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Laboratoire d’Immunopathologie, Institut d’Hématologie et d’Immunologie, Strasbourg, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. In
the absence of human IgG, nAAb-transgenic B cells develop normally. By
crossing these mice with animals expressing knockin chimeric IgG with
the human Fc, we now show that the constitutive expression of
chimeric IgG promotes the increase of nAAb-expressing B cells. This
positive selection is critically dependent on the presence of IgD,
occurs in the spleen, and concerns all mature B cell subsets, with a
relative preferential enrichment of marginal zone B cells. These data
support the view that soluble self-Ags can result in positive clonal
selection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Generally speaking, the idea of positive selection of B cells has left many groups skeptical for a long time, not only because of a lack of direct proof, but also because the model was initially proposed by analogy with T cell development and, even though some level of Ag receptor engagement by interaction with self-Ag has an obvious role in the establishment of a functional T cell repertoire, the biological function of a similar phenomenon in B cell ontogeny remains mysterious.
At present, the concept of positive selection of B cells is based on the following findings. A functional B cell receptor (BCR) is required for the emigration of immature B cells from the bone marrow to the spleen, and only a small fraction of them enters the long-lived pool (15, 16). The survival of follicular (FO) B cells in the periphery is also dependent on the expression of the BCR (17). Syk-deficient mice have a developmental block at the immature to mature B cell transition in the periphery, suggesting that a survival signal delivered in a receptor-specific fashion is mandatory at this stage (18). However, it is not clear whether these data reflect the necessity of a certain level of constitutive signaling through the BCR, as recently suggested (19), or whether endogenous Ags mediate the selection of the "chosen few" (20). Although the initial findings that the VH gene repertoires expressed in bone marrow pre-B cells (21) or in fetal liver (22) are more limited than that found in mature B cells could be explained by negative selection, a recent report by Shlomchik, Janeway, and coworkers (23) demonstrated a significant skewing of the VL repertoires in H chain-only Tg mice occurring at the immature to mature B cell transition and hardly attributable to pure negative selection. Recent studies of mutants that directly or indirectly perturb BCR signaling capacity concur to support a strength of signal model, in which there is a range of BCR-mediated signals less intense than those responsible for negative selection or full activation and differentiation, but necessary for complete B cell maturation (24, 25 , and references cited therein). In this model, the strength of the signal may also determine in which subset the newly generated B cell will reside. Experiments showing that B cells expressing a transgenic H chain derived from a neonatal mouse are positively selected in the marginal zone (MZ) repertoire also support this model (26).
Therefore, there is mounting indirect evidence that self-Ags drive the
development of naive B cells, but Hardy’s (14) murine
model, dealing with a monoreactive autoantibody directed against a
membrane (mb)-bound Ag, is, to date, the only direct proof of such a
positive selection of B cells. However, as mentioned earlier, nAAbs are
mostly polyreactive, and mainly react with conserved soluble self-Ags
such as ssDNA, IgG, thyroglobulin, or cytokines (10, 11).
Precisely because of the polyreactivity profile of these nAAbs,
demonstrating the role of a given autoantigen by its elimination is
difficult, or even impossible. For this reason, we have generated Tg
mice that express a prototypical human nAAb that reacts with different
self-Ags, including ssDNA and human IgG (rheumatoid factor (RF)
activity), but not with murine IgG. We have previously shown that, in
the absence of constitutive expression of human IgG, these
nAAb-producing B cells develop normally on a nonautoimmune background,
without being anergic (27). Indeed, it was not possible,
in these mice, to determine the role, if any, of ssDNA in the
maturation of the Tg B cells. By crossing these animals with
genetically modified mice constitutively expressing another soluble
self-Ag (chimeric IgG1 with human -chain C regions), we now observe
a clear increase of the nAAb-producing B cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Transgenic mouse lines and conventional inbred C57BL/6 (The
Jackson Laboratory, Bar Harbor, ME) were housed under standard
conditions in the Institute’s animal facility. The RF transgenic mice
expressing H and L chain genes encoding the chimeric murine-human nAAb
bearing the G6 VH Id and the 17109 V
Id have
been previously described (27). Briefly, founder lines
were maintained by backcross mating with the C57BL/6 strain. H + L Tg
mice were obtained by crossing H chain Tg mice with the L chain Tg
mice. Double Tg mice (H + L) (nAAbµ or nAAbµ
) were
identified by PCR assay of tail DNA. These double Tg mice were bred to
human IgG1 knockin mice (cIgG; a gift from W. Mueller and K. Rajewsky,
Institute for Genetics, University of Cologne, Cologne, Germany)
to generate mice that carry both the chimeric RF and the human IgG1
transgenes (nAAbµ x cIgG and nAAbµ x cIgG
mice). Positive progeny of transgenic matings were identified by PCR
assay of tail DNA for the detection of the RF transgene and by ELISA
for the determination of humanized IgG1 (28).
