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The Journal of Immunology, 2006, 176: 3311-3314.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Hormonal Milieu, Not Antigenic Specificity, Determines the Mature Phenotype of Autoreactive B Cells1

Jeganathan Venkatesh*,{dagger}, Elena Peeva{ddagger}, Xiaonan Xu{ddagger} and Betty Diamond2,*,{dagger}

Department of * Medicine and {dagger} Department of Microbiology, Columbia University, New York, NY 10032; and {ddagger} Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY 10461


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Although both marginal zone and follicular B cells produce anti-DNA Abs in murine models of systemic lupus erythematosus, it has been unclear whether these distinct B cell subsets make identical or different Abs. Single-cell analysis demonstrates that the same DNA-reactive B cells can mature to either subset, depending on the hormonal environment. Anti-DNA B cells in estradiol-treated mice become marginal zone cells while identical cells from prolactin-treated mice become follicular cells. The B cell receptor signaling pathway is influenced by hormonal milieu. Thus, hormonal milieu and perhaps B cell receptor signaling, but not antigenic specificity, correlates with the differentiation pathway. These observations have implications for the pathogenesis and treatment of autoimmune disease.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
There are three B cell subsets: B1, marginal zone (MZ),3 and follicular. B1 cells are produced during fetal development by the fetal liver and, thereafter, are self-renewing. They express a restricted repertoire of BCRs (1, 2, 3). MZ B cells develop in the bone marrow and also display restricted antigenic specificities (4). Like B1 cells, they target repetitive epitopes on bacterial polysaccharide (5). These B cell subsets participate in T cell-independent Ab responses and function as part of the innate immune response, recognizing a narrow spectrum of Ags. Follicular B cells, like MZ B cells, arise in the bone marrow. In contrast to B1 and MZ cells, they recognize protein Ags and participate in T cell-dependent responses, characterized by germinal center formation, somatic hypermutation, and class switch recombination (5, 6). The expanded diversity of BCRs present on follicular B cells ensures that the host will be competent to mount an adaptive Ab response to a vast spectrum of pathogens or toxins.

Studies of murine systemic lupus erythematosus have demonstrated that all B cell lineages can contribute to an anti-DNA Ab response (7, 8). What determines whether an anti-DNA B cell will mature as a B1, MZ, or follicular cell and whether the same autoreactive B cell can mature to more than one B cell subset is not known. BALB/c mice transgenic for the H chain of an anti-DNA Ab (R4A-{gamma}2b) maintain B cell tolerance (9). Transgene-expressing B cells mature normally despite the fact that the H chain is IgG and autoreactive transgene-expressing B cells undergo negative selection. Under hormonal influence, the autoreactive B cells mature to immunocompetence and secrete pathogenic anti-DNA Abs (10, 11). DNA-reactive B cells maturing under estrogenic stimulation become MZ cells (12). DNA-reactive B cells maturing in the context of increased prolactin develop as follicular cells; their survival is T cell-dependent and appears to depend on up-regulation of CD40 and CD40 ligand expression (11). This model provided the opportunity to determine whether the same B cells could acquire either a MZ or follicular phenotype and to investigate factors governing that cell fate decision.

We now demonstrate that identical B cells can become either MZ or follicular cells and that hormonal milieu may be an important determinant of mature B cell differentiation. This observation has implications for the heterogeneous presentation of patients with lupus.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice

Female BALB/c mice (8–14 wk old) from The Jackson Laboratory and 8–12 wk old female R4A-{gamma}2b BALB/c mice bred in a specific pathogen-free barrier facility at the Albert Einstein College of Medicine and Columbia University were used. Mice were ovariectomized before hormonal treatment.

Hormonal treatment

Mice were implanted s.c. with 60-day time release pellets containing placebo, 17beta-estradiol (0.18 mg), or prolactin (6 mg) (Innovative Research of America).

Cell surface staining and flow cytometry

Spleen cells were isolated from R4A-{gamma}2b BALB/c mice as well as from BALB/c mice treated with estradiol, prolactin, or placebo. RBC were lysed and splenocytes were stained with the following Abs for subset analysis: CD19 (clone 1D3), CD21 (clone 7G6), CD23 (clone B3B4), AA4.1, and IgG2b (clone R12-3) (for R4A-{gamma}2b BALB/c mice only) and analyzed by flow cytometry (BD Biosciences). For single-cell sorting, cells were stained for expression of CD19, heat-stable Ag (HSA; CD24), CD21, and CD23. All Abs used in this study were obtained from BD Pharmingen except for AA4.1 (eBioscience).

