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*
Deutsches Rheuma-Forschungszentrum Berlin and
Department of Rheumatology and Clinical Immunology and
Outpatients’ Department, Charite University Hospital, Berlin, Germany;
National Institute of Arthritis and Musculoscletal and Skin Diseases; National Institutes of Health, Bethesda, MD 20892
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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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In vivo, Ag-specific activation and differentiation of B cells occur in germinal centers (12, 13, 14, 15, 16). Within germinal centers, naive B cells undergo activation, proliferation, somatic hypermutation of rearranged V region genes, Ig isotype switching, and subsequent positive and/or negative selection by Ag (13, 15, 17, 18, 19). Within germinal centers, activated B cells mature into Ab-producing plasma cells or, alternatively, become memory B cells. This developmental dichotomy of B cells is reflected by differential expression of a variety of B cell surface Ags, such as surface Ig, CD38, CD20, and CD138 (syndecan-1; see Refs. 14, 20). In peripheral blood as well as in the bone marrow, memory B cells have been identified in populations of B cells expressing either class-switched Ig isotypes: IgM and IgD, or IgM only (21, 22, 23, 24, 25). More recently, IgD+/CD27+ B cells have been identified as having somatically mutated Ig genes and, therefore, being memory B cells (25). In normal persons, IgM+/IgD+/CD27- naive B cells represent about 60% of the peripheral blood B cell population (25, 26).
In this study, we demonstrate that the frequencies of CD27-expressing B cells were significantly enhanced as a result of a relative and absolute reduction of the total number of naive B cells and a less prominent reduction of memory B cells in the periphery of patients with SLE. A significant population of CD27high plasma cells was identified in the periphery of patients with active SLE. Upon immunosuppressive therapy, the CD27+ B cell population in SLE patients remained stable, whereas the frequencies of naive B cells and CD27high plasma blasts decreased significantly.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Heparinized whole blood (10–20 ml) from patients with various
autoimmune diseases (Table I
) were
obtained from the Department of Rheumatic Diseases, University
Hospitals Charite (Berlin, Germany). In detail, we analyzed 13 patients
with SLE, fulfilling the criteria revised in 1982 (27),
and a group of 9 patients with other autoimmune diseases (2 patients
with primary Sjögren’s syndrome, 2 patients with polymyositis, 2
patients with progressive systemic sclerosis, 1 patient with
polymyalgia rheumatica, 1 patient with polychondritis, and 1
patient with acquired factor VIII resistance) (Table I). Six patients
with SLE exhibited a flare at the time of analysis and subsequently
underwent immunosuppressive therapy. Two patients had not been
diagnosed before (patients 11 and 13), one patient discontinued taking
prednisolone 3 wk before the analysis (patient 6), and
three patients were taking <10 mg of prednisolone/day (patients 1, 5,
and 10) at the time of disease flare. The remaining patients with SLE
were being treated with azathioprine (100–150 mg daily) and/or
methylprednisolone (12 mg daily) or prednisolone, respectively
(
20 mg daily). As a control, fresh blood from 14 apparently normal
healthy blood donors (NHS) were also analyzed. PBMC were prepared as
reported previously (24).
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Immunofluorescence staining for flow cytometric analysis was
performed by incubating PBMC with biotinylated anti-CD19 (SJ25-C1;
Southern Biotechnology Associates, Birmingham, AL), anti-CD27 Cy5
(clone 2E4), and either anti-CD38 FITC (clone HIT-2; PharMingen,
San Diego, CA.), anti-HLA-DR FITC (clone R30), anti-CD95 FITC
(clone CH-11; Immunotech, Marseille, France), anti-CD20 FITC (clone
B-Ly1; Southern Biotechnology Associates), anti-human CD138
biotinylated (clone B-B4; Diaclone, Sunnyvale, CA.), anti-human
Ig
FITC (G20–193; PharMingen) and 
light chain FITC (JDC-12;
PharMingen), anti-human IgG FITC (rabbit anti-human IgG; Dako,
Hamburg, Germany), anti-human IgM FITC (rabbit anti-human IgM;
Dako), or anti-human IgD FITC (clone IA6-2, mouse anti-human
IgD; PharMingen). Incubation with Abs was performed in PBS/0.5%BSA/5
mM EDTA at 4°C for 10 min. Propidium iodide (1 µg/ml; Sigma,
Munich, Germany) was added immediately before cytometric analysis
to exclude dead cells. Before incubation with streptavidin-PE (0.5
µg/ml; PharMingen), cells were washed twice. For intracellular
staining, the cells were fixed in 2% (w/v) formaldehyde (Merck,
Darmstadt, Germany) for 20 min at room temperature, washed, and stored
at 6–8°C in PBS/0.5%BSA. The cells were then incubated in
PBS/0.5%BSA, with or without 0.5% saponin (saponin buffer; Sigma),
and fluoresceinated Ab for 10 min at 4°C and then washed in saponin
buffer and PBS. For intracellular analyses, anti-IgE FITC (rabbit
anti-human IgE; Dako) was used. In addition, anti-CD5 FITC
(clone UCHT2, mouse anti-human CD5; PharMingen) was used to
characterize the expression of this molecule and CD27. Flow cytometric
analysis was performed using a FACSCalibur and CellQuest software
(Becton Dickinson, San Jose, CA). Thirty thousand to 200,000 events
were collected for each analysis.