Serum ELISA
Quantifications of IgMtot, IgMa, and IgMa/17109 were performed as described (27).
Flow cytometry analysis
Cells were prepared from bone marrow, spleen, and peritoneum, then stained as described (27). Cell phenotype was determined using the following reagents: anti-mouse B220 FITC, anti-mouse IgMa FITC, anti-mouse CD19 FITC, anti-mouse CD21 FITC, anti-mouse IgMa biotin, anti-mouse IgMb biotin, anti-mouse IgDa biotin, anti-mouse CD19 biotin, anti-mouse CD23 biotin, anti-mouse CD43 biotin, anti-mouse CD11b (Mac-1) biotin, anti-mouse CD86 (B7.2) biotin, anti-mouse CD44 PE, anti-mouse CD5 PE (all from BD PharMingen, San Diego, CA), 17109 biotin (provided by D. A. Carson, University of California, San Diego, CA), and G6 biotin (provided by R. Jefferis, University of Birmingham, Birmingham, U.K.).
Immunohistochemistry
Tissue samples were laid on a piece of cardboard in a drop of Tissue-Tek medium (Euromedex, Souffelweyersheim, France) and snap frozen in melting isopentane. Sections (8 µm thick) were cut in a cryostat and triple stained with fluorescein (dichlorotriazinyl amino fluorescein)-conjugated Affinipure F(ab')2 goat anti-human IgG (Jackson ImmunoResearch Laboratories, West Grove, PA), PE anti-mouse IgMa (PharMingen), and biotin 17109, followed by Cy-5 streptavidin (Amersham Pharmacia Biotech, Piscataway, NJ).
In vitro B cell activation and proliferation assays
Spleen cells were cultured, as described (27), in presence of one of the following reagents: LPS from Salmonella typhosa (Difco Laboratories, Detroit, MI), F(ab')2 goat anti-mouse IgM (Jackson ImmunoResearch), or monomeric human IgG (mhIgG). After 12 h of culture at 37°C, the phenotype of the cells was determined by two-color fluorescence analysis. For proliferation assays, splenocytes were labeled with CFSE (Molecular Probes, Eugene, OR), before the culture with LPS or anti-IgM or mhIgG. Suspensions of 107 cells/ml in 0.1% PBS/BSA were incubated with CFSE at a final concentration of 10 µM for 10 min at 37°C, then cells were washed and resuspended in the culture medium. After 4 days of culture, cells were analyzed by flow cytometry.
