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Stem Cells 2002;20:293-300 www.StemCells.com
© 2002 AlphaMed Press

Age-Related Alterations in the Lymphohematopoietic and B-Lineage Precursor Populations in NZB Mice

Zhe-Xiong Liana, Tomoyuki Okadaa,b, Hiroto Kitaa, Tom Hsua, Leonard D. Shultzc, Kenneth Dorshkindd, Aftab A. Ansarie, Mitsuru Naikib, Susumu Ikeharaf, M. Eric Gershwina

a Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA;
b Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co., Ltd., Kinashi, Hyogo, Japan;
c The Jackson Laboratory, Bar Harbor, Maine, USA;
d Department of Pathology and Laboratory Medicine and Josson Comprehensive Cancer Center, School of Medicine, University of California, Los Angeles, California, USA;
e Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
f First Department of Pathology, Transplantation Center, Kansai Medical University, Moriguchi, Osaka, Japan

Key Words. Autoimmunity • B lymphocytes • IL-7R • Pro-B cells • Aging B cells • NZB mice

Correspondence: M. Eric Gershwin, M.D., Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, TB 192, One Shields Avenue, Davis, California 95616, USA. Telephone: 530-752-2884; Fax: 530-752-4669; e-mail: megershwin{at}ucdavis.edu


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Significant disturbances in B lineage populations of New Zealand Black (NZB) mice have been reported, both with respect to their phenotypes as well as to their function. Notably, there is a profound age-dependent decrease in B-cell precursors in this strain of lupus prone mice. In efforts to characterize the impact of this disturbance in disease, we performed an intensive phenotypic and B-cell population analysis in young and old NZB mice. Our results revealed that there was a significant age-dependent decrease in B cell precursors at all levels of the B-cell-lineage developmental pathway. Analysis of the proliferative capacity of these cell populations showed a comparative decrease in cycling activity in the B-cell-lineage populations of old NZB mice. Furthermore, these cell subsets were much more susceptible to spontaneous apoptosis when compared with similar populations from age-matched BALB/c or young NZB mice. Since the frequency of cells that express the interleukin-7 receptor (IL-7R) declines as NZB mice age, we hypothesize that impairment of IL-7R signal transduction pathways could contribute to severe perturbations of B-cell function in aged NZB mice.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
New Zealand Black (NZB) mice are one of the most intensely studied animal models of autoimmunity [1, 2]. Multiple defects in primary lymphocyte development have been described, including those in the B-cell lineage [3–7]. In an effort to further define the precursor stage of B-cell development at which the defects reside in NZB mice, Merchant et al. [5] fractionated enriched populations of developmental stage-specific pro- and pre-B cells [8]. Analysis of these cells from NZB mice showed that there were marked, age-associated reductions in both of these subsets. In view of these results, we reasoned that additional studies of more primitive precursors of B-cell-lineage populations were warranted. Using comprehensive phenotypic and functional assays, we analyzed primitive precursor B cells and demonstrated that the bone marrow (BM) of NZB mice contained deficiencies in B-cell subpopulations at the earliest stages of development. We also noted that the decrease in B-lineage cells is accompanied by an accelerated accumulation of hematopoietic stem cells (HSCs) (Lin-, c-kit+, Sca-1+). Our results further characterize the potential stages and mechanisms of the age-associated B-cell developmental defects in NZB mice.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice and Cell Preparation
Female NZB/BlnJ and BALB/cJ mice, aged 1 month or 6-8 months, were obtained from the Jackson Laboratory (Bar Harbor, ME; http://www.jax.org) and subsequently maintained by the Animal Resource Service of the University of California at Davis. Bone marrow cells (BMCs) were obtained by flushing femurs and tibiae of several mice per group with phosphate-buffered solution (PBS) containing 0.2% bovine serum albumin. Single-cell suspensions were prepared utilizing repeated passage through a 25-gauge needle. Cell suspensions were washed, quantitated, and their viability determined using trypan blue exclusion.

