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Prepublished online as a Blood First Edition Paper on January 23, 2003; DOI 10.1182/blood-2002-08-2673.
IMMUNOBIOLOGY
From the Department of Biomedical Engineering,
Northwestern University, Evanston, IL; the Pediatric Brain Tumor
Research Program, Department of Neurological Surgery, Northwestern
University Medical School and Children's Memorial Institute of
Education and Research, Chicago, IL; Robert H. Lurie Comprehensive
Cancer Center, Northwestern University Medical School, Chicago, IL; and
the Department of Microbiology-Immunology, Northwestern Medical School,
Chicago, IL.
The formation of terminally differentiated plasma cells represents
the critical final step in B-cell differentiation. In this study,
utilizing oligonucleotide microarray analysis, we describe the highly
specialized genetic profile exhibited by terminally differentiated
plasma cells. A total of 1476 known genes were differentially expressed
by plasma cells compared with B cells. Plasma cells displayed an
up-regulation, induction, or a selective retention of a unique
constellation of transcription factors, including members of the AP-1,
nuclear factor- Plasma cells, which constitute the final stage of
B-cell differentiation, are specialized terminally differentiated cells with one primary function, the secretion of antibody. Recent work has
begun to reveal some of the factors that regulate plasma cell formation
and function. The transcription factors XBP-1, Blimp-1, and IRF-4 have
each been demonstrated to be critically involved in plasma cell
differentiation.1-4 Furthermore, B-cell transcription factors Pax5 and BCL-6, which can repress transcription of XBP-1 and
Blimp-1, respectively, are down-regulated during plasma cell differentiation.5-7 Recent analysis has provided important
information regarding the critical role of Blimp-1 in regulating plasma
cell gene expression, including, among other aspects, the repression of
Pax5, BCL-6, and B-cell transcription factors Spi-B and
Id3.8,9
Mice deficient in both E- and P-selectin display extremely elevated
serum immunoglobulin G (IgG) levels and severe cervical lymphadenopathy consisting of expanded numbers of lymphocytes, including numerous plasma cells.10 Previously, we have
demonstrated that the cervical lymph nodes of these mice provide a
unique system for the investigation of B-cell differentiation.
Furthermore, we described the purification of significant numbers of
B220 Although recent advances have provided insight into plasma cell
biology, many aspects of plasma cell function have yet to be
determined, including many factors that modulate plasma cell differentiation and function in vivo. Plasma cell gene expression profiles potentially represent crucial information regarding
unidentified transcription factors and signaling molecules important in
plasma cells, the adhesion molecules, and secreted factors that
regulate the interaction of plasma cells with their microenvironment as well as mechanisms of terminal differentiation. Here we report gene
expression profiling of B220 Mice
Cell isolation
Complementary RNA probe preparation and chip hybridization Total RNA was isolated from either plasma cells or B cells using Trizol (Life Technologies, Carlsbad, CA), followed by an additional purification with the RNeasy Mini Kit (Qiagen, Valencia, CA). Double-stranded cDNA was synthesized using a (dT)24 primer containing a T7 RNA polymerase initiation site (Genset, La Jolla, CA) and the Superscript Double Stranded cDNA Synthesis Kit (Life Technologies), with 5 to 10 µg total RNA as a template. Following phenol-chloroform extraction of the cDNA, biotinylated cRNA was generated using the Bioarray HighYield RNA Transcript Labeling Kit (Enzo Diagnostics, Farmingdale, NY) and purified using the RNeasy Mini Kit (Qiagen). A total of 15 µg labeled cRNA was fragmented according to Affymetrix procedures, and the chip hybridization was performed as described.12 Briefly, the cRNA with hybridization controls was hybridized to the murine chip, MG-U74 AV2, according to the Affymetrix protocol. Staining was performed in the GeneChip Fluidics station, and chips were scanned in the Affymetrix GeneChip scanner. Three replicates were performed