5-Bromo-2'deoxyuridine (BrdU) assay and cell cycle analysis
BrdU (Sigma-Aldrich, St. Louis, MO) was administered to mice in the drinking water at a concentration of 1 mg/ml for 1–4 days. The method used to detect BrdU in B cell DNA has been described in detail elsewhere (16). Briefly, spleen and bone marrow cells (1 x 106) were labeled with anti-mouse CD23 PE and anti-mouse IgMa biotin, then stained with streptavidin Cy-5 (Jackson ImmunoResearch). After washing with PBS, cells were resuspended in 0.5 ml ice-cold 0.15 M NaCl, then 1.2 ml ice-cold 95% ethanol was slowly added while gently vortex mixing the cells. Cells were incubated on ice for 30 min, then washed with PBS. One milliliter of PBS 1%, paraformaldehyde 0.01%, and Tween 20 was then added, and cells were incubated for 30 min at room temperature. Cells were pelleted by centrifugation (4000 rpm for 5 min, 4°C), then incubated for 10 min at room temperature with 1 ml 0.15 M saline that contained 4.2 mM MgCl2 (pH 5) and 50 Kunitz U/ml DNase I (Sigma-Aldrich). Samples were then washed with PBS, stained with anti-BrdU FITC (Caltag Laboratories, Burlingame, CA; 30 min, room temperature), washed with PBS, and analyzed by flow cytometry, as above. Gates for BrdU incorporation were set between two clearly separate populations, the negative population corresponding to that obtained in control mice not fed BrdU.
For cell cycle analysis, splenic cells were first stained with FITC- and Cy-5-labeled Abs directed against surface markers. Cells were then fixed with 70% ethanol. Propidium iodide (PI; 10 µg/ml) was added after a 30-min treatment with RNase.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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only and µ) that express a nAAb with V regions of human
origin (previously described in Ref. 27). The original Ab
is a human nAAb reacting with low affinity with ssDNA as well as with
soluble autoantigens, including thyroglobulin and human IgG (this nAAb
is a prototype of natural
G6+/17109+ RF
(12)). We previously showed that grafting mouse C regions
does not alter the nAAb reactivity toward the different Ags
(27). Soluble chimeric IgG (cIgG) induces an increase of autoreactive B cells in IgM/IgD, but not in IgM-only, Tg mice
By crossing double Tg mice nAAb µ and nAAb µ with
cIgG knockin mice expressing the human -chain C region
(28), we generated animals that carry both the chimeric
nAAb and the cIgG transgenes (µ x cIgG and µ x
cIgG mice). These animals were analyzed at 6–8 wk of age. They had
nAAb B cells and cIgG-producing B cells that secreted variable amounts
of cIgG in their serum (see below). In these animals, as judged by
triple immunofluorescence analysis with anti-IgMa, 17109, and
anti-human IgG, cIgG were produced by a small proportion of
IgManegative/17109negative
B cells, which were present in the spleens (close to 2%), excluding a
cis effect (not shown).
Fig. 1
shows clearly that, in µ
x cIgG and µ x cIgG mice, the vast majority of splenic
B220+ B cells coexpress the Tg H and L chains,
respectively, µa+ and
17109+. Similar results were obtained in the bone
marrow (data not shown). Thus, the transgene-encoded H and L chains
exclude endogenous gene rearrangements and support B cell development.
Staining with anti-IgMa (Tg) and
anti-IgMb reveals that almost all of the
IgM-expressing B cells in Tg mice use the transgene-encoded H chain.
Only 3.5% of the splenocytes and 2% of the bone marrow cells express
endogenous IgMb H chains in µ x cIgG
mice compared with 3% (spleen) and 1.5% (bone marrow) in
µ x cIgG mice (Table I).
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and Fig. 2, the percentages and absolute numbers
of nAAb B cells are significantly increased in µ x cIgG
mice (58%, 35.106 in spleen; 36% in bone
marrow) compared with µ x cIgG mice (35%,
17.106 in spleen; 27% in bone marrow), and
compared with control nAAb Tg animals µ (34%,
8.106 in spleen; 20% in bone marrow) and µ
(30%, 10.106 in spleen; 24% in bone marrow).
Both the absolute numbers and the proportions of mature splenic B cells
(CD23+) are increased; they are also more
abundant in the bone marrow, where they probably represent
recirculating B cells from the periphery. We also observe an increase
of nAAb Tg B cells in the peritoneal cavity of µ-cIgG mice, but
this increase is not associated with a significant rise of
CD5+ or CD11b/Mac-1+ cells.