Antibodies
Fluorescein isothiocyanate- (FITC), phycoerythrin- (PE), and biotin-conjugated or purified monoclonal antibodies (mAbs) RA3.6B2 (anti-CD45R, B220), S7 (anti-CD43), GK1.4 (anti-CD4), 53-6.7 (anti-CD8), M1/70 (anti-CD11b, Mac-1), RB6-8C5 (anti-Ly6G, Gr-1), TER-119 (anti-TER-119), E13-161.7 (anti-Ly6A/E, Sca-1), 2B8 (anti-CD117, c-kit), 53-7.3 (anti-CD5), and 17A2 (anti-CD3) were obtained from BD PharMingen (San Diego, CA; http://www.bdbiosciences.com/pharmingen). PE- and Tri-1D3 (anti-CD19) and purified 2.4G2 (anti-CD32/CD16 [Fc{gamma}II/IIIR]) and Streptavidin TRI were purchased from Caltag Laboratories (Burlingame, CA; http://www.caltag.com). PE-A7R34 (anti-CD127, interleukin-7 receptor [IL-7R]) and biotin-2B8 (anti-CD117, c-kit) were obtained from e-Bioscience (San Diego, CA; http://www.ebioscience.com).

Immunofluorescence Labeling, FACS Analysis, and Sorting
Immunofluorescence labeling was performed as previously described [9]. Expression of cell surface antigens was measured by three-color flow cytometry analysis. Briefly, BMCs were aliquoted (106 cells) into tubes and preincubated with CD32/CD16 (Fc BlockTM) at 4°C for 5 minutes. FITC-labeled anti-CD43 and PE-labeled anti-CD19, IL-7R, or c-kit together with biotin-labeled anti-IgM, BP-1, or c-kit were added directly to cells in the Fc BlockTM at 4°C for 30 minutes. The cells were then washed and subsequently incubated with streptavidin TRI®. The frequencies of cells expressing individual and/or sets of cell surface markers and the mean densities of expression of such markers were determined by analysis of a minimum of 50,000 cells utilizing a fluorescence-activated cell sorting flow cytometer (FACScan; Becton Dickinson; San Diego, CA; http://www.bd.com) and CellQuest software (Becton Dickinson).

Each B-cell subset population was purified utilizing a 10-parameter MoFlo cell sorter (Cytomation; Fort Collins, CO).

Pluripotent Stem Cell (HSC) and Lymphoid Precursor (lin-c-kitlowIL-7R+) Analysis
BMCs were collected and were layered onto a NycoPrepTM (NycoMed Pharma As; Oslo, Norway; http://www.nycomed-amersham.com) discontinuous density gradient. After centrifugation at 750 g for 25 minutes, cells with a density of 1.066 < p < 1.077 were collected [10]. The low-density cells were treated with a mixture of rat mAbs against mouse CD3, CD4, CD8, Mac-1, Gr-1, TER119, sIgM, and CD19 followed by incubation with anti-rat IgG-conjugated magnetic beads (Dynabeads®; Dynal Biotech, Lake Success, NY). Passage through a magnetic field was utilized to deplete the lineage-positive (lin+) cells. Lin- cells were aliquoted (106 cells) into tubes and preincubated with CD32/CD16 (Fc BlockTM) at 4°C for 5 minutes. FITC-labeled anti-Sca-1 and PE-labeled anti-IL-7R, together with biotin-labeled anti-c-kit, were added directly to cells in the Fc BlockTM at 4°C for 30 minutes. The cells were then washed and subsequently incubated with streptavidin TRI®. The frequencies of cells expressing individual and/or sets of cell surface markers and the mean densities of expression of such markers were determined by analysis of a minimum of 50,000 cells utilizing a FACScan and Cell Quest software.

Cell Cycle Analysis
Cell cycling was detected by the bromodeoxyuridine (BrdU) Flow Kit (BD PharMingen). Mice received an i.p. injection of 1 mg BrdU dissolved in PBS. BMCs were obtained 2 hours later, and the red blood cells were lysed. Enriched populations of CD19+ B-lineage cells were then prepared using CD19 microbeads (purity higher than 97%). The purified CD19+ cells were stained with PE-labeled anti-CD43 mAb and biotin-labeled anti-IgM, fixed with Cytofix/ CytopermTM buffer, and permeabilized with Cytoperm PlusTM buffer. The cells were then incubated again with Cytofix/ CytopermTM buffer, followed by treatment with DNase to expose the BrdU epitopes. Finally, immunofluorescent staining was performed with FITC-conjugated anti-BrdU (for defining the frequency of dividing cells), and the cells were analyzed using a FACScan.

