1 Laboratory of Oncology, G. Gaslini Institute, Largo G. Gaslini 5, 16148 Genova, Italy 2 Department of Internal Medicine, University of Genova, Genova, Italy 3 Department of Immunology, Mario Negri Institute, Milano, Italy 4 Division of Otolaryngology, G. Gaslini Institute, Genova, Italy 5 Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
Correspondence to: A. Corcione; E-mail: annacorcione{at}ospedale-gaslini.ge.it
Transmitting editor: L. Moretta
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Abstract |
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Keywords: B cell subsets, chemokines, chemokine receptors, locomotion
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Introduction |
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Naive B cells migrate from the bone marrow to the peripheral lymphoid organs where, following re-circulation through blood, they encounter specific antigen, undergo clonal expansion and colonize the primary lymphoid follicles (4,5). Here naive B cells differentiate into germinal center (GC) cells which first proliferate, then somatically mutate Ig variable region genes and finally are positively selected according to the affinity of surface Ig for antigen presented by follicular dendritic cells (69).
GC B cells are a resident cell subset with poor propensity to migrate. Following positive selection, GC B cells differentiate into memory or effector cells (plasma cells) outside the lymphoid follicles (69).
Memory B cells home to specific anatomical sites, such as the splenic marginal zone (10) or the tonsil subepithelial criptae (11), where they settle until they interact with specific antigens. Thereafter, the majority of antigen-activated memory B lymphocytes re-circulate (9).
Chemokines represent a group of chemotactic cytokines that mobilize subsets of effector leukocytes during inflammatory reactions or regulate the constitutive homing of B cells and T cells to peripheral lymphoid organs (1217).
The best characterized B cell tropic chemokines are stromal cell derived factor (SDF)-1 (1821), secondary lymphoid tissue chemokine (SLC) (21,22), EpsteinBarr virus gene 1-ligand chemokine (ELC), also known as macrophage inflammatory protein (MIP)-3ß (21,23,24), and B cell-attracting (BCA)-1 chemokine, also known as B lymphocyte chemoattractant (BLC) (21,25,26).
SDF-1 has been reported to be a potent chemoattractant for both normal and malignant human B lymphocytes (1821,27). Furthermore, mice lacking the SDF-1 gene or the gene encoding the SDF-1 receptor, i.e. CXC chemokine receptor (CXCR) 4, show gross defects in B cell development (19,28,29).
The SLC and ELC chemokines, expressed constitutively in the thymus, lymph nodes and other lymphoid tissues, have been shown to regulate lymphocyte homing (22,30). Mice deficient for CC chemokine receptor (CCR) 7, which binds to both SLC and ELC, display a severely impaired migration of B cells to lymph nodes (LN) or Peyers patches (PP) (31).
BCA-1, expressed in lymphoid tissues at high levels, strongly attracts B lymphocytes (25,26). BCA-1 selectively binds to CXCR5, that is widely expressed on blood and tonsil B cells (32). Disruption of the CXCR5 gene leads to loss of B cell follicles and GC in the LN and PP, suggesting a crucial role of BCA-1CXCR5 interactions in B lymphocyte recruitment to secondary lymphoid organs (33).
Recently, it has been shown that thymus-expressed chemokine (TECK) attracts murine pre-pro-B cells and cells capable of generating pro-B colonies in the presence of IL-7 and flt3 ligand, whereas such response is lost in later stages of B cell development (3). In contrast, human peripheral blood B cells displayed low but consistent migratory responses to TECK (21).
Finally, MIP-1 (34), IL-8 (35), growth-related oncogene (GRO)-
(35) and monocyte chemoattractant protein (MCP)-1 (36) have been reported to be chemotactic for human peripheral blood B cells and, in the case of MCP-1, also for human tonsil B cells (36).
In this study we have investigated the chemoattractant activity of 9 CC chemokines [MIP-1/CCL3, MIP-1ß/CCL4, MIP-3
/CCL20, MIP-5/CCL15, MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, eotaxin/CCL11 and macrophage derived chemokine (MDC)/CCL22] on human tonsil B lymphocytes, and, in particular, on the GC and non-GC subsets, since limited information exists on the latter issue (37).