Statistical analysis of the data was performed by using GraphPad Prism software (GraphPad, San Diego, CA). Frequencies of B cell populations were calculated using CellQuest software (Becton Dickinson) and differences between blood donor groups were compared using the nonparametric Mann-Whitney U test. To analyze the relationship between total white blood cell count and total B cells, the total numbers of B cells of various phenotypes were calculated per milliliter of blood, based on the frequencies of those cells among PBMC, and the total numbers of PBMC. p values <0.05 were considered as statistically significant.
Molecular analysis of V gene usage
For analysis of VH gene rearrangements, CD27-/IgD+ cells, CD27+/IgD+ cells, and CD27high/IgD- B cells were individually sorted into wells of a 96-well PCR plate into lysing solution (28) (Robbins Scientific, Sunnyvale, CA). For this analysis, PBMC from an untreated SLE patient (patient 10; butterfly rush, nephritis, hypocomplemenaemia, anti-dsDNA titer 1:8 using Crithidia luciliae immune fluorescence) were stained with biotinylated anti-CD19, streptavidin-PE, anti-CD27 Cy5, and anti-IgD FITC. Cells were sorted using a FACSVantage (Becton Dickinson).
Rearranged VHDJH gene
rearrangements employing specific VH gene
segments were amplified for all VH families as
described previously (28). The PCR error rate for this
analysis has been shown to be 10-4/bp
(29). After column purification of PCR products (GenElute
Agarose Spin Column; Supelco, Bellefonte, PA), they were directly
sequenced using the Applied Biosystems Prism Dye Termination Cycle
Sequencing kit (Perkin-Elmer, Foster City, CA) and analyzed with an
automated Sequencer (Applied Biosystems Prism 377; Perkin-Elmer).
Sequences were analyzed using the V BASE Sequence Directory to identify
the respective germline V genes, using DNAPlot (University of
Cologne/http://www.genetik.uni-koeln.de/dnaplot/) and Sequencher (Gene
Codes, Ann Arbor, MI) software. The mutational frequencies of the
productively rearranged VH gene segments obtained
from individual cells of the three B cell populations were analyzed
with the 
2 test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMC of all 13 patients with SLE, 9 patients with other autoimmune
diseases, and 14 NHS were analyzed for the expression of CD27 as a
marker of memory B cells. Some of these were also analyzed for the
expression of surface IgM (sIgM), sIgG, sIgD, CD38, CD138, CD20, CD95,
and HLA-DR. The frequencies of
CD27+/CD19+ cells were
calculated according to statistical threshold sets in reference to
control stainings, as shown in Fig. 1.
Patients with inactive SLE treated with azathioprine and/or
glucocorticoids had significantly lower total numbers of peripheral B
cells regardless of their treatment regimen (Fig. 2) compared with both control groups.
When the overall frequency of peripheral B cells expressing CD27 was
examined, SLE patients with active and inactive disease had
significantly higher frequencies of CD27-expressing B cells than both
control groups (Fig. 3). The two control
groups did not differ in the overall frequency of CD27-expressing B
cells (p = 0.4310).
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The increase in the frequency of
CD19+/CD27+ peripheral B
cells in SLE patients was not caused by an expansion of the
CD19+/CD27+ subpopulation.
Rather, it was a consequence of a significantly reduced total number of
naive CD19+/CD27-
peripheral B cells of SLE patients with active (85 ± 54 x
106 cells/l) and inactive disease (74 ±
70 x 106 cells/l) compared with other
patients (546 ± 941 x 106 cells/l,
p = 0.012 and p = 0.0052, respectively)
and normal controls (418 ± 204 x 106
cells/l, p = 0.0006 and p = 0.0004,
respectively) (Fig. 4). Patients with
active disease did not differ in their frequency of naive B cells
compared with those without disease flares (p =
0.7308, Fig. 4). In contrast, the total number of
CD27- B cells was not significantly lower in
patients with other autoimmune diseases than in normal controls
(p = 0.0833). As shown in Fig. 4, the reduction in these absolute numbers of naive B cells coincided with
a reduced frequency of CD27- B cells in SLE
patients compared with both control groups, whereas these frequencies
did not differ between the two groups of SLE patients
(p = 0.9452) or between the control groups
(p = 0.8749).
