [Full Text] [PDF]
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T R D J Radstake, K C A M Nabbe, M H Wenink, M F Roelofs, A Oosterlaar, A W T van Lieshout, P Barrera, P L E M van Lent, and W B van den Berg Dendritic cells from patients with rheumatoid arthritis lack the interleukin 13 mediated increase of Fc{gamma}RII expression, which has clear functional consequences Ann Rheum Dis, December 1, 2005; 64(12): 1737 - 1743. [Abstract] [Full Text] [PDF]
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T R D J Radstake, A W T van Lieshout, P L C M van Riel, W B van den Berg, and G J Adema Dendritic cells, Fc{gamma} receptors, and Toll-like receptors: potential allies in the battle against rheumatoid arthritis Ann Rheum Dis, November 1, 2005; 64(11): 1532 - 1538. [Abstract] [Full Text] [PDF]
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 E. Schutyser, A. Richmond, and J. Van Damme Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes J. Leukoc. Biol., July 1, 2005; 78(1): 14 - 26. [Abstract] [Full Text] [PDF]
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A W T van Lieshout, P Barrera, R L Smeets, G J Pesman, P L C M van Riel, W B van den Berg, and T R D J Radstake Inhibition of TNF{alpha} during maturation of dendritic cells results in the development of semi-mature cells: a potential mechanism for the beneficial effects of TNF{alpha} blockade in rheumatoid arthritis Ann Rheum Dis, March 1, 2005; 64(3): 408 - 414. [Abstract] [Full Text] [PDF]
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T R D J Radstake, R van der Voort, M ten Brummelhuis, M de Waal Malefijt, M Looman, C G Figdor, W B van den Berg, P Barrera, and G J Adema Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors Ann Rheum Dis, March 1, 2005; 64(3): 359 - 367. [Abstract] [Full Text] [PDF]
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T. Cupedo and R. E. Mebius Cellular Interactions in Lymph Node Development J. Immunol., January 1, 2005; 174(1): 21 - 25. [Abstract] [Full Text] [PDF]
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Y. W. Park, Y. M. Kang, J. Butterfield, M. Detmar, J. J. Goronzy, and C. M. Weyand Thrombospondin 2 Functions as an Endogenous Regulator of Angiogenesis and Inflammation in Rheumatoid Arthritis Am. J. Pathol., December 1, 2004; 165(6): 2087 - 2098. [Abstract] [Full Text] [PDF]
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T R D J Radstake, A B Blom, A W Sloetjes, E O F van Gorselen, G J Pesman, L Engelen, R Torensma, W B van den Berg, C G Figdor, P L E M van Lent, et al. Increased Fc{gamma}RII expression and aberrant tumour necrosis factor {alpha} production by mature dendritic cells from patients with active rheumatoid arthritis Ann Rheum Dis, December 1, 2004; 63(12): 1556 - 1563. [Abstract] [Full Text] [PDF]
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J J Haringman, J Ludikhuize, and P P Tak Chemokines in joint disease: the key to inflammation? Ann Rheum Dis, October 1, 2004; 63(10): 1186 - 1194. [Abstract] [Full Text] [PDF]
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R. Lande, E. Giacomini, B. Serafini, B. Rosicarelli, G. D. Sebastiani, G. Minisola, U. Tarantino, V. Riccieri, G. Valesini, and E. M. Coccia Characterization and Recruitment of Plasmacytoid Dendritic Cells in Synovial Fluid and Tissue of Patients with Chronic Inflammatory Arthritis J. Immunol., August 15, 2004; 173(4): 2815 - 2824. [Abstract] [Full Text] [PDF]
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 T. Luft, E. Maraskovsky, M. Schnurr, K. Knebel, M. Kirsch, M. Gorner, R. Skoda, A. D. Ho, P. Nawroth, and A. Bierhaus Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells Blood, August 15, 2004; 104(4): 1066 - 1074. [Abstract] [Full Text] [PDF]
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C. H. Van Krinks, M. K. Matyszak, and J. S. Hill Gaston Characterization of plasmacytoid dendritic cells in inflammatory arthritis synovial fluid Rheumatology, April 1, 2004; 43(4): 453 - 460. [Abstract] [Full Text] [PDF]
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 M. Movassagh, A. Spatz, J. Davoust, S. Lebecque, P. Romero, M. Pittet, D. Rimoldi, D. Lienard, O. Gugerli, L. Ferradini, et al. Selective Accumulation of Mature DC-Lamp+ Dendritic Cells in Tumor Sites Is Associated with Efficient T-Cell-Mediated Antitumor Response and Control of Metastatic Dissemination in Melanoma Cancer Res., March 15, 2004; 64(6): 2192 - 2198. [Abstract] [Full Text] [PDF]
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H. Kobayashi, S. Miura, H. Nagata, Y. Tsuzuki, R. Hokari, T. Ogino, C. Watanabe, T. Azuma, and H. Ishii In situ demonstration of dendritic cell migration from rat intestine to mesenteric lymph nodes: relationships to maturation and role of chemokines J. Leukoc. Biol., March 1, 2004; 75(3): 434 - 442. [Abstract] [Full Text] [PDF]
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G. Page, A. Sattler, S. Kersten, A. Thiel, A. Radbruch, and P. Miossec Plasma Cell-Like Morphology of Th1-Cytokine-Producing Cells Associated with the Loss of CD3 Expression Am. J. Pathol., February 1, 2004; 164(2): 409 - 417. [Abstract] [Full Text] [PDF]
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P. Chomarat, C. Dantin, L. Bennett, J. Banchereau, and A. K. Palucka TNF Skews Monocyte Differentiation from Macrophages to Dendritic Cells J. Immunol., September 1, 2003; 171(5): 2262 - 2269. [Abstract] [Full Text] [PDF]
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I. B. McInnes, B. P. Leung, M. Harnett, J. A. Gracie, F. Y. Liew, and W. Harnett A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62 J. Immunol., August 15, 2003; 171(4): 2127 - 2133. [Abstract] [Full Text] [PDF]
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W. Weninger, H. S. Carlsen, M. Goodarzi, F. Moazed, M. A. Crowley, E. S. Baekkevold, L. L. Cavanagh, and U. H. von Andrian Naive T Cell Recruitment to Nonlymphoid Tissues: A Role for Endothelium-Expressed CC Chemokine Ligand 21 in Autoimmune Disease and Lymphoid Neogenesis J. Immunol., May 1, 2003; 170(9): 4638 - 4648. [Abstract] [Full Text] [PDF]
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