for both plasma cells and surface IgM+ B cells, each from independent cell preparations.Data analysis Gene expression analysis was performed using Gene Spring (Silicon Genetics, Redwood City, CA). Per chip and per gene normalizations of the expression values (average differences) were executed with Gene Spring, and normalized expression values less than 0.01 were set to 0.01. Gene trees were generated by hierarchical clustering using the standard correlation (Pearson correlation around 0) with a separation ratio of 0.5 and a minimum distance of 0.001.To eliminate genes from the analysis that were not expressed by either plasma cells or B cells, 3 categories of interest were formulated using the present/absent calls generated by the Affymetrix Microarray Suite 4.0. These categories were the following: present in plasma cells/absent in B cells, absent in plasma cells/present in B cells, and present in both cell types. A marginal call was considered absent for these purposes. The cutoff for inclusion in these groups was that 5 of 6 samples had to correspond with the category criteria. For example, to be included in the present in plasma cells/absent in B cells group, a present call in at least 2 plasma cell replicates with an absent call in all 3 B-cell replicates, or a present call in all 3 plasma cell replicates with an absent call in at least 2 B-cell replicates was required. A gene was classified as differentially expressed in plasma cells and B cells if it was (1) among one of these categories and (2) exhibited a statistically significant (P < .05, Mann-Whitney test) and (3) exhibited 2-fold or greater change in the mean expression level. When multiple oligo sets for one gene appeared on the chip, the set derived from the complete cDNA sequence was used. If multiple cDNA-derived sets appeared on the chip, a representative result is shown. A complete list of all the genes examined and all values for each replicate is available on the Blood website; see the Supplemental Data link at the top of the online article. SDS-PAGE and Western Blot analysis Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis of plasma cell and B-cell lysates were performed as described.11 Cell lysates were made from equal numbers of cells with the following high-salt RIPA lysis buffer: 50 mM Tris (tris(hydroxymethyl)aminomethane) (pH 8), 150 mM NaCl, 1% Triton X-100, 1% deoxycholate, 0.1% SDS, and 1 mM EDTA (ethylenediaminetetraacetic acid), with protease inhibitors. Rabbit antimouse TBP antiserum was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Horseradish peroxidase-conjugated antirabbit and antimouse IgG antibodies were purchased from Biosource, and nitrocellulose membranes were developed using enhanced chemiluminescence reagents (Amersham Biosciences, Arlington Heights, IL). The murine plasmacytoma cell line, J558, was used as a positive control for TBP.Real-time quantitative RT-PCR Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using the 7700 sequence detector system as previously described.12 Twenty-five nanograms of total RNA isolated from plasma cells or B cells was used as a template in a 50-µL RT-PCR reaction with the following components: 1 × TaqMan buffer, 5 mM MgCl2, 0.3 mM deoxyadenosine monophosphate (dATP), 0.3 mM deoxycytidine triphosphate (dCTP), 0.3 mM deoxyguanosine triphosphate (dGTP), 0.6 mM deoxyuridine triphosphate (dUTP), 0.1 µM forward and reverse primers, 0.1 µM TaqMan probe, 1.25 units AmpliTaq Gold, 20 units RNase inhibitor, and 12.5 units murine leukemia virus (MuLV) reverse transcriptase. The primers and TaqMan probes were designed using Primer Express software (Perkin Elmer Life Sciences, Shelton, CT), and the sequences are listed in the methods document in the supplemental data. The primers were purchased from Integrated DNA Technologies, and the TaqMan probes were purchased from MegaBases. The cycling parameters were 48°C for 30 minutes, then 95°C for 15 minutes, followed by 40 cycles at 95°C for 15 seconds and 59°C for 1 minute. Rn represents the reporter signal with the baseline
subtracted, and the threshold cycle (CT) is the cycle at
which Rn crosses the threshold for the given sample. The default
threshold was used, which is set at 10 standard deviations above baseline.