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). Moreover, patients with
active lupus and those with inactive treated disease did not differ in
regard to the frequency of CD27+ peripheral B
cells (p = 0.2949). In most patients with SLE
(10/13), CD27+ B cells comprised 39.2% or more
of the peripheral B cells, with a mean frequency of 43 ± 17% in
active and 55 ± 22% in inactive SLE patients. One female patient
(donor 4) was exceptional in that only 15.9% of her B cells expressed
CD27, a frequency in the range of NHS controls. Interestingly, this
patient had delivered a healthy child 1 wk before the analysis and did
not manifest any disease activity at that time. Her white blood cell
count and levels of complement factors C3 and C4 were normal.
Anti-dsDNA Abs were not detectable, although previously she had had a
1:8 titer of anti-dsDNA and 1:80 titer of anti-nuclear Abs
(fine speckled pattern).
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Although the frequency of CD27+ B cells among
CD19+ cells was significantly increased in
inactive SLE patients compared with patients with other autoimmune
diseases (p < 0.017) and NHS
(p < 0.016, Fig. 5
) only, the absolute number
of these cells was significantly higher in NHS compared with the other
groups analyzed (Fig. 5). Moreover, the absolute number of
CD27+ cells did not differ between any of the
patient groups. Although the absolute number of
CD27+ B cells was diminished in all patient
groups, the magnitude of the decrease noted in the SLE patients was
markedly less than the decrease in the number of circulating
CD19+/CD27- naive B
cells.
An increase in the frequency and the number of the peripheral CD27high/CD19+ B cell subpopulation is characteristic of active SLE
Patients with active and inactive SLE showed an increased
frequency of peripheral B cells expressing high levels of CD27
(CD27high, Figs. 1 and 6) in contrast to NHS
(p < 0.0006 and p < 0.001,
respectively, Fig. 6) and to controls with other autoimmune diseases
(p < 0.004 and p < 0.0007,
respectively). Among the SLE patients with active disease, the mean
frequency of these cells was 26 ± 15%, ranging between 7.4 and
43.1% of peripheral B cells, significantly higher than in SLE patients
with inactive disease (mean, 6 ± 4%; minimum, 1.9%; maximum,
11.2%; p < 0.022). The CD27high
B cell subpopulation was uncommon in the blood of NHS (1.4 ±
0.8% of peripheral B cells). In patients with autoimmune diseases
other than SLE, such cells were found at frequencies of 0.9 ±
0.9%. The frequencies of CD27high B cells in the
seven SLE patients without disease activity were higher than those in
patients with other autoimmune diseases (p <
0.0007) as well as in NHS (p < 0.001).
However, the absolute numbers of CD27high B cells
were only significantly increased in active SLE patients compared with
inactive SLE patients (p < 0.008), patients
with other autoimmune diseases (p < 0.0004),
and NHS (p < 0.002). It should be pointed out
that among the non-SLE autoimmune controls, one of the patients with
Sjögren’s syndrome was the only one with a significantly
increased population of CD27high B cells
(3.2%).
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As shown in Fig. 7, and representative for the SLE patients analyzed, the
CD27high cells of patients with active disease
showed a higher forward scatter than the other B cells (Fig. 7b), indicating that they were larger cells. Both
CD27+ and CD27high, but not
CD27-, cells had distinct subpopulations of even
larger cells, which might reflect distinct activation stages. This
contention was supported by the HLA-DR staining, which also revealed a
heterogeneity among CD27+ and
CD27high cells indicative of recent activation of
at least some cells. In addition, and unlike
CD27+ cells, all CD27high
cells expressed lower levels of CD19, high amounts of CD38 and CD138,
and no CD20, markers of plasma cells (30). Of note, they
also expressed high levels of CD95, expression of which had not
previously been described for plasma cells, but rather on early plasma
blasts (Fig. 7, d–f, l; see Refs. 30, 31).
Few, if any CD27high cells expressed sIgM, IgD,
IgG, or Ig light chains (Fig. 7, g–i), but all stained
intracellularly for or light chains (Fig. 7k). As
shown in Fig. 8, most
CD27high cells express either IgG or IgA in four
SLE patients analyzed. Few IgM- and no IgE-expressing cells were
detectable. In the patients analyzed, most CD27+
and CD27high B cells did not express CD5 (data
not shown). In summary, the cytometric phenotype of
CD27high cells was indicative of plasma
cells.