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Methods |
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The following mAb were used: CD19FITC, CD3FITC, CD68phycoerythrin (PE), CD56PE, CD38FITC and anti-HLA-DRFITC (Becton Dickinson Immunocytometry Systems, San Jose, CA). Unconjugated CD3, CD56 and CD68 (Becton Dickinson) were used in cell separation experiments at the final concentration of 1 µg/ml. The CD39PE mAb was from PharMingen (San Diego, CA). The CD38 mAb was produced by one of us (F. M.) (38). The unconjugated anti-IgD mAb was purchased from Dako (Glostrup, Denmark) and used at the concentration of 1 µg/ml. The unconjugated CD39 mAb was obtained from Immunotech (Marseille, France) and used at the 1 µg/ml concentration.
CCR were detected by staining B cells, either freshly isolated or 4 h cultured, in the absence of stimuli, with the following mAb: anti-CCR1biotin (clone 53504.111), anti-CCR2-biotin (clone 48607.211), anti-CCR3PE (clone 61828.111) and anti-CCR6PE (clone 53103.111) from R & D Systems (Minneapolis, MN). An unconjugated anti-CCR5 mAb (clone 2D7) was from PharMingen. The anti-CCR4 mAb (clone 305L) was kindly donated by Drs Carol Raport and Pat Gray (ICOS, Bothell, WA). A mAb to CCR2 (LS132) was donated by Dr Craig La Rosa (Millennium Pharmaceuticals, Cambridge, MA) and used in blocking experiments at the concentration of 1 µg/ml. Flow cytometric analyses were performed as previously reported (27). Controls for each of the above mAb were isotype-matched mAb of irrelevant specificity conjugated with the same fluorochromes. All of the flow cytometry experiments were performed using a FACScan (Becton Dickinson).
B lymphocyte purification
Normal tonsils were obtained from patients undergoing tonsillectomy for inflammatory disorders. Mononuclear cells were isolated by Ficoll-Hypaque density gradients and depleted of lymphocytes forming rosettes with sheep red blood cells (T lymphocytes). Non-T cells were then incubated with the CD3, CD56 and CD68 mAb, treated with MACS goat anti-mouse IgG microbeads according to the instructions of the manufacturer (Milteny Biotec, Auburn, CA), and separated by applying a magnetic field. Negatively selected cells contained on average 99% B cells, as assessed by staining for CD19 (27).
Fractionation of tonsil B lymphocytes into GC and non-GC cells was performed as follows. Purified B lymphocyte suspensions were incubated first with the CD38 mAb for 30 min at 4°C and subsequently with MACS goat anti-mouse IgG microbeads. CD38+ (GC) and CD38 (non-GC) cells were separated by applying a magnetic field. Naive B lymphocytes were isolated as IgD+ cells from total B lymphocyte suspensions by immunomagnetic bead manipulation. The IgD B cell fractions were further separated into CD38+ (GC) cells and CD38 (memory) cells by the same technique (11). All of the above separation procedures were performed at 4°C in order to prevent spontaneous apoptosis of GC B cells.
In some experiments, B lymphocytes were run on a discontinuous Percoll (Pharmacia, Uppsala, Sweden) density gradient consisting of 100, 60, 50, 40 and 30% Percoll dilutions respectively from the bottom to the top of the tubes, as previously reported (6,39). Cells collected from the low-density fractions of the gradient (30 and 40%) were treated with CD39 and anti-IgD mAb, and subsequently with anti-mouse IgG magnetic beads. Unbound B cells represented homogeneous populations (>98%) of GC B lymphocytes, as shown by expression of CD38, and by negative staining for IgD and CD39 (6,39).
Migration assay
Cell locomotion was studied using the leading front method in a modified Boyden chamber assay (27,40). Duplicate tests were carried out in 48-well microchemotaxis chambers (Neuro Probe, Cabin John, MA) with an 8-µm pore size cellulose ester filter (SCWPO 1300, lot. no R4MM58776; Millipore, Milano, Italy) separating the cells (4 x 105) from the chemoattractant tested at different concentrations or from medium alone (control). Cells were cultured 2 h in RPMI 1640 medium (Seromed; Biochrom, Berlin, Germany) containing 0.1% human albumin and subsequently subjected to the migration assay in the presence of the chemoattractant at 37°C for 2 h. The filters were then removed, fixed in ethanol, stained with Harris hematoxylin, dehydrated, cleared with xylene and mounted in Eukitt (Kindler, Freiburg, Germany). Duplicate chambers were run in each case and the distance (micrometers) traveled by the leading front of cells was measured at x400 magnification (40). For blocking experiments, 2-h cultured B cells were incubated for 30 min at 4°C with the anti-CCR2 mAb (1 µg/ml) or with an isotype-matched control mAb, washed and tested for migration.