Plasma cells and IgM+ B cells display highly distinct gene expression profiles The gene expression profile of plasma cells was compared with surface IgM+ B cells using the Affymetrix murine oligonucleotide array, MG-U74 AV2. With this array, the expression of 12 422 genes was examined, and 3 replicates of each cell type were performed. Hierarchical clustering of these genes demonstrates the high degree of reproducibility of the replicates. As expected, the gene expression profiles of IgM+ B cells and plasma cells were extremely distinct (Figure 1). Furthermore, it was clear from initial observations that plasma cells in general lose expression of many more genes than they gain. Genes were initially categorized based on the present and absent determinations: 396 genes were consistently expressed in plasma cells although absent in B cells, whereas 1395 genes were absent in plasma cells and expressed in B cells, and 3676 genes were expressed in both cell types. Genes were considered altered in plasma cells if they were (1) among one of these categories and additionally displayed (2) a statistically different and (3) 2-fold or greater change in mean expression. With these criteria, 2469 genes were determined to be significantly altered in plasma cells, which included 1476 known genes and 993 unknown expressed sequence tags (ESTs). The altered expression in plasma cells of numerous genes, including Blimp-1, IRF-4, XBP-1, Pax5, CIITA, BCL-6, syndecan-1, CD43, CD19, CD22, MHC class II, CD37, CD79A, L-selectin, CD38, and CD44, were all consistent with previous findings for plasma cells,9,11,13 confirming the fidelity of the analysis.
Plasma cells express a unique constellation of transcription factors Among the many genes differentially expressed in plasma cells and IgM+ B cells were numerous transcription factors (Figure 2). As expected and mentioned above, these included the transcription factors Blimp-1, IRF-4, and XBP-1, which were increased in plasma cells 29.4-, 4.0-, and 17.2-fold, respectively, and have been previously identified as important in plasma cell differentiation.1,2,4 In addition, the loss of multiple B-cell transcription factors in plasma cells, including CIITA, BCL-6, c-myc, EBF, Stat6, and Pax5 (Figure 2), were all consistent with previous findings and with the role of Blimp-1 in repression of these genes.9,14,15 Alterations in expression of several genes were confirmed by quantitative RT-PCR, and these results are shown in Table 1 and Figure 3A. These genes included, among others, XBP-1, Blimp-1, Stat6, and CIITA.
Additionally, these IgG plasma cells also displayed an induction, loss, or selective retention of specific members of multiple other transcription factor families. Among the AP-1 family, c-jun was induced 23.0-fold in plasma cells, and c-fos and fos-B were both up-regulated 5.1-fold and 4.5-fold, respectively (Figure 2). In contrast, jun-B was down-regulated 13.3-fold in plasma cells (Figure 2), whereas jun-D was retained equally in all samples (supplemental data). This altered expression of AP-1 proteins is particularly interesting considering recent data demonstrating that BCL-6 represses Blimp-1 by inhibiting AP-1 transcriptional activation of Blimp-1.16 Furthermore, the plasma cells demonstrated a selective down-regulation
of several components of the nuclear factor-
Examination of mice with lymphocytes deficient in both nuclear factor of activated T cells c1 (NFATc1) and NFATc2 suggested an intrinsic role for these transcription factors in B-cell function, with expanded numbers of plasma cells and elevated IgG1 and IgE serum levels, despite impaired T-cell effector function.19 The plasma cells examined here demonstrate a down-regulation of NFATc1 mRNA as well as NFATc3 (Figure 2). The down-regulation of NFATc1 was also confirmed by quantitative RT-PCR (Table 1). However, NFATc2 is maintained in plasma cells equal to surface IgM+ B cells (supplemental data). Although not required for plasma cell differentiation,19,20 the selective retention of NFATc2 mRNA described here suggests a possible role for NFATc2, nonredundant with NFATc1, in plasma cell function. Conversely, the selective loss of NFATc1 and NFATc3 may be important in plasma cell function through the loss of certain inhibitory functions. The plasma cells demonstrated a loss in c-myc expression, consistent
with Blimp-1 expression by these cells (Figure 2)11 and
previous results that illustrate the role of Blimp-1 in c-myc repression.15 In addition to the loss of c-myc, the c-myc
dimerization partner Max was down-regulated in plasma cells 5.9-fold,
and Mxi1, a member of the Mad family of c-myc antagonists, was
up-regulated in plasma cells 3.6-fold (Figure 2). The c-myc adaptor
protein BIN1 was also lost in plasma cells (Figure 2). In contrast to the up-regulation of Mxi1, another c-myc antagonist, Mnt/ROX, was lost
in plasma cells (Figure 2). Unlike Mxi1, which interacts only with Max,
Mnt can interact with Max and the Max-like protein, Mlx.21
Interestingly, Mlx and the Mad protein Mad4 were retained in plasma
cells equal to B cells (supplemental data), suggesting that they could
possibly play a role in plasma cell function. Although further analysis
is certainly required to determine the mechanism, this expression
profile suggests a cooperative effect of additional members of the
Myc/Mad/Max system in the antagonism of c-myc function in plasma cells.