Thus, the analysis of the four Tg lines strongly supports the notion of
a positive selection of the nAAb B cells, which requires both the
introduction of the new soluble self-Ag and the presence of the mb
IgD.
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To make sure that the specificity of the Tg BCR for its ligand
(cIgG) is indeed involved in the observed phenomenon and mediates the
selection signal, we analyzed µ H chain-only Tg mice crossed with
cIgG mice (µ x cIgG), a condition that allows natural
pairing of the transgenic H chains with endogenous L chains. The
results, indicated in Table I and Fig. 2, show a lack of increase of
IgMa+ B cells, despite the presence of both the
cIgG and the -chain in these mice. This comparison, added to the
µ x cIgG analysis, also argues against the possible
influence of the genetic background of the cIgG knockin animals on the
observed results.
As indicated in Table I, the levels of cIgG present in the serum of the
cIgG Tg mice are quite variable, ranging from as few as 5 to 200
µg/ml (compared with 20–150 µg/ml in cIgG non-Tg mice), with the
highest mean concentration in µ animals. However, within the
observed range of cIgG, there is no statistical correlation between the
level of soluble self-Ag and the nAAb B cell increase.
Is the nAAb B cell development driven into a particular B cell subset?
Considering the possible influence of the BCR specificity on the
generation of the different peripheral B cell subsets, we analyzed the
phenotypic characteristics of the selected nAAb splenic B cells and
compared them with nonselected B cells originating from nAAb Tg mice
without cIgG, and from non-Tg control littermates.
IgMa+-gated cells (or
IgMb+-gated cells in control animals) were
stained with anti-CD23 and anti- CD21 reagents (Fig. 3). It is clear that all the B cell
subsets (6) are enlarged in µ x cIgG
compared with µ mice: the absolute numbers of
CD23highCD21positive
(mature recirculating/B-2 cells) are increased, as well as the numbers
of
CD23negativeCD21low/negative
(immature or transitional T1 B cells),
CD23negativeCD21high (MZ B
cells), and
CD23positiveCD21high
(transitional T2 B cells). However, it is interesting to note that the
most important increase concerns the MZ B cells (11% vs 0.5%).
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In the spleen, transitional cells represent recent immigrants from
the bone marrow (Hardy’s fraction E). In normal mice, they are
short-lived with a life span of 3–4 days. Subsequently, they are
either incorporated in the mature long-lived compartment or eliminated
(16, 29, 30). To investigate the significance of the
increased cell numbers in the spleen of µ x cIgG mice, we
used the BrdU-labeling technique. Mice were analyzed 1, 2, 3, and 4
days after the beginning of BrdU administration. In the bone marrow,
the labeling rates of CD23negative Tg cells are
lower than in control non-Tg animals, but comparable between
µ x cIgG and µ animals, confirming that the
presence of cIgG does not significantly influence the early steps of B
cell development (Fig. 4a). In
the spleens, the fraction of CD23negative
Tg-labeled cells reaches a maximum of 25 ± 5% and of 10 ±
1.5% in µ x cIgG and µ mice, respectively, after
4 days of continuous treatment (Fig. 4b). The percentages of
CD23negative-labeled cells remain constant
thereafter (not shown), suggesting that they have comparable life spans
in both types of Tg animals. Splenic B cells that are labeled after
such a short BrdU pulse represent the balance of: 1) newly generated B
cells that have just migrated from the bone marrow; 2) cycling splenic
B cells that have incorporated BrdU in the spleen; and 3) labeled cells
that died during the BrdU treatment (6). Because immature
B cell numbers and labeling rates are comparable in the bone
marrow, the increase of labeled cells in the spleens of µ
x cIgG can be attributed either to a better recruitment of labeled
transgenic B cells just after leaving the bone marrow, or to an
increased splenic B cell proliferation, or to a reduction in the
proportion of labeled cells that died during the BrdU
incorporation time.
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). The results show that the great
majority of mature and T1 cells are in the
G0-G1 phase of the cell
cycle, whereas 20–25% of the T2 cells from µ mice and
30–35% of the T2 cells from µ x cIgG animals are in the
G2-M phase, confirming that T2 B cells are a
population of cycling cells (6). These results are similar
when identifying B cell subsets with
anti-IgMa and anti-CD21 Abs (not shown).