Checkerboard analysis
Assays of cell migration with different doses of chemokines on both sides of the filter were performed. The results of these experiments were collected in checkerboard form by which chemokinesis (i.e. change in the intensity of random locomotion) and true chemotaxis (i.e. change in the directional response to the stimulus) were calculated according to Zigmond and Hirsch (40).
Gene expression analysis by RT-PCR
Total RNA was extracted from purified tonsil B lymphocytes by the guanidium thiocyanate method (41) and reverse transcribed into complementary DNA using Superscript Preamplification System (Gibco/BRL Life Technologies, San Giuliano Milanese, Italy). Primer sequences were as follows: hCCR1: 5'-GGAAACTCCAAACACCACAGAGG-3' and 5'-GC CTGGCATGGAAGCCAAGATG-3', amplifying a 502-bp product; hCCR2b: 5'-CAGATATCATGCTGTCCACATCTCGTTCT CGG-3' and 5'-CAGGATCCTTATAAACCAGCCGAGACTTC CTGC-3', amplifying a 1082-bp product; hCCR3: 5'-ATATCT GCGGCCGCAATGACAACCTCACTAGATACAGTTG-3' and 5'-TGAATCCTAAAACACAATAGAGAGTTCCGGC-3', amplifying a 1068-bp product; hCCR4: 5'-ATATCTGCGGCCGCAA TGAACCCCACGGATATAGCAGATAC-3' and 5'-ATCGGAT CCTACAGAGCATCATGAAGATCATG-3', amplifying a 1083-bp product; hCCR5: 5' ATATCTGCGGCCGCGATGGATTAT CAAGTGTCAAGTCCAA-3' and 5'-ATC:GGATCCTCACAAG CCCACAGATATTTCCAGC-3', amplifying a 1058-bp product; hCCR6: 5'-ATGAGCGGGGAATCAATGATTTC-3' and 5'-TCA CATAGTGAAGGACGACGCA-3', amplifying a 1124-bp product; CD3: 5'-GGTTCGGTACTTCTGACT-3' and 5'-TGGTTTT GACTTGTTCTG-3' amplifying a 171-bp product; CD68: 5'-CATCCAACAAGCAATAGCA-3' and 5'-CTGAGCCGAGAAT GTCCACT-3' amplifying a 507-bp product; CD56: 5'-AGGG CAGATGGGAGAGGA-3' and 5'-AACCACCAGGAGCAGGA C-3' amplifying a 361-bp product; ß-actin: 5'-GGAGCAAT GATCTTGATCTTC-3' and 5'-AAGATGACCCAGATCATGTTT GAG-3' amplifying a 500-bp product.
cDNAs were amplified as follows. hCCR1 to hCCR6 and ß-actin genes: 1 cycle of 5 min at 94°C, 30 cycles of 1 min at 94°C, 1 min at 55, 58 or 60°C (depending on the primer pair) and 1 min at 72°C followed by one cycle of 10 min at 72°C. Amplification conditions for the remaining primers were the following: CD3, 1 min at 94°C, 1 min at 48°C, 1 min at 72°C, 32 cycles; CD68, 1 min at 94°C, 1 min at 54°C, 1 min at 72°C, 32 cycles; CD56, 1 min at 94°C, 1 min at 58°C, 1 min at 72°C, 32 cycles. For semiquantitative RT-PCR, cDNAs were co-amplified using different experimental conditions to safeguard against non-linear amplification: 1 cycle of 5 min at 94°C, 25 cycles (ß-actin) and 30 cycles (CCR1, CCR3, CCR5 and CCR6) or 35 cycles (CCR2 and CCR4) of 1 min at 72°C, followed by one cycle of 10 min at 72°C.
The PCR products were subjected to electrophoresis through 1% agarose with ethidium bromide to confirm the base pair sequence length. In control experiments, RNA samples were subjected to PCR amplification omitting the step of reverse transcription. These experiments were addressed at investigating whether genomic DNA possibly contaminating RNA was detected using the primers specified above.