Furthermore, as demonstrated previously, the repression of c-myc
is necessary but not sufficient for plasma cell terminal
differentiation.22 Accordingly, the plasma cells also
displayed a down-regulation in many additional genes involved in
cell cycle control and proliferation (Table 2).
Octamer site binding transcription factors have been implicated in
B-cell function, including the transcriptional activity of Ig promoters
and the 3' C In addition to the multiple specific transcription factors whose expression was altered in plasma cells, plasma cells also demonstrated expression changes in components of the basal transcription apparatus as well as in several transcriptional cofactors that play critical roles in the transcription of numerous genes. Among these were histone deacetylase-1 (HDAC1), the TATA box binding protein (TBP), the large subunit of RNA polymerase II (RPB1), and the coactivator PCAF, which all displayed reduced expression in plasma cells (Figure 2). Thus, consistent with the highly specialized function of the plasma cell, plasma cells may exhibit unique general transcription mechanisms. Although unexpected, a down-regulation of TBP mRNA in plasma cells was confirmed by quantitative RT-PCR (Figure 3A and Table 1), and TBP protein levels were sharply reduced in plasma cells as well (Figure 3B). In contrast, mRNA encoding TBP-like factor (TLF) was expressed by both the plasma cells and B cells examined here (supplemental data), and TBP and TLF can differentially regulate the transcription of certain genes.26 Consequently, further analysis is required to elucidate the role of decreased TBP levels and the possible function of TLF in primary plasma cells. Additionally, 3 components of the RNA polymerase I complex important in rRNA transcription, the transcription factors UBF, TAFI48, and TAFI95, also showed a reduced expression in plasma cells (Figure 2). A down-regulation of UBF was also confirmed by quantitative RT-PCR (Table 1). Down-regulation of these components and concomitant decreases in rRNA transcription have been observed previously upon cellular differentiation with cell cycle exit. For example, UBF, TAFI48, and TAFI95 down-regulation was associated with the differentiation of F9 embryonal carcinoma cells into parietal endoderm.27 Strikingly, overall TBP protein was also reduced following F9 cell differentiation.27 Furthermore, decreased rRNA transcription was correlated with the down-regulation of UBF during the terminal differentiation of skeletal muscle cells.28 Consequently, similar to other terminally differentiated cell types, the terminal differentiation of plasma cells is associated with a reduction in the expression of TBP and with a decrease in ribosomal RNA transcription. Plasma cells show alterations in many receptors and signaling molecules, including cytokine receptor-associated factors and members of the Wnt and Notch pathways Plasma cells and B cells displayed numerous differences in the expression of receptors and signaling molecules, and a selection of these genes is shown in Figure 4. For example, IRS2, which plays a role in the signaling via several receptors, including the interleukin-4 (IL-4) receptor and the insulin-like growth factor-1 (IGF-1) receptor,29,30 was induced in plasma cells (Figure 4). The IGF-1 receptor itself was also induced, consistent with results obtained with multiple myeloma cells.31 The presence of both the IGF-1 receptor and IRS2 suggests a possible role of this signaling pathway in primary plasma cell function. In contrast, the receptor for IL-4 as well as receptors for the cytokines IL-10, IL-17, and the / and  interferons were lost or
down-regulated in plasma cells (Figure 4). Among the Janus kinase (Jak)
family, Jak1 and Jak2 were lost in plasma cells (Figure 4), whereas
Jak3 was expressed equally in both cell types (supplemental data). In
accordance with Stat6 as a target of Blimp-1-mediated
down-regulation,9 Stat6 was lost in the plasma cells
examined here (Figure 2 and Table 1). In addition, Stat4 and Stat5b
were also lost (Figure 2), whereas Stat1 and Stat3 were retained at
levels equal to B cells (supplemental data).