Sorting of single cells

Cells were sorted using the MoFlo cell sorter (DakoCytomation). {gamma}2b+ MZ and follicular B cells were isolated for single-cell PCR as described by Yamagami et al. (13) by directly sorting into 96-well plates (Fisher Scientific) containing 3 µl of PCR buffer (Roche Applied Science) and 7 µl of distilled water. DNA was prepared by the addition of 2 µl of proteinase K (5 mg/ml; Boehringer Mannheim) followed by incubation of cells for 1 h at 55°C and for 10 min at 90°C to inactivate the proteinase K. The plates were stored at –70°C until use for DNA amplification.

Single-cell PCR analysis of {kappa} gene rearrangement

DNA amplification from single cells was conducted by two rounds of PCR using a GeneAmp PCR system 9700 PCR machine (Applied Biosystems). V{kappa} primers described by Yamagami et al. (13) were used. The first-round PCR contained all of the 5' and 3' primers listed above in a 30-µl reaction volume. PCR amplification conditions were as previously described by Ehlich et al. (14). The PCR products were identified as follows: V{kappa}J{kappa}1, 650 bp; V{kappa}J{kappa}2, 280 bp; V{kappa}J{kappa}4, 600 bp; and V{kappa}J{kappa}5, 260 bp. An initial analysis of the expressed light chains of B cells in the spleen of an unimmunized mouse showed that the primer set detected multiple V{kappa} genes, confirming that these primers were capable of hybridizing to many, if not all, V{kappa} sequences.

Cloning and sequencing of PCR products

PCR products were either cloned into the TOPO TA cloning vector (Invitrogen Life Technologies) or directly purified from the agarose gels and sequenced. Nucleotide sequences were determined by Genewiz. Analysis of the DNA sequences was conducted using the BLAST program (<www.ncbi.nlm.nih.gov/blast/>).

Real-time PCR

B cells were isolated from splenocytes by depletion using biotin-labeled anti-CD43 (cloneS7; BD Pharmingen), anti-CD11c (clone HL3; BD Pharmingen), anti-CD90 (clone CT-TH1; Caltag Laboratories), and streptavidin-labeled Dynabeads (Dynal). Splenocyte and B cell RNA was isolated using the RNeasy kit from Qiagen and cDNA was synthesized using the iScript cDNA synthesis kit (Bio-Rad). Real-time PCR was performed by using a MyiQ single-color Real-Time PCR detection system (Bio-Rad). The reactions were performed by using TaqMan universal PCR master mix and TaqMan primers (Applied Biosystems) in a 15-µl final volume. The relative expression of B cell-activating factor (BAFF), BAFF-R, and transmembrane activator and calcium modulator ligand interactor (TACI) was determined in comparison to Polr2a, and data were analyzed using the Pfaffl method (15). ABI primer identifications for BAFF, BAFF-R, TACI, and Polr2a were Mm00446347_m1, Mm00840578_m1, Mm00840192_m1, and Mm00839493_m1, respectively.

Calcium influx

Splenocytes from BALB/c mice treated with estradiol, prolactin, or placebo pellets (five mice in each group) were loaded with Indo-1 AM ester (5 µg/ml; Molecular Probes) for 1 h at 37°C. The cells were then stained for CD19, CD21, CD23, and AA4.1. Calcium influx was measured by the MoFlo cell sorter following stimulation with anti-IgM Ab (20 µg/ml; Southern Biotechnology Associates) using the following lasers: UV, blue (488 nm), green (543 nm), and red (633–635 nm). Similarly, phospho-ERK1/2 expression was determined by flow cytometry using an LSR II (BD Biosciences) and Abs to B220, CD24, and phospho-ERK1/2 from BD PharMingen. Analysis was performed using FlowJo software (Tree Star).

Statistical analysis

Data were analyzed with standard statistical tests (mean value, SD, and two-tailed Student’s t test).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
MZ and follicular B cells can produce identical anti-DNA Abs

The R4A-{gamma}2b mice are transgenic for the IgG2b H chain of an anti-DNA Ab. Maturation of the transgene-expressing B cells is normal and allelic exclusion is maintained in naive B cells. In R4A-{gamma}2b mice, >90% of the B cells express endogenous H and L chains; the remaining 5–10% of B cells express a {gamma}2b H chain (9). In previous studies, we were unable to identify IgG2b-expressing B cells that were not expressing the transgene-encoded H chain (16, 17, 18, 19). The R4A H chain can pair with a large spectrum of endogenous L chains, resulting in B cells with a spectrum of reactivity to DNA. Certain L chains associate with the R4A H chain to form high-affinity anti-DNA Abs; other L chains encode low-affinity anti-DNA Abs (16, 17, 18). Low-affinity DNA-reactive B cells mature to immunocompetence, but high-affinity DNA-reactive B cells arising in the bone marrow are deleted.