Statistical methods
Data are expressed as mean ± SD. Differences were determined by repeated measures ANOVA followed by the Bonferroni multiple comparisons post test. Differences were accepted as significant when P < 0.05.
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Results |
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To investigate the nature of the CC chemokine-dependent increase in B cell locomotion, the checkerboard analysis was performed. As shown in Table 1, MIP-1, MDC, MIP-5, MCP-1, MCP-2 and MCP-3 stimulated both the rate of cell locomotion and the true chemotaxis. In two different experiments, taking into account spontaneous migration (i.e. in the absence of chemokines above and below the filter), the following individual concentrations above and below the filter (chemokinetic conditions) enhanced cell migration as indicated (mean percent increment ± SD): MIP-1
(100 ng/ml; 33.7 ± 14.8), MDC (100 ng/ml; 31.9 ± 14.1), MIP-5 (100 ng/ml; 21.1 ± 2.1), MCP-1 (300 ng/ml; 17.8 ± 4.2), MCP-2 (300 ng/ml; 56 ± 21.3) and MCP-3 (300 ng/ml; 42.8 ± 1.4).
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In conclusion, MIP-1, MDC, MIP-5, MCP-1, MCP-2 and MCP-3 stimulated both true chemotaxis and chemokinesis, the former being predominant over the latter.
CCR expression in tonsil B lymphocytes
The CC chemokines here investigated interact with CCR1 to CCR6 (1217). Therefore, the expression of CCR1 to CCR6 mRNA was investigated in tonsil B lymphocytes by RT-PCR. Figure 2 shows the results obtained in three different experiments. CCR1 to CCR6 transcripts were consistently detected both in B cells and in control cells (i.e. monocytes for CCR1 to CCR5, dendritic cells differentiated from CD34+ hemopoietic progenitors for CCR6).
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Tonsil B cells were found to express CCR1 (720%), CCR2 (1024%), CCR4 (435%), CCR5 (710%) and CCR6 (2040%), whereas CCR3 was detected on a minor proportion of cells (36%) (data not shown).
Studies carried out with different human leukocyte subsets (T and NK lymphocytes, eosinophils, basophils, monocytes and dendritic cells) have demonstrated that CCR2 binds to MCP-1, MCP-2 and MCP-3 [reviewed in (42)]. However, MCP-2 and MCP-3 may utilize alternative CCR (42). Therefore, the respective contribution of MCP-1, MCP-2 and MCP-3 to the triggering of B cell-associated CCR2 was studied.
Purified tonsil B cells were pre-incubated with an anti-CCR2 blocking mAb or with an isotype-matched irrelevant mAb and were subsequently tested in the modified Boyden chamber assay in the presence of MCP-1, MCP-2 or MCP-3. In three different experiments, blocking of CCR2 inhibited significantly B cell migration in response to MCP-1 (P < 0.001) and to MCP-2 (P < 0.01), but not to MCP-3 (P > 0.05) (Fig. 3).
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In subsequent experiments, purified tonsil B cells were fractionated into the GC and non-GC subpopulations by incubation with CD38 mAb followed by immunomagnetic bead manipulation. These B cell subsets were tested for their migratory responses to MIP-1, MIP-5, MCP1, MCP2, MCP3 and MDC, in comparison with unfractionated B cells from the same tonsils. Positive control for the latter cells was SDF-1.
As shown in Fig. 4, non-GC B cells, as well as unfractionated B cells, migrated significantly faster in the presence that in the absence of the above CC chemokines (P < 0.001 for all chemokines). Furthermore, as expected, the same cell fractions displayed a significantly increased locomotion in response to SDF-1 (P < 0.001) (Fig. 4). In contrast, the spontaneous migration of GC B cells was not enhanced by incubation with MIP-1, MIP-5, MCP1, MCP2, MCP3 or MDC (Fig. 4).
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Control experiments ruled out that the failure of GC B lymphocytes to migrate in vitro in response to the above chemokines was related to their propensity to undergo apoptosis (9). Thus, all the separation procedures were conducted at 4°C to prevent spontaneous apoptosis, and freshly isolated GC B cells contained consistently >90% viable lymphocytes, as assessed by Trypan blue staining. An equivalent proportion of viable cells was detected after 2 h incubation for the locomotory assays.