The slight increase in the fraction of T2 (CD23+)
cells in G2-M cannot account by itself for the
augmentation of the BrdU-labeled cells (that are mostly
CD23-) as well as for the increases of the T1
and mature B cells in µ x cIgG mice. Thus, we are left
with a complex picture suggesting that self-IgG: 1) increase the
recruitment rate into the T1 compartment of immature Tg B cells that
have left the bone marrow; 2) increase the recruitment rate of the T1
cells into the T2 pool, where the cells have a slight proliferating
advantage; and 3) increase the recruitment of T2 cells into the
long-lived compartment of mature cells.
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Different data argue against spontaneous activation of
nAAb-expressing B cells in µ x cIgG mice. First, the Tg
IgMa+/17109+ Abs are poorly
secreted in these animals: despite the overrepresentation of nAAb B
cells, their contribution to the total secreted IgM is weak (5–10% of
the total secreted IgM), and quite similar in presence or in absence of
cIgG. Second, as determined by immunohistology (not shown), nAAb B
cells are strictly localized in the B cell zones and are never detected
within the germinal centers of secondary follicles or within the T cell
zones, which could have indicated Ag-driven activation. And third, the
Tg nAAb B cells are not phenotypically in vivo activated, as judged by
unchanged basal expression of CD86, CD44, CD80, and CD69 on
CD23- and CD23+ Tg B cells
(data not shown).
We have previously shown that nAAb Tg B cells originating from mice
lacking the cIgG self-Ag were ignorant to human IgG stimulation in
vitro, but were activatable by both anti-IgM and LPS
(27). The introduction of the new self-Ag in these mice
does not modify the reactivity profile of the nAAb B cells when
stimulating by LPS, anti-IgM, monomeric, and aggregated human IgG
both in terms of the levels of expression of activation markers CD86,
CD44, and MHC class II (Fig. 6a), and in terms of
proliferation (CFSE labeling) (Fig. 6b). In addition, LPS
stimulation at 72 h results in secretion of Tg-IgM from
µ x cIgG mice (913 ± 110 ng/ml, vs 107 ± 21
ng/ml before stimulation). Thus, these data indicate that BCR-dependent
and BCR-independent pathways of B cell activation are functional in the
positively selected B cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To our surprise, soluble self-Ag induced positive selection of all mature nAAb B cell compartments. Our nAAb being a prototype of Abs usually produced by CD5+ B-1 cells, the results emphasize our current ignorance of all the molecular actors in B subpopulation commitment. Although transgenic animals with BCRs characteristic of CD5+ B-1 cells were shown to mainly develop into this cell subset (35, 36), our results indicate that this is not always true. Other parameters seem to influence the B cell decision, the most influential probably being the signal strength. Using Ig Tg mice, Lam and Rajewsky (35) demonstrated that when surface expression of a B1-canonical receptor is reduced through the expression of a second H chain, B cell development proceeds toward the B2 compartment. This suggests that, within the range of signals compatible with B cell positive selection, the strongest ones would lead to differentiation to the B-1 compartment. Also, Pillai and colleagues (25) recently showed that Btk is epistatic to Aiolos; in the absence of Aiolos, BCR signaling is enhanced and B cells accumulate as mature FO cells, whereas MZ B cells are absent. Conversely, in CD21/Cr2 null mice, there is a decrease in the absolute numbers of FO B cells, but a significant increase of MZ B cells (25). Together, these data support the idea that the intensity of the signal might determine the mature B cell subset in which the transitional cell will differentiate.