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and representative for six individuals
analyzed, B cells positive for CD138 almost exclusively express
CD27high (Fig. 9a) and the majority of
them coexpress CD19 (Fig. 9b), whereas only two-thirds of
the CD19dim/CD27high B
cells do express CD138 (Fig. 9, c and d).
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To determine whether the presence of
CD27high B cells in peripheral blood was related
to disease activity and/or treatment, we performed a follow-up analysis
on two of the patients who initially had a prominent population of
these cells in the periphery at the time of flare symptoms and
consequently had been treated with immunosuppressive therapy. As seen
in Fig. 10, the administration of i.v.
methylprednisolone, 1000-mg bolus for 2 days and 500 mg for the
successive 3 days, led to a marked reduction of the peripheral
CD27high plasma cell subpopulation. Subsequently,
the patient received i.v. cyclophosphamide (800 mg bolus) once.
Afterward, the patient’s condition improved and the
CD27high B cells had almost completely
disappeared from the periphery and the number of naive B cells was
reduced significantly, with CD27+ memory B cells
not detectably affected. The phenotype shown in Fig. 10c was
characteristic of three SLE patients treated with immunosuppressive
therapy and without apparent disease activity. Another SLE patient
(Fig. 1c), treated with hemodialysis, still exhibited
smoldering activity including lowered complement factors. This patient
still showed an increased frequency of peripheral plasma cells (10.7%)
but a low frequency of naive B cells (5.3%).
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Individual
IgD+/CD27-,
CD27+/IgD+, and
CD27high/IgD- B cells were
sorted by FACS using single-cell deposition. The mutational frequencies
of VH gene segments were determined for the three
cell types (Table II). Among productively
rearranged VH genes, there was a significant
difference in the mean frequency of mutations between the
CD27- (mutational frequency, 0.4%) and the
CD27-expressing B cell populations (mutational frequency, 6.46%,
p < 0.0001), which is consistent with the
classification of CD27+ cells as memory B cells.
CD27+ (mutational frequency, 6.1%) and
CD27high cells (mutational frequency, 6.9%) did
not differ in their mutational frequencies (p =
0.191).
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). Whereas
VH3 genes were preferentially used by B cells
expressing IgD but not CD27 (13/14) and no
IgD+/CD27- B cell used
VH4 gene segments, the latter gene segments were
used by some IgD+/CD27+
memory B cells (2/15) and >50% of
IgD-/CD27high plasma cells
(8/15, if the genes used by all cells of a clone were considered as
one). With regard to individual genes, the
VH3–23 gene was found most often in
CD27-/IgD+ naive (6/14)
and CD27+/IgD+ memory B
cells (4/15), whereas VH4–34 was amplified from
3 of 15 and VH4–59 from 3 of 15
CD27high/IgD- cells. The
increase in mutational frequencies coincided with an increase in
frequencies of B cells using VH4 in the
productive repertoire. Notably, VH1 family
members were found to be rearranged in all B cell subpopulations.
However, productively rearranged VH1 family
members occurred in CD27+ B cells (2/15) and
CD27high plasma cells (1/15) only.
In addition, a clonally expanded population within the
CD27high plasma cells employing
VH4–61/D3–09/JH4 could be
identified with an almost identical CDR3 of 66 bp and a common
insertion of 6 inserted bp in CDR1 (Fig. 11). The three rearranged
VH4–61 genes of this clone carried 25 mutations
(gene D12 IV VH4 A1), 44 mutations (gene D12 IV
VH4 F1), and 54 mutations (gene D12 IV
VH4 H3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Extensive work has been devoted to analysis of autoantibody-producing cells and perturbation of T lymphocyte homeostasis in patients with SLE (32 ; reviewed in Ref. 5). With regard to B lymphocytes, spontaneously activated B cells and polyclonal production of Ig, including autoantibodies, have been repeatedly demonstrated in the peripheral blood and in the bone marrow of SLE patients (reviewed in Refs. 5, 6, 8, 9, 10, 11). The current data are consistent with these findings, indicating that there are expanded numbers of phenotypically defined plasma cells in the blood of patients with active SLE. For the first time, we show here that these plasma cells express high levels of CD27.
CD27 belongs to the TNF receptor family and is expressed preferentially by T cells but also by B cells. CD27 signals after interaction with its ligand, CD70, which is expressed on T cells. CD27/CD70 signaling appears to act at late stages of B cell differentiation, providing a key signal for the maturation of memory B cells into Ig-secreting cells in the germinal center reaction (33, 34, 35). Expression of CD27 on B cells is apparently induced in the context of germinal center reactions and is maintained on memory B cells (25). CD27+ B cells in human peripheral blood show extensive somatic hypermutation of their V genes, irrespective of the isotype they express, marking them as descendants of cells activated previously in vivo (25, 36). Here, we confirm this observation and extend it to peripheral CD27+/IgD+ B cells and CD27high B cells from a patient with a lupus flare.