Detection of Apoptotic Cells
The frequencies of B-lineage cells undergoing apoptosis within the B-C developmental stage fraction- (Fr.B-C-), Fr.D-, and Fr.E-F-enriched populations [8] were detected by Annexin V staining (BD PharMingen). Red-blood-cell-depleted BMCs were enriched for CD19+ B-lineage cells as above and labeled with PE-labeled anti-CD43 mAb and biotin-labeled anti-IgM and resuspended in binding buffer (10 nM HEPES/NaOH, pH 7.4, 140 mM NaCl, and 2.5 nM CaCl2). The cells were incubated with a predetermined optimal concentration of FITC-conjugated annexin V for 15 minutes at room temperature in the dark, washed, and then analyzed using a FACScan.

RNA Isolation and Reverse Transcription-Polymerase Chain Reaction Analysis for Bcl-X1 Expression
Total RNA for cDNA synthesis was prepared from freshly sorted Fr.B-C (pro-B), Fr.D (pre-B), and Fr.E-F (immature B) enriched from the BMCs of NZB mice; each sorted population had a purity greater than 95%. The RNA was obtained with the RNAeasy Mini kit (Qiagen Inc.; Santa Clarita, CA; http://www.qiagen.com), eluted into diethylpyrocarbonate-treated H2O (DEPC-H2O), and stored at -70°C. The RNA was used to synthesize first-strand cDNA using SuperscriptTM II reverse transcriptase ([RT] GIBCO Life Technologies; Gaithersburg, MD; http://www.invitrogen.com), 1 mM dNTPs, 1 µg random hexameric oligonucleotides, and the supplied RT buffer (GIBCO BRL). The polymerase chain reaction assay was carried out using the following primer pairs: ß-actin, 5'-CCT AAG GCC AAC CGT GAA AAG, 5'-TCT TCA TGG TGC TAG GAG CCA; Bcl-XL, 5'-TGA TTC CCA TGG CAG CAG TGA, 5'-AAC CAC ACC AGC CAC AGT CAT-3'.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Age-Related Decline of B-Lineage Cells in NZB Mice
In order to assess age-related effects on lymphohematopoietic cells in NZB mice, the frequencies of precursors at various stages of development were measured in young and old NZB mice. As shown in Table 1Go, the lin- cell number was similar in old and young mice. In addition, the frequency of the HSC population (lin-Sca-1+c-kit+) was significantly greater in old NZB mice. In contrast, the frequency of lymphoid precursors (lin-c-kitlowIL-7R+) was significantly lower in old NZB mice (Fig. 1Go and Table 1Go).


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  		Table 1. Distribution of New Zealand Black mice lin- bone marrow cells*
 


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  		Figure 1. Fluorescence-activated cell sorting analysis of hematopoietic stem cells and lymphoid precursor cells from young and old New Zealand Black mice. Data are representative of one of three experiments using two to four mice per group.

 
In an effort to confirm and quantitate the frequency of cells in the B-lymphocyte lineage, precursors were enumerated based on the Hardy fractionation protocol; BMCs from young (1 month) and old (6-8 months) NZB mice and, for control comparison, BALB/c mice were examined. The frequency of cells at the Fraction A stage of development was greater in old NZB mice (data not shown). However, as shown in Figure 2Go, the frequencies of cells in all other B-cell-lineage fractions were lower in old NZB mice. Specifically, the proportions of Fr.E-F (immature B cells) were 8.12% and 3.55%, Fr.D (pre-B cells) were 16.62% and 2.86%, and Fr.B-C (pro-B cells) were 3.79% and 0.50% for young and old mice, respectively. In contrast, the frequency of B-lineage cells in BALB/c mice did not exhibit these age-related changes (Fig. 2Go). Consistent with these declines, in old NZB mice, the frequencies of c-kit+ cells in Fr.B-C cells was significantly lower (Table 2Go).



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  		Figure 2. Age-related decreases in the proportions of E-F developmental stage fraction (Fr.E-F) (CD19+CD43-IgM+), Fr.D (CD19+CD43-IgM-), and Fr.B-C (CD19+CD43+IgM-) B-cell subsets in old New Zealand Black (NZB) mice. Bone marrow cells from young (1 month) and old (6-8 months) NZB and BALB/c mice were stained with anti-IgM-biotin/Tri, anti-CD19-phycoerythrin, and CD43-fluorescein isothiocyanate and analyzed by fluorescence-activated cell sorting. The data averages represent three to four mice per group in three independent experiments. * indicates significant differences between young and old NZB mice, p < 0.05. Statistical significance determined through Student’s t test.