In addition to the selective retention of Stat3 itself, the plasma
cells exhibited a loss in the expression of the protein inhibitor of
activated Stat3 (PIAS3) (Figure 4). In contrast, the protein inhibitor
of activated Stat1 (PIAS1) was expressed equally in plasma cells and B
cells (supplemental data). Strikingly, mRNA encoding the suppressor of
cytokine signaling-3 (SOCS3), which can inhibit IL-6 receptor
signaling through Stat3,32 also displayed a reduced
expression in plasma cells (Figure 4). This down-regulation of SOCS3
expression in plasma cells was confirmed by quantitative RT-PCR (Figure
3A and Table 1). On the contrary, SOCS2, which can be induced by IL-6
signaling but does not effectively inhibit IL-6
signaling,32,33 was induced in plasma cells. Additionally, the chaperone protein Grp58, which has been shown to interact with
Stat3,34 was up-regulated in plasma cells. The signaling component of the IL-6 receptor, gp130, was expressed by both B cells
and plasma cells and displayed a 1.8-fold statistically significant
increase in plasma cells (supplemental data). In contrast, the IL-6
receptor Several components of the Wnt signaling pathway also displayed an
altered expression in plasma cells relative to B cells. In the absence
of a Wnt signal, Interestingly, the plasma cells also demonstrated alterations in the
mRNA levels of several secreted factors, including an induction of
VEGF-A (Table 3). The expression of VEGF
by plasma cells has previously been associated with multiple myeloma,
where an autocrine loop of vascular endothelial growth factor
(VEGF) signaling can stimulate myeloma cell
proliferation.48 In contrast to myeloma, the VEGF receptor
Flt-1 was not expressed by the primary plasma cells examined here (nor
was the receptor KDR), suggesting that an autocrine loop is not present
in primary plasma cells. VEGF expression by plasma cells has also been
demonstrated in the lymph nodes of patients with Castleman disease but
not in normal lymph nodes.49 Recently, it was demonstrated
that VEGF gene expression can be induced in B-cell lines by the
introduction of Blimp-1.9 Consequently, Blimp-1 may
initially allow VEGF expression, which is then regulated by modifying
factors in vivo. Perhaps VEGF expression by plasma cells in the
E/P
Plasma cells up-regulate antiapoptotic factors, including Bcl-xL, Bcl-w, and XIAP, but lose Bcl-2 In accordance with other categories of genes, many more genes associated with apoptosis were lost rather than gained in plasma cells (Table 4). For example, Bcl-2 expression was lost in plasma cells. However, 2 other Bcl-2 family members, Bcl-xL and Bcl-w, were up-regulated in plasma cells 2.1-fold and 4.8-fold, respectively (Table 4). The higher expression of Bcl-xL versus Bcl-2 was reported previously in human plasma cells.50 Additionally, several proapoptotic factors were lost or down-regulated in plasma cells, including, among others, the Bcl-2 family member BID, the Bcl-2 binding protein Bax, and caspases 6 and 2 (Table 4). Another factor that has been associated with B-cell survival is the Pim-1 kinase.51 Interestingly, although Pim-1 kinase activity in B cells has been attributed to BCR activation, CD40 signaling, or lipopolysaccharide (LPS) stimulation,51 the microarray analysis demonstrated a 21.2-fold up-regulation in Pim-1 expression in plasma cells (Figure 4), which have lost CD40 and multiple BCR signaling components (Table 5 and Figure 4). However, Pim-1 can also be induced by Stat3-mediated transcription through gp130 signaling,52 a pathway that is retained in plasma cells (mentioned above). Furthermore, valosine-containing protein (VCP), which is a target of Pim-1 signaling and involved in Pim-1-mediated protection against apoptosis,52 is up-regulated in plasma cells 2.9-fold (Table 4). An up-regulation of Pim-1 mRNA expression in plasma cells was also confirmed by quantitiative RT-PCR (Table 1). Consequently, Pim-1 kinase expression resulting from IL-6 signaling and Stat3 activation may be a critical component in the protection of plasma cells against apoptosis.