When R4A-{gamma}2b mice are treated with exogenous estradiol to maintain a constant serum concentration of ~75 pg/ml, which is similar to estradiol levels present at the peak of the estrous cycle, or with exogenous prolactin which causes a doubling in serum concentration (50 ng/ml vs 20–35 ng/ml), high-affinity autoreactive B cells mature to immunocompetence and secrete anti-DNA Abs (10, 11). In estrogen-treated mice, MZ B cells produce the anti-DNA Ab, whereas in prolactin-treated mice follicular B cells are responsible for autoantibody production (11, 20). We, therefore, were able to ask whether the same DNA-reactive B cells are present in both mature subsets.

Hormonal treatment did not alter the total splenic B cell number (Table I). There was a decrease in T1 cells in both estradiol- and prolactin-treated mice (AA4.1+, CD21–, CD23–) but no overall decrease in mature B cells, although estradiol led to an anticipated expansion of MZ cells (Table I). As shown in Fig. 1, sorting for both MZ and follicular B cells (HSAlow, CD21high, CD23 and HSAlow, CD21int, CD23high, respectively) yielded populations with >95% purity (Fig. 1). The transgene-expressing MZ cells isolated from estradiol-treated mice expressed a fairly restricted spectrum of L chains (Table II). Only four L chains were detected among 36 sequences; all were known to encode DNA reactivity in association with the R4A H chain. Three V-J combinations encoded high-affinity DNA binding. The fourth L chain, V{kappa}1A-J{kappa}5, encoded a low-affinity, nonglomerular-binding anti-DNA Ab which is normally not subject to tolerance induction.


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  		Table I. B cell subsets in BALB/c mice treated with placebo, estradiol, and prolactina

 

Figure 1
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  		FIGURE 1. Purity of isolated B cell subsets. Splenic MZ and follicular B cells were identified (A) and MZ (B) and follicular (C) B cells were isolated based on CD19, HSA, CD21, and CD23 expression. The purity of the sorted populations was >95%.

 

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  		Table II. Ig Light chain gene usage in MZ B cells from estradiol-treated mice and in follicular B cells from prolactin-treated micea

 
A restricted spectrum of L chains was also present in the transgene-expressing follicular B cells of prolactin-treated mice, with only 4 V-J combinations detected among 37 sequences (Table II). More than 70% of the follicular B cells of prolactin-treated mice expressed one of the three sequences encoding high-affinity DNA binding found in the MZ population of estradiol-treated mice. The L chains from MZ and follicular cells had identical junctional sequences (data not shown). No low-affinity V{kappa}1A-J{kappa}5 L chains were found in the follicular population of prolactin-treated mice. A population with V{kappa}21E-J{kappa}5 L chains and unknown antigenic specificity was present.

Transitional B cells from estradiol- and prolactin-treated mice differ in BCR signaling

A number of recent studies have suggested that the strength of BCR signaling is key to determining the phenotype of the mature B cell (21, 22) with MZ B cells induced by weak BCR signaling and follicular B cells induced by stronger signaling. We, therefore, investigated whether hormonal treatment altered BCR signaling. As previously demonstrated (20), estradiol led to a diminished calcium flux in transitional B cells following incubation with anti-IgM Ab which was used as a surrogate Ag (Fig. 2A). Prolactin, however, did not alter BCR signaling (Fig. 2B). Thus, transitional B cells from estradiol-treated mice displayed a diminished calcium flux compared with transitional B cells of prolactin-treated mice (Fig. 2C). The decrease in calcium flux in estradiol-treated cells was evident in both the T1 and T2 subset (Fig. 2D). ERK1/2 phosphorylation following incubation with anti-IgM Ab was less in transitional cells of estradiol-treated mice than in prolactin-treated mice (Fig. 2E), while there was no difference in Syk phosphorylation (data not shown).


Figure 2
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  		FIGURE 2. Ca2+ flux in transitional B cells of mice treated with estradiol or prolactin. Calcium mobilization was measured in transitional (AA4.1high) B cells from estradiol-treated mice (A) and prolactin-treated mice (B) after stimulation with 20 µg/ml anti-IgM. A, A decreased calcium flux was present in B cells of estradiol-treated mice. B, Prolactin induced no change in calcium flux. C, Calcium flux in transitional B cells of estradiol-treated mice was lower than that in prolactin-treated mice. Each figure part shows calcium flux from B cells of one hormone and one placebo-treated mouse. D, Calcium flux was diminished in both the T1 and T2 subset by estradiol treatment. E, Phospho-ERK1/2 expression in transitional B cells of estradiol- and prolactin-treated BALB/c mice. A significant decrease in phospho-ERK1/2 expression was observed in estradiol-treated mice compared with both placebo- and prolactin-treated mice. F, Expression of BAFF is increased in splenocytes of both estradiol- and prolactin-treated BALB/c mice as determined by real-time PCR. Expression of BAFF-R (G) and TACI (H) is unchanged in splenic B cells of estradiol- and prolactin-treated BALB/c mice. Data in A–F are derived from four to five mice in each cohort.