Of the VH gene rearrangements from the CD27+/IgD+ B cells analyzed, 14 of 15 showed mutation rates of 2–15% (overall mutational frequency, 6.1%). In comparison, 10 productively rearranged VH segments from CD27-/IgD+ B cells showed an overall mutational frequency of only 0.4%. In peripheral B cells from normal subjects, Klein et al. (25) had observed similar frequencies for CD27- and for CD27+ B cells. Eleven of 14 VH regions obtained from CD27high plasma cells were highly mutated (3.4–10.5%; mean, 6.9%), In addition, three cells of a heavily mutated CD27high plasma cell clone expressed the VH4–61 gene segment with 25–54 mutations. CD27+ and CD27high cells both showed a high degree of somatic hypermutation, but they differed in their VH gene preference. Thirteen of 14 IgH loci of CD27-/IgD+ B cells and 11 of 15 IgH loci of CD27+/IgD+ cells used VH3 genes in VDJ recombination. In CD27high B cells, however, only 5 of 15 IgH loci used VH3 but 9 genes of the VH4 family. In addition, the three clonally related cells used the VH4–61 segment. Preferential usage of VH4 genes by postswitch cells has been reported by other groups for patients with rheumatoid arthritis (37, 38), whereas VH3 was most frequently found in naive B cells or in unfractionated peripheral B cells from normal subjects (24, 28, 39). Moreover, the gene VH4–34 frequently used in the clonally unrelated CD27high cells analyzed here has been reported previously to be involved in the formation of anti-dsDNA Abs in SLE patients (40, 41, 42) and to be expanded in patients with disease activity (41). This VH4 gene encodes cold agglutinins (43, 44, 45). It was also frequently used in immune responses of infectious mononucleosis (41, 46). In normal subjects, this particular gene occurred at frequencies of 3.5% among peripheral CD5+ and 3.9% among CD5- B cells (24) or 3–10.8% among peripheral B cells (44, 45, 47, 48). The high frequency of VH4–34 usage in peripheral CD27high B cells, the high frequency of such cells in untreated SLE patients, and their disappearance upon successful immunosuppressive treatment imply that CD27high plasma cells expressing this VH gene rearrangement may be involved in the etiopathogenesis of SLE.
The identification of CD27high/CD19+ B cells as a prominent population of peripheral B cells in patients with active SLE represents a central finding of the present study. These cells express little if any surface, but increased intracellular, Ig compared with CD27+ B cells. Apart from CD27, the CD27high cells express CD38, HLA-DR, and CD95, but not CD20 or CD5 and little CD19. All cells expressing intracellular Ig are CD19dim (data not shown). The expression of CD19 on peripheral plasma cells has been shown before (49, 50) and contrasts with the apparent absence of CD19 on myeloma cells (50, 51). Only two-thirds of them also express CD138+ (syndecan-1). As for CD5, it has been shown that both CD5+ as well as CD5- B cells (52) obtained from SLE patients can produce anti-DNA Abs. The current data indicate that CD27+ and CD27high B cells are almost exclusively members of the CD5- B cell population, also in patients with an SLE flare. The expression of CD38, CD138, CD95, and intracellular Ig, down-modulation of CD20 and CD19, and hypermutated rearranged VH genes identifies these cells as plasma cells (30, 53).
For CD27+ memory B cells, Agematsu et al. (34, 35) have shown that these cells can be induced in vitro to differentiate into Ig-secreting plasma blasts upon stimulation with CD70, IL-2, and IL-10. CD38+ peripheral cells have been shown by Lakew et al. (54) to secrete Ig in vitro spontaneously. Since expression of CD38 and CD27high on peripheral B cells is perfectly correlated, it can be inferred that CD27high/CD19dim cells are Ab-secreting plasma cells.
In summary, the current study provides clear evidence that the expression of CD27 identifies marked disturbances of B cell homeostasis with respect to naive and memory B cells and plasma cells. Notably, a striking B lymphocytopenia and a marked reduction of CD27- B cells appear to be characteristic of SLE and not only the result of therapeutic interventions. In addition, active SLE is characterized by a marked increase in circulating plasma cells that is dramatically reduced by immunosuppressive therapy. The pool of CD27+ peripheral B cells is less susceptible to immunosuppressive therapy in contrast to the pools of naive B cells and CD27high plasma cells. These results have clear implications for diagnosis and therapy of SLE. Cytometric monitoring of the various B cell populations using CD27 in conjunction with CD19 may provide an important diagnostic parameter for monitoring disease activity in SLE patients.