 

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  		Table 2. Percentage of c-kit+ cells in B-C developmental stage fraction B cells*
 
Diminished Proliferative Capacity of B-Lineage Cells from Old NZB Mice
The lower number of B-lineage cells in the BM of old NZB mice could be attributed to a decreased proliferative capacity. To examine this possibility, the cell cycle statuses of B-lineage cells from young and old NZB mice were examined with BrdU staining. Two hours after BrdU injection, CD19+ BMCs were stained with anti-CD43, IgM, and anti-BrdU antibodies. As shown in Figure 3Go, the frequencies of BrdU+ cells in Fr.E-F, Fr.D, and Fr.B-C cells in old NZB mice were significantly lower than in young NZB mice. These data suggest that decreased proliferation could account for the lower frequency of B-lineage cells in the BM of old NZB mice.



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  		Figure 3. Cell cycle analysis of the frequency of E-F developmental stage fraction (Fr.E-F), Fr.D, and Fr.B-C B cells that have incorporated bromodeoxyuridine (BrdU) using two to four mice per group from three different experiments. *p< 0.05, **p < 0.01. Statistical significance determined through Student’s t test.

 
Decreased Survival of Fr.E-F, Fr.D, and Fr.B-C Cells from Old NZB Mice
The lower frequency of B-lineage cells in old NZB mice could also be due to decreased survival. To address this issue, the frequency of cells undergoing spontaneous apoptosis was measured. The data in Figure 4AGo demonstrate that the frequencies of apoptotic B-lineage cells within the Fr.E-F, Fr.D, and Fr.B-C populations from old NZB mice were higher than those of B-lineage cells from young NZB mice. Because apoptotic cells are rapidly removed from the BM, the number of such cells detectable at any one time is very low [11]. In an effort to gain additional insight into the degree to which apoptosis is occurring, a short-term culture system in which apoptotic cells accumulate was employed [11]; CD19+ purified BMCs from young and old NZB mice were incubated for 24 hours, and apoptosis was examined by annexin V staining. Once again, the frequency of apoptotic B-lineage cells in old NZB mice was found to be markedly higher than in young NZB mice (data not shown). These findings were consistent with additional studies showing that Bcl-X1 mRNA levels were markedly lower in Fr.E-F, Fr.D, and Fr.B-C cells from old NZB mice (Fig. 4BGo). Quantitative estimates of these data suggest that the expression of Bcl-XL by each of the three B-cell subsets from old NZB mice was <20% of that expressed by the same fractions of B-cell precursors from young NZB mice. In contrast, previous studies have shown that BALB/c mice fail to exhibit an age-dependent change in the percentage of apoptotic cells in B-cell-precursor populations through 18 months of age [12].



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  		Figure 4. A) Frequency of B-lineage subsets from young and old New Zealand Black (NZB) mice undergoing spontaneous apoptosis using a total of two to four mice per group from three different experiments. *p <0.05, **p <0.01. Statistical significance determined through Student’s t test. B) Bcl-XL mRNA in E-F developmental stage fraction (Fr.E-F), Fr.D, and Fr.B-C B cells from young and old NZB mice. B-lineage cells were sorted from pooled BM cells from young and old mice. Bcl-XL mRNA levels were analyzed by reverse transcriptase-polymerase chain reaction with ß-actin mRNA used as a control. Identical results were obtained in two independent experiments.

 
Comparison of IL-7R Expression in Young and Old NZB Mice Fr.B-C B Cells
IL-7 has been shown to be an indispensable cytokine for B-cell development in adult mice. The IL-7 receptor, IL-7R, is composed of the IL-7R{alpha} chain and the common cytokine receptor {gamma} chain ({gamma}c), and mice that are genetically deficient in their capacity to express IL-7R genes lack B cells. We therefore studied the expression of the IL-7R{alpha} chain in young and old NZB mice. Examination of Fr.B-C B cells from young and old NZB mice indicated that the frequency of IL-7R+ cells in the Fr.B-C B-cell population was nearly twofold lower in old NZB mice (Fig. 5Go), at 52.60 ± 6.13% and 95.55 ± 0.57% in old and young mice, respectively (Table 3Go). Importantly, the frequency of IL-7R+ Fr.B-C B cells remained unchanged in old BALB/c mice (Table 3Go).



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  		Figure 5. Fluorescence-activated cell sorting analysis of IL-7 receptor expression in B-C developmental stage fraction B cells from young and old New Zealand Black mice. Data are representative of one of three experiments using two to four mice per group.

