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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3772-3779
Susceptibility Alleles for Aberrant B-1 Cell Proliferation Involved
in Spontaneously Occurring B-Cell Chronic Lymphocytic Leukemia in a
Model of New Zealand White Mice
By
Yoshitomo Hamano,
Sachiko Hirose,
Akinori Ida,
Masaaki Abe,
Danqing Zhang,
Sanki Kodera,
Yi Jiang,
Jun Shirai,
Yuko Miura,
Hiroyuki Nishimura, and
Toshikazu Shirai
From the Department of Pathology, Juntendo University School of
Medicine, Tokyo, Japan; Core Research for Evolutional Science and
Technology, Japan Science and Technology Corp, Kawaguchi,
Japan; the Department of Obstetrics and Gynecology, Hyogo
College of Medicine, Hyogo, Japan; and Toin Human Science and
Technology Center, Toin University of Yokohama, Yokohama, Japan.
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ABSTRACT |
B-cell chronic lymphocytic leukemia (B-CLL) and autoimmune disease
are a related event, and genetic factors are linked to both diseases.
As B-CLL is mainly of B-1 cell type that participates in autoantibody
production, genetically-determined regulatory abnormalities in
proliferation and/or differentiation of B-1 cells may determine
their fate. We earlier found that, in H-2-congenic (NZB × NZW) F1
mice, while H-2d/z heterozygosity predisposes to autoimmune
disease, H-2z/z homozygosity predisposes to B-CLL. Studies
also suggested the involvement of non-H-2-linked NZW allele(s) in
leukemogenesis. Using H-2-congenic NZW and B10 mouse strains, their F1
and backcross progeny, we have now identified three major NZW
susceptibility loci for abnormal proliferation of B-1 cells, which form
the basis of leukemogenesis; one H-2-linked locus on chromosome 17 and
the other two non-H-2-linked loci, each on chromosome 13 and
chromosome 17. Each susceptibility allele functioned independently, in
an incomplete dominant fashion, the sum of effects determining the extent of aberrant B-1 cell frequencies. The development of leukemia was associated with age-related increase in B-1 cell frequencies in the
blood. Thus, these alleles probably predispose B-1 cells to accumulate
genetic alterations, giving rise to B-CLL. Potentially important
candidate genes and correlation of the findings with autoimmune disease
are discussed.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
CHRONIC LYMPHOCYTIC leukemia (CLL),
mostly the B-cell type, has two intriguing characteristics; one, the
significance of hereditary factors in the pathogenesis, and the other,
frequent association of immunologic abnormalities, including autoimmune diseases among patients or their family members. First-degree relatives
of patients develop B-CLL or other lymphoid neoplasms at more than
three times as high a risk as found in the general population.1 While B-CLL is the most common adult leukemia in Caucasians, it is rare in Asians, including those who immigrated to
the United States.2-5 The frequent association of
autoimmunity with B-CLL has been well described. Patients with B-CLL or
their family members frequently have immunologic abnormalities,
including autoimmune hemolytic anemia, thrombocytopenic purpura,
systemic lupus erythematosus (SLE), and Sjögren's
syndrome.6-11 Patients with B-CLL often share common HLA
haplotypes with relatives who have autoimmune diseases.12
Evidence suggesting that most B-CLL cells originate from the
CD5+ B (B-1) cell lineage has implicated B-1 cells as a
crossroad between B-CLL and autoimmune diseases.13,14
B-CLL cells and intact B-1 cells share several
characteristics, including production of
autoantibodies,15-20 usage of rather restricted repertoires of nonmutated Ig V genes,21-24 cross-reactive
idiotypes,13,20,25 and surface markers.26,27
Murine B-1 cells, which belong to a developmental lineage distinct from
that of conventional B (B-2) cells, have unique surface phenotypes and
are localized in distinctly different patterns from conventional B
cells; these cells are maintained by a self-renewal
capacity.28,29 B-1 cells, in mice and in humans,
participate in immune systems mainly by providing natural immunity and
even autoimmunity, as opposed to conventional B-2 cells in acquired
immunity. B-1 cells produce most IgM natural antibodies, the majority
of which are polyreactive and cross-react with a variety of
self-antigens.29,30 At least part of the B-1 cell
repertoire appears to be selected and maintained by self-antigens and
can protect themselves from elimination by bystander activated T cells
through downregulation of Fas levels.31 Further selection, class-switch, and affinity maturation of such a long-lived B-1 cell
repertoire are implicated in the development of highly pathogenic autoantibodies in genetically susceptible autoimmune disease-prone strains of mice.32,33 Hence, it is highly likely that
certain regulatory abnormalities in proliferation and/or
differentiation of B-1 cells are involved in both B-CLL and autoimmune
disease.14
In earlier studies on newly established H-2-congenic New
Zealand mouse strains, NZB, NZW, and (NZB x NZW) F1, carrying either homozygous or heterozygous haplotypes of H-2d
derived from NZB and H-2z from NZW, we provided
evidence that different, but related major histocompatibility complex
(MHC) haplotypes predispose either to autoimmune disease resembling SLE
or to B-CLL, in which while H-2d/z heterozygosity
acts as one genetic predisposing element for SLE,34,35 H-2z/z homozygosity acts as one element for
B-CLL.36,37 For example, while H-2d/z
heterozygous (NZB x NZW) F1 mice