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Acknowledgments |
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Footnotes |
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2 A.R. and T.D. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Thomas Dörner, Department of Medicine/Rheumatology and Clinical Immunology, University Hospital Charite, Schumannstrasse 20/21, 10098 Berlin, Germany.
4 Abbreviations used in this paper: SLE, systemic lupus erythematosus; NHS, normal healthy subject; s, surface.
Received for publication May 4, 2000. Accepted for publication August 21, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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genes with no or little somatic mutation throughout life. Eur. J. Immunol. 23:3272.[Medline]
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 R. Garcia-Munoz, E. Panizo, P. Rodriguez-Otero, M. C. Mugueta-Uriaque, J. Rifon, L. Llorente, and C. Panizo Systemic lupus erythematosus and Franklin's disease: when the somatic mutation mechanism makes a mistake Rheumatology, July 1, 2008; 47(7): 1105 - 1106. [Full Text] [PDF]
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D. Saadoun, M. Rosenzwajg, D. Landau, J. C. Piette, D. Klatzmann, and P. Cacoub Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis Blood, June 1, 2008; 111(11): 5334 - 5341. [Abstract] [Full Text] [PDF]
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N.-H. Chang, T. McKenzie, G. Bonventi, C. Landolt-Marticorena, P. R. Fortin, D. Gladman, M. Urowitz, and J. E. Wither Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus J. Immunol., January 15, 2008; 180(2): 1276 - 1284. [Abstract] [Full Text] [PDF]
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 A. Lim, B. Lemercier, X. Wertz, S. L. Pottier, F. Huetz, and P. Kourilsky Many human peripheral VH5-expressing IgM+ B cells display a unique heavy-chain rearrangement Int. Immunol., January 1, 2008; 20(1): 105 - 116. [Abstract] [Full Text] [PDF]
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C. Wei, J. Anolik, A. Cappione, B. Zheng, A. Pugh-Bernard, J. Brooks, E.-H. Lee, E. C. B. Milner, and I. Sanz A New Population of Cells Lacking Expression of CD27 Represents a Notable Component of the B Cell Memory Compartment in Systemic Lupus Erythematosus J. Immunol., May 15, 2007; 178(10): 6624 - 6633. [Abstract] [Full Text] [PDF]
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K. Su, H. Yang, X. Li, X. Li, A. W. Gibson, J. M. Cafardi, T. Zhou, J. C. Edberg, and R. P. Kimberly Expression Profile of Fc{gamma}RIIb on Leukocytes and Its Dysregulation in Systemic Lupus Erythematosus J. Immunol., March 1, 2007; 178(5): 3272 - 3280. [Abstract] [Full Text] [PDF]
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K. L. Good, V. L. Bryant, and S. G. Tangye Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21 J. Immunol., October 15, 2006; 177(8): 5236 - 5247. [Abstract] [Full Text] [PDF]
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R W-Y Chan, F M-M Lai, E K-M Li, L-S Tam, K-Y Chung, K-M Chow, P K-T Li, and C-C Szeto Urinary mononuclear cell and disease activity of systemic lupus erythematosus Lupus, May 1, 2006; 15(5): 262 - 267. [Abstract] [PDF]
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A. K. Cuss, D. T. Avery, J. L. Cannons, L. J. Yu, K. E. Nichols, P. J. Shaw, and S. G. Tangye Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity J. Immunol., February 1, 2006; 176(3): 1506 - 1516. [Abstract] [Full Text] [PDF]
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B K Han, A M White, K H Dao, D R Karp, E K Wakeland, and L S Davis Increased prevalence of activated CD70+CD4+ T cells in the periphery of patients with systemic lupus erythematosus Lupus, August 1, 2005; 14(8): 598 - 606. [Abstract] [PDF]
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K. Maeda, Y. Baba, Y. Nagai, K. Miyazaki, A. Malykhin, K. Nakamura, P. W. Kincade, N. Sakaguchi, and K. M. Coggeshall IL-6 blocks a discrete early step in lymphopoiesis Blood, August 1, 2005; 106(3): 879 - 885. [Abstract] [Full Text] [PDF]
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 S. Cepok, B. Rosche, V. Grummel, F. Vogel, D. Zhou, J. Sayn, N. Sommer, H.-P. Hartung, and B. Hemmer Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis Brain, July 1, 2005; 128(7): 1667 - 1676. [Abstract] [Full Text] [PDF]
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A. J. Gross, D. Hochberg, W. M. Rand, and D. A. Thorley-Lawson EBV and Systemic Lupus Erythematosus: A New Perspective J. Immunol., June 1, 2005; 174(11): 6599 - 6607. [Abstract] [Full Text] [PDF]