 

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  		Table 3. Percentage of IL-7R+ cells in B-C developmental stage fraction B cells*
 

   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
NZB mice, as well as several other models of murine lupus, manifest abnormal patterns of B-cell-lineage cell development [1]. Previous studies have shown that the development of B-cell precursors is abnormal in old NZB mice and in the BWF1 (NZBxNZW F1) strains [3, 13, 14] and that the numbers of detectable BM pre-B cells and immature B cells decline in an age-dependent manner. It has been reported that this lineage-specific dysfunction progresses with age and eventually affects both pre-B and pro-B cell populations [5]. In addition, even in a supportive microenvironment for B lymphopoiesis, the pre-B-cell-deficient phenotype of older NZB BM is retained, denoting an intrinsic defect. Both in vivo and in vitro experiments suggest that microenvironmental elements required for promoting pre-B cell development and differentiation remain functional [13, 15].

B lymphocytes, like all other members of the hematopoietic system, are derived from HSCs [16, 17]. Development of mature B cells from HSCs is accompanied by qualitative and/or quantitative differences in the expression of cell surface molecules. Such differences permit enumeration, depletion, and enrichment of stage-specific precursor cells. Numerous studies have demonstrated that allogeneic BM transplantation can prevent disease in systemic lupus erythematosus models of systemic and organ-specific autoimmune diseases [18–24]. Recently, our lab reported that stem cells from adult NZB mouse BM exhibit defective T-cell-lineage development in fetal thymic organ culture [25]. In addition, we also demonstrated that the T-lymphopoietic defect resulted from an impaired ability of HSCs to generate committed lymphoid progenitor (CLP) and/or T-cell-committed progenitors [26]. These findings suggest that the autoimmune disease of NZB mice may originate from intrinsic disorders of the HSCs and that abnormalities in B-cell developmental pathways may contribute to the induction of autoimmune disease, associated with an accumulation of autoreactive lymphocytes [20, 27]. Further, there is an unusual greater number of HSCs in the BM of old NZB mice, while, in contrast, the lin-c-kitlowIL-7R+ population, which contains the CLP, is lower in the BM of old NZB mice. Surprisingly, however, there is a greater frequency of cells at the fraction A stage of development (unpublished data). The reasons for these fluctuations in precursor frequency are not clear, but the data clearly indicate that events during early lymphoid development in NZB mice are dysregulated.

IL-7 is an essential cytokine for early T- and B-cell development when V(D)J recombination takes place [28, 29]. IL-7 exerts its effect through ligation with its cognate IL-7R, which contains a unique {alpha} chain and a common {gamma} chain shared by other cytokine receptors. IL-7 activity has also been shown to be indispensable for normal lymphocyte development [30]. In the BM of IL-7R-/- mice, there is a block in B-cell development at the transition from the Fr.B-C (pro-B) B-cell to the Fr.D (pre-B) B-cell stage [29, 31]. Transgenic expression of the antiapoptotic protein Bcl-2 in IL-7R-/- mice does not rescue impaired B lymphopoiesis [32]. IL-7R transmits at least two types of signals in T- and B-cell progenitors. One signal is for proliferation. The second IL-7R signal is to promote V(D)J recombination in IgH and TCR{gamma} loci [28, 33, 34].

Results of previous studies suggest that microenvironmental elements required for promoting pre-B-cell development and differentiation remain functional in old NZB mice [13, 15]. However, significant decreases in IL-7 responsiveness were seen in old NZB mice accompanied by alterations in the numbers of both pre-B and pro-B cells in the BM [6]. In contrast, in BALB/c mice, there is no difference in mitotic activity of B cells between young and old mice, and the capacity of B-lineage precursor cells to proliferate upon stimulation with recombinant IL-7 is retained even in very old mice (24 months) [35]. In our experiments, a lower rate of proliferation and greater amount of apoptosis were observed in Fr.B-C cells from old NZB mice (Fr. D-F are non-IL-7 responsive). In view of the fact that the IL-7R is expressed at a comparable density on the surface of individual B-lineage cells at this stage of development, we hypothesize that as NZB mice age, their IL-7 signal transduction pathway becomes disrupted. As a result, signals required for cell growth and survival are not delivered to developing pro-B cells, which then proliferate less and are more prone to apoptosis. Taken together, these events would account for the lower frequency of CD45R+ cells in aging NZB mice.


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Grant support provided by NIH CA20816 and CA20408.


   REFERENCES
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received on December 14, 2001; accepted for publication on March 11, 2002.





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