Next, the expression of CCR1 to CCR6 was investigated by flow cytometry on naive (IgD+), GC (CD38+, IgD) and memory (CD38, IgD) B cells isolated by immunomagnetic bead manipulation. Figure 5 shows the results from three experiments. CCR1 and CCR2 were detected on naive (2645% for CCR1 and 3140% for CCR2) and memory (2844% for CCR1 and 1640% for CCR2) B cells, but not on GC B cells. CCR4 was expressed on the majority of naive (5670%) and memory (4073%) B cells, whereas it was found on 612% GC B cells (Fig. 5). Naive and memory B cells expressed CCR3 (610% for naive B cells and 512% for memory B cells) and CCR5 (910% for naive B cells and 313% for memory B cells), while these receptors were detected on 68% of GC B cells for CCR3 and 38% of the same cells for CCR5 (Fig. 5). Finally, CCR6 was detected on 1830% of naive B cells, 2028% of memory B cells and 24% of GC B cells (Fig. 5).
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The results of flow cytometry experiments shown in Fig. 5 raised the possibility that CCR1 and CCR2 genes were not expressed in GC B cells. Therefore, tonsil B cells were separated into the CD38+ GC and the CD38 naive and memory subsets; these cell fractions were subjected to RNA extraction and semiquantitative RT-PCR for CCR1 to CCR6 gene expression. As shown in Fig. 6, the transcripts of all receptors were detected in both CD38+ and CD38 B cells. The CCR2, CCR3 and CCR4 amplified bands were of comparable intensity in the two cell fractions, whereas CCR1, CCR5 and CCR6 mRNA were more expressed in CD38 than in CD38+ cells (Fig. 6).
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Discussion |
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mRNA of CCR1 to CCR6 was detected in purified tonsil B cells and, accordingly, flow cytometric analyses showed the expression of the corresponding proteins on the cell surface.
Some of the CC chemokines tested bind to a single CCR, whereas others share different receptors. For example, MCP-1 binds exclusively to CCR2; this receptor binds also to MCP-2 and MCP-3. Both of the latter chemokines interact with CCR1 and CCR3; furthermore, MCP-2 interacts with CCR5 (42). In this study, treatment of B cells with a CCR2-blocking mAb inhibited significantly B cell migration induced by MCP-1 and MCP-2, but not that triggered by MCP-3. These results indicate that not only MCP-1, but also MCP-2-driven B cell migration largely depends on CCR2 engagement. It is conceivable that MCP-3 interacted predominantly with CCR1 to stimulate B cell motility, since eotaxin, that binds exclusively to CCR3 (42), was ineffective.
The same considerations apply to MIP-5, a ligand of CCR1 and CCR3 (48), that likely enhanced B cell migration by engaging CCR1.
MDC is known to interact exclusively with CCR4 (49). In this study, we provide the first evidence that MDC attracts human B lymphocytes and that CCR4 is abundantly expressed on the surface of freshly isolated B cells. Since MDC is produced in the T cell areas of secondary lymphoid organs, these observations may suggest novel B cell-tropic functions of MDC, in addition to its postulated role in attracting activated T cells and keeping them in close contact with dendritic cells (50).
MIP-1 binds to CCR5 (5153) and CCR1 (5456); since MIP-1ß, that binds predominantly to CCR5 (5052), did not enhance the locomotion of peripheral blood (46) or tonsil (this study) B cells, it is conceivable that MIP-1
increased B cell migration through CCR1 activation.
CCR6 binds to MIP-3 only and vice versa (57). In our experiments, CCR6 was strongly expressed on the surface of tonsil B cells (21,37,47), but its ligand MIP-3
had no effect on B lymphocyte migration. This result is consistent with some (21,47), but not other (37) reports; notably, in the latter study (37), MIP-3
was found to attract naive and memory, but not GC, B lymphocytes isolated from human tonsils.
Taken together, our findings suggest that the key receptors involved in tonsil B cell mobilization by MIP-1, MIP-5, MCP-1, MCP-2 and MCP-3 are CCR1 and CCR2, while CCR4 binds to MDC only.