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J. William, C. Euler, E. Leadbetter, A. Marshak-Rothstein, and M. J. Shlomchik Visualizing the Onset and Evolution of an Autoantibody Response in Systemic Autoimmunity J. Immunol., June 1, 2005; 174(11): 6872 - 6878. [Abstract] [Full Text] [PDF]
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J. William, C. Euler, and M. J. Shlomchik Short-Lived Plasmablasts Dominate the Early Spontaneous Rheumatoid Factor Response: Differentiation Pathways, Hypermutating Cell Types, and Affinity Maturation Outside the Germinal Center J. Immunol., June 1, 2005; 174(11): 6879 - 6887. [Abstract] [Full Text] [PDF]
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G. P. Sims, R. Ettinger, Y. Shirota, C. H. Yarboro, G. G. Illei, and P. E. Lipsky Identification and characterization of circulating human transitional B cells Blood, June 1, 2005; 105(11): 4390 - 4398. [Abstract] [Full Text] [PDF]
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D. T. Avery, J. I. Ellyard, F. Mackay, L. M. Corcoran, P. D. Hodgkin, and S. G. Tangye Increased Expression of CD27 on Activated Human Memory B Cells Correlates with Their Commitment to the Plasma Cell Lineage J. Immunol., April 1, 2005; 174(7): 4034 - 4042. [Abstract] [Full Text] [PDF]
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 S. Yurasov, H. Wardemann, J. Hammersen, M. Tsuiji, E. Meffre, V. Pascual, and M. C. Nussenzweig Defective B cell tolerance checkpoints in systemic lupus erythematosus J. Exp. Med., March 7, 2005; 201(5): 703 - 711. [Abstract] [Full Text] [PDF]
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M. Odendahl, H. Mei, B. F. Hoyer, A. M. Jacobi, A. Hansen, G. Muehlinghaus, C. Berek, F. Hiepe, R. Manz, A. Radbruch, et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response Blood, February 15, 2005; 105(4): 1614 - 1621. [Abstract] [Full Text] [PDF]
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 N. L. Monson, P. D. Cravens, E. M. Frohman, K. Hawker, and M. K. Racke Effect of Rituximab on the Peripheral Blood and Cerebrospinal Fluid B Cells in Patients With Primary Progressive Multiple Sclerosis Arch Neurol, February 1, 2005; 62(2): 258 - 264. [Abstract] [Full Text] [PDF]
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W Klapper, F Moosig, A Sotnikova, W Qian, J O Schroder, and R Parwaresch Telomerase activity in B and T lymphocytes of patients with systemic lupus erythematosus Ann Rheum Dis, December 1, 2004; 63(12): 1681 - 1683. [Abstract] [Full Text] [PDF]
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M. C. Jaimes, O. L. Rojas, E. J. Kunkel, N. H. Lazarus, D. Soler, E. C. Butcher, D. Bass, J. Angel, M. A. Franco, and H. B. Greenberg Maturation and Trafficking Markers on Rotavirus-Specific B Cells during Acute Infection and Convalescence in Children J. Virol., October 15, 2004; 78(20): 10967 - 10976. [Abstract] [Full Text] [PDF]
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Z.-X. Lian, K. Kikuchi, G.-X. Yang, A. A. Ansari, S. Ikehara, and M. E. Gershwin Expansion of Bone Marrow IFN-{alpha}-Producing Dendritic Cells in New Zealand Black (NZB) Mice: High Level Expression of TLR9 and Secretion of IFN-{alpha} in NZB Bone Marrow J. Immunol., October 15, 2004; 173(8): 5283 - 5289. [Abstract] [Full Text] [PDF]
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M. Ramanujam, X. Wang, W. Huang, L. Schiffer, C. Grimaldi, A. Akkerman, B. Diamond, M. P. Madaio, and A. Davidson Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus J. Immunol., September 1, 2004; 173(5): 3524 - 3534. [Abstract] [Full Text] [PDF]
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 C. R. Morris, M. Poljakovic, L. Lavrisha, L. Machado, F. A. Kuypers, and S. M. Morris Jr. Decreased Arginine Bioavailability and Increased Serum Arginase Activity in Asthma Am. J. Respir. Crit. Care Med., July 15, 2004; 170(2): 148 - 153. [Abstract] [Full Text] [PDF]
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 S. Arce, E. Luger, G. Muehlinghaus, G. Cassese, A. Hauser, A. Horst, K. Lehnert, M. Odendahl, D. Honemann, K.-D. Heller, et al. CD38 low IgG-secreting cells are precursors of various CD38 high-expressing plasma cell populations J. Leukoc. Biol., June 1, 2004; 75(6): 1022 - 1028. [Abstract] [Full Text] [PDF]
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J. I. Ellyard, D. T. Avery, T. G. Phan, N. J. Hare, P. D. Hodgkin, and S. G. Tangye Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow Blood, May 15, 2004; 103(10): 3805 - 3812. [Abstract] [Full Text] [PDF]