Another surprise comes from the contribution of mb IgD in the selection
process. According to Watanabe et al. (37) and Kouskoff et
al. (38), a possible explanation could be a lower density
of the BCR on the surface of Tg B cells from µ x cIgG due to
the lack of IgD. However, both types of Tg mice express similar amounts
of BCR, based on anti--chain staining and on the identity of the
titration curves for binding of IgG (27). We previously
observed that nAAb Tg mice expressing mb IgD and IgM have in proportion
an increased mature B cell pool compared with Tg mice expressing only
mb IgM (27). Similar findings were reported by others,
supporting a role for mb IgD in B cell maturation (39).
The reasons remain unclear because mb IgD and IgM apparently signal
equally (40, 41, 42). However, this result suggests that B
cells undergo positive selection mainly at a stage when they express mb
IgD. In fact, our data show that self-Ag positively regulates B cell
development at different steps between immature and mature stages. The
effect on T1 cells, which classically do not yet express mb IgD, is
probably responsible for the slight positive selection observed in
µ x cIgG mice.
Finally, our results raise two questions of importance: are all mature B cells naturally self-reactive and naturally selected on this basis? And what could be the significance of B cell positive selection? Clearly, natural autoreactive B cells are most probably selected by low affinity interactions with soluble or mb-bound autoantigens. Recently, it was suggested, on the basis of preliminary experiments, that all B cells are submitted to such a selection via BCR V region cross-recognition (43). Our results show that other conserved self-Ags are also able to select B cells. In contrast, the reduced numbers of mature B cells in germfree animals also suggest a role for xenoantigens in B cell ontogeny (6).
This leads to the last issue, namely the intriguing biological
significance of B cell positive selection. Several lines of evidence,
including recent data on 
NKT and on T cell specificities
(44), suggest that, from a phylogenetic point of view, the
immune system has evolved to components that are less and less
dependent on self recognition for their development and functions. In
this view, B cell positive selection might be a mere trace of the
evolution of adaptive immunity. In contrast, natural Abs, after having
been regarded as byproducts of B cell development, are now thought to
play an important role in the early defense against bacteria and
viruses (45, 46, 47). Positive selection of natural Abs could
confer a biological advantage because the selecting Ags may give them
the potential to cross-react with generic molecular patterns such as
surface carbohydrates or nucleic acids of pathogens. In that case,
positive selection of FO B cells would logically confer an analogous
advantage. In addition to antigenic specificity, B cell positive
selection also seems to determine in which subset the BCR-selected
clones reside. This may be important to direct B cells with given
specificities in strategically located sites (47).
Although in our model differentiation into the MZ pool is only partial,
it is interesting to note that a proposed role for natural RF B cells
may be to function as universal APC for Ags trapped as immune complexes
(48). This could be particularly useful and efficient to
initiate secondary immune responses when the concentration of Ag is
low. Because MZ B cells can develop more potent APC properties than
naive FO B cells (49), preferential differentiation of
natural RF B cells into the MZ pool may indeed confer a biological
advantage.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jean-Louis Pasquali, Laboratoire d’Immunopathologie, Institut d’Hématologie et d’Immunologie, 1 place de l’hôpital, 67091 Strasbourg Cedex, France. E-mail address: Jean-Louis.Pasquali{at}hemato-ulp.u-strasbg.fr
3 Abbreviations used in this paper: Tg, transgenic; BCR, B cell receptor; BrdU, 5-bromo-2'deoxyuridine; cIgG, chimeric IgG; FO, follicular; mb, membrane; mhIgG, monomeric human IgG; MZ, marginal zone; nAAb, natural autoantibody; PI, propidium iodide; RF, rheumatoid factor.
Received for publication May 17, 2002. Accepted for publication August 9, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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membrane heavy chains of Ig. Int. Immunol. 6:1905.This article has been cited by other articles:
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J. E. Wither, C. Loh, G. Lajoie, S. Heinrichs, Y.-C. Cai, G. Bonventi, and R. MacLeod Colocalization of Expansion of the Splenic Marginal Zone Population with Abnormal B Cell Activation and Autoantibody Production in B6 Mice with an Introgressed New Zealand Black Chromosome 13 Interval J. Immunol., October 1, 2005; 175(7): 4309 - 4319. [Abstract] [Full Text] [PDF]
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