A recent study has addressed chemokine responsiveness of murine B cells at all stages of differentiation (3), providing important information on this issue. Some of the chemokines herein investigated were among those tested in such study: MIP-1, MIP-1ß, MCP-1 (JE), MCP-3, MIP-3
and eotaxin (3). MIP-1
, MIP-1ß, MCP-1 (JE) and MCP-3 were found to attract early progenitor murine B cells, but not peripheral B cells; eotaxin was completely inactive versus any B cell fraction and, finally, MIP-3
stimulated the locomotion of all peripheral B cell subsets, but not that of bone marrow B cells (3). The results on murine, mature B cells differ remarkably from those obtained in this study with human B lymphocytes. Other discrepancies between the two experimental systems are (i) the failure of freshly isolated human GC B cells to migrate to SDF-1 (18,27), as opposed to their murine counterparts (3), and (ii) the failure of TECK to attract murine (3), but not human (21), mature B lymphocytes. Collectively, these findings raise a note of caution in extrapolating murine data to the human system or vice versa.
Separation of tonsil B lymphocytes in the GC and non-GC subpopulations showed that non-GC cells only were attracted by MIP-1, MIP-5, MCP-1, MCP-2, MCP-3 and MDC. Accordingly, CCR1, CCR2 and CCR4 were detected on both naive and memory B cells.
Non-GC B cells re-circulate physiologically through blood, lymph and secondary lymphoid organs (4,5). These cells, freshly isolated from human tonsils, have been shown to migrate in vitro in response to various chemoattractants, such as tumor necrosis factor (57), C5a (58) and SDF-1 (18). The present results are therefore in line with the well-characterized locomotory activity of non-GC B cells, both in vivo (4,5) and in vitro (18,58,59).
In contrast, most GC B lymphocytes are resident cells that complete their life cycle in the GC, where they die by apoptosis (59). The poor propensity of human GC B cells to migrate has been related to the low expression of CD62 ligand (43), that is instrumental for cell interaction with high endothelial venules (60), and of CD44 (43,61). Furthermore, in vitro studies have demonstrated that freshly isolated GC B cells are not attracted by various stimuli (18,58,59,62).
In human GC B cells, two different patterns of chemoattractant receptor expression have been described: (i) GC B cells do not express such receptors at the cell surface, as in the case of TNF or C5a receptors, and therefore are not responsive to their specific ligands (58,59); and (ii) GC B cells express chemoattractant receptors, such as CXCR4 that binds to SDF-1 but does not trigger cell migration due to delayed internalization of the receptorligand complex (18).
Consistently with this scheme, staining of GC B cells for CCR1 and CCR2 was negative (although their transcripts were detected in the same cells), whereas CCR3, CCR4, CCR5 and CCR6 were on a minor proportion of cells. Thus, the failure of GC B cells to migrate in response to MIP-1, MIP-5, MCP-1, MCP-2 and MCP-3 is related to the absence of the relevant receptors, i.e. CCR1 and CCR2. In contrast, CCR4, although expressed on a minor but sizeable proportion of GC B cells, was ineffective at delivering stimulatory signals to the same cells following interaction with MDC.
In conclusion, this study demonstrates that, in addition to chemokines synthesized constitutively in the secondary lymphoid tissues, inducible chemokines produced at the periphery may also stimulate B cell locomotion. A major functional difference between the two groups of chemokines is that the former regulate B cell homing to lymphoid follicles, whereas the latter mobilize effector cells to sites of inflammation (12).
In pathological conditions, human B lymphocytes may cross the vascular endothelium and migrate to inflamed tissues. For example, in rheumatoid arthritis and Sjögrens syndrome, B cells infiltrate the synovial membrane or the salivary glands respectively, where they often cluster in newly formed lymphoid follicles (63,64). The present results support the hypothesis that some CC chemokines synthesized on demand at the site of an inflammatory process generate chemotactic gradients that contribute to promote extravasation of B cells, in particular of the memory subset, and their tissue localization. Notably, the B cells themselves can produce certain CC chemokines, such as MIP-1 (65) and MDC (66), which may amplify B cell recruitment to inflammatory foci through paracrine and/or autocrine interactions.
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Acknowledgements |
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Abbreviations |
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BLCB lymphocyte chemoattractant
CCRCC chemokine receptor
CXCRCXC chemokine receptor
ELCEpsteinBarr virus gene 1-ligand chemokine
GCgerminal center
GROgrowth-related oncogene
LNlymph node
MCPmonocyte chemoattractant protein
MDCmacrophage-derived chemokine
MIPmacrophage inflammatory protein
PPPeyers patch
SDFstromal cell derived factor
SLCsecondary lymphoid tissue chemokine
TECKthymus-expressed chemokine
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References |
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