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T Dorner and P E Lipsky Correlation of circulating CD27high plasma cells and disease activity in systemic lupus erythematosus Lupus, May 1, 2004; 13(5): 283 - 289. [Abstract] [PDF]
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R J Looney, J Anolik, and I Sanz B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells Lupus, May 1, 2004; 13(5): 381 - 390. [Abstract] [PDF]
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P I Sidiropoulos and D T Boumpas Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients Lupus, May 1, 2004; 13(5): 391 - 397. [Abstract] [PDF]
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A. J. Cappione, A. E. Pugh-Bernard, J. H. Anolik, and I. Sanz Lupus IgG VH4.34 Antibodies Bind to a 220-kDa Glycoform of CD45/B220 on the Surface of Human B Lymphocytes J. Immunol., April 1, 2004; 172(7): 4298 - 4307. [Abstract] [Full Text] [PDF]
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L. D. Erickson, L.-L. Lin, B. Duan, L. Morel, and R. J. Noelle A genetic lesion that arrests plasma cell homing to the bone marrow PNAS, October 28, 2003; 100(22): 12905 - 12910. [Abstract] [Full Text] [PDF]
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R Weide, J Heymanns, A Pandorf, and H Koppler Successful long-term treatment of systemic lupus erythematosus with rituximab maintenance therapy Lupus, October 1, 2003; 12(10): 779 - 782. [Abstract] [PDF]
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M Odendahl, R Keitzer, U Wahn, F Hiepe, A Radbruch, T Dorner, and R Bunikowski Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus Ann Rheum Dis, September 1, 2003; 62(9): 851 - 858. [Abstract] [Full Text] [PDF]
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 N. L. Bernasconi, E. Traggiai, and A. Lanzavecchia Maintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells Science, December 13, 2002; 298(5601): 2199 - 2202. [Abstract] [Full Text] [PDF]
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M R Ehrenstein and B Hahn T cell--B cell interactions Lupus, December 1, 2002; 11(12): 790 - 792. [Abstract] [PDF]
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K N Potter, C I Mockridge, A Rahman, S Buchan, T Hamblin, B Davidson, D A Isenberg, and F K Stevenson Disturbances in peripheral blood B cell subpopulations in autoimmune patients Lupus, December 1, 2002; 11(12): 872 - 877. [Abstract] [PDF]
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S. Ruzickova, A. Pruss, M. Odendahl, K. Wolbart, G.-R. Burmester, J. Scholze, T. Dorner, and A. Hansen Chronic lymphocytic leukemia preceded by cold agglutinin disease: intraclonal immunoglobulin light-chain diversity in VH4-34 expressing single leukemic B cells Blood, October 16, 2002; 100(9): 3419 - 3422. [Abstract] [Full Text] [PDF]
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P. P. L. Chiu, A. M. Jevnikar, and J. S. Danska Genetic Control of T and B Lymphocyte Activation in Nonobese Diabetic Mice J. Immunol., December 15, 2001; 167(12): 7169 - 7179. [Abstract] [Full Text] [PDF]
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P. Blanco, A. K. Palucka, M. Gill, V. Pascual, and J. Banchereau Induction of Dendritic Cell Differentiation by IFN-alpha in Systemic Lupus Erythematosus Science, November 16, 2001; 294(5546): 1540 - 1543. [Abstract] [Full Text] [PDF]
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E. Arce, D. G. Jackson, M. A. Gill, L. B. Bennett, J. Banchereau, and V. Pascual Increased Frequency of Pre-germinal Center B Cells and Plasma Cell Precursors in the Blood of Children with Systemic Lupus Erythematosus J. Immunol., August 15, 2001; 167(4): 2361 - 2369. [Abstract] [Full Text] [PDF]
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S. Moir, A. Malaspina, K. M. Ogwaro, E. T. Donoghue, C. W. Hallahan, L. A. Ehler, S. Liu, J. Adelsberger, R. Lapointe, P. Hwu, et al. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals PNAS, August 10, 2001; (2001) 181347898. [Abstract] [Full Text] [PDF]
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S. Moir, A. Malaspina, K. M. Ogwaro, E. T. Donoghue, C. W. Hallahan, L. A. Ehler, S. Liu, J. Adelsberger, R. Lapointe, P. Hwu, et al. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals PNAS, August 28, 2001; 98(18): 10362 - 10367. [Abstract] [Full Text] [PDF]
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