 
Since increased BAFF expression can lead to the expansion of MZ B cells (23), we assayed BAFF expression in splenic cells. Both estradiol and prolactin led to a similar significant increase in BAFF mRNA (Fig. 2F). There was no hormone-induced change in BAFF-R or in TACI mRNA in splenic B cells (Fig. 2, G and H). The expansion of MZ B cells in estradiol-treated mice appeared, therefore, not to be a consequence of altered BAFF expression but rather to correlate with decreased BCR signaling.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
This study demonstrates that the same B cell can become a MZ B cell in an estrogenic environment and a follicular B cell in a prolactinemic environment. BCR signaling strength has been postulated to be one factor that helps determine mature B cell phenotype. Pillai and colleagues (21) have recently proposed that transitional B cells receiving a relatively weak BCR-mediated signal acquire a MZ phenotype while differentiation to a follicular phenotype requires a strong BCR-mediated signal. An alternative model of B cell maturation, proposed by Allman et al. (24), suggests that strong BCR signaling contributes to MZ B cell differentiation. Our study shows that B cells maturing in an estrogenic milieu have a reduced BCR-mediated calcium influx and ERK1/2 phosphorylation. This is consistent with a CD22-mediated reduction in BCR signal (25) that we have previously shown is up-regulated by estradiol (20). The decrease in ERK1/2 phosphorylation may contribute to the resistance to BCR-triggered apoptosis in estradiol-treated B cells as increased ERK phosphorylation correlates with increased B cell apoptosis (26). Interestingly, changes in CD22 expression do not appear to alter Syk phosphorylation (27) and we detect no estradiol-induced change in Syk phosphorylation (data not shown).

Studies of altered B cell subsets have not addressed the antigenic specificities of cells in different B cell compartments. Thus, it is not known whether, when the MZ population is expanded, there is an expansion of anti-polysaccharide B cells within the MZ or whether B cells specific for protein Ags can be made to mature into a T cell-independent subset. Conversely, when the MZ population is diminished, it is not clear whether polysaccharide-specific B cells reside in the follicular compartment. Although studies have shown that B cells with an identical antigenic specificity can mature as either B1 or B2 cells and that this cell fate decision is determined by the strength of the BCR signal (22), no study to date has addressed whether identical B cells can mature as either MZ or follicular cells.

Thien et al. (28) have studied follicular vs MZ B cell development in B cells specific for hen egg lysozyme (HEL). When BAFF is increased, B cells that would normally experience developmental arrest in the presence of HEL become immunocompetent follicular B cells while B cells with lower affinity for HEL become MZ B cells. Although this is consistent with weak BCR signaling leading to MZ development and strong BCR signaling leading to follicular development, the MZ and follicular B cells in this study differ in fine antigenic specificity and cross-reactivity.

We show for the first time that the identical cells mature as either MZ or follicular cells and that antigenic specificity, per se, does not determine the differentiation pathway. Rather, hormonal milieu determines cell fate and BCR signaling strength. DNA-reactive B cells from estradiol-treated mice display increased expression of Bc1–2; however, by itself, this will favor the generation of follicular B cells (29). Prolactin increases CD40 expression on B cells (11), which we believe mediates their rescue from negative selection; perhaps, it also helps recruit them to a T cell-dependent B cell compartment.

The human lupus population is likely to include individuals with MZ B cells and others with follicular B cells as the source of anti-DNA Ab. Perhaps the autoreactive B cell phenotype might distinguish those patients who develop long-term remissions from those with more recurrent disease. That in different individuals the same Abs may be made by B cells from different B cell subsets, depending on the hormonal milieu, and perhaps on BCR signaling strength, has implications for protective as well as pathogenic Abs.


   Acknowledgments
 
We thank Kristie Gordon for assistance with flow cytometry and Sylvia Jones for helping in the preparation of this manuscript.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by grants from the National Institutes of Health. Back

2 Address correspondence and reprint requests to Dr. Betty Diamond, Department of Medicine, Columbia University, Audobon III Building, 9th Floor, Room 916, New York, NY 10032. E-mail address: bd2137{at}columbia.edu Back

3 Abbreviations used in this paper: MZ, marginal zone; HSA, heat-stable Ag; BAFF, B cell-activating factor; TACI, transmembrane activator and calcium modulator ligand interactor; HEL, hen egg lysozyme. Back

Received for publication September 7, 2005. Accepted for publication January 10, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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