Recently, the induction of GADD45 Plasma cells express the nervous system genes, reelin and neuropilin Select additional alterations in plasma cell gene expression are displayed in Table 5. Unexpectedly, the plasma cells expressed factors that have previously been associated with nervous system function. One such gene that was highly induced in plasma cells encodes the protein reelin (Table 5), which regulates the migration of neurons in the developing cortex and is mutated in the reeler mouse strain.59 The induction of reelin in plasma cells was confirmed by quantitative RT-PCR (Figure 3A and Table 1). Receptors for reelin include the very low density lipoprotein receptor (Vldlr), the apolipoprotein E receptor-2 (ApoER2), and the integrin31. ApoE
can block receptor binding of reelin and subsequent
signaling60 and, interestingly, ApoE expression was lost
in the plasma cells examined here (Table 5). In contrast, mRNA for ApoE
has been reported previously to be expressed by bone marrow plasma
cells and significantly down-regulated in myeloma.42
Consequently, the expression shift from ApoE to reelin upon plasma cell
differentiation may be important in regulating the migration of plasma
cells or an associated cell type with which plasma cells interact
within distinct anatomic sites. Further analysis into reelin expression by plasma cells could provide insight into additional physiological roles of reelin and the possibility that analogous to its function in
the nervous system, reelin could function in cell positioning within
lymphoid organs.
Another factor up-regulated in plasma cells that plays an important role in the organization of cells within the nervous system was neuropilin-1 (Table 5),61,62 and this up-regulation was also confirmed by quantitative RT-PCR (Figure 3A and Table 1). Neuropilin-1 has also been shown to bind VEGF and modulate VEGF signaling through the VEGF receptor, KDR.63 Recently, neuropilin-1 was shown to be expressed by dendritic cells and resting T cells and to be involved in a homotypic interaction between these 2 cell types, suggesting that neuropilin-1 plays a role in the initiation of the immune response.64 Furthermore, neuropilin-1 expression was described in bone marrow stromal cell lines as well as bone marrow adherent cells.65 Collectively, these findings strongly suggest that neuropilin-1 may be involved in positioning of plasma cells within appropriate bone marrow microenvironments. In summary, by utilizing oligonucleotide microarray analysis of primary plasma cells and B cells, we have demonstrated that plasma cells exhibit multiple genetic alterations specific to plasma cell differentiation. The plasma cells displayed a unique pattern of expression of transcription factors, signaling molecules, as well as genes involved in the regulation of proliferation and apoptosis. Additionally, the comparison of plasma cells and B cells provides important information regarding not only gene expression alterations but also genes that are selectively retained during plasma cell differentiation. In conclusion, these results provide insight into the gene expression changes underlying the mechanisms of plasma cell terminal differentiation and the factors that govern plasma cell function in vivo. Furthermore, the plasma cell profile of gene expression described here provides a solid foundation for future research into plasma cell biology.
We thank Dr Susan Winandy for critical review of this manuscript.
Submitted September 3, 2002; accepted January 7, 2003.
Prepublished online as Blood First Edition Paper, January 23, 2003; DOI 10.1182/blood- 2002-08-2673.
Supported by National Institutes of Health grant HL58710 (G.S.K.). The microarray facility at the Children's Memorial Institute of Education and Research is supported by the Falk Foundation.
The online version of the article contains a data supplement.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Geoffrey S. Kansas, Department of Microbiology-Immunology, Northwestern Medical School, 303 E Chicago Ave, Chicago, IL 60611; e-mail: gsk{at}northwestern.edu.
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Top
Abstract
Introduction
B (NF-
terminally differentiated plasma cells as well as
the distinct adhesion characteristics of these
cells.
) versus IgM+ B cells (
) by
real-time quantitative RT-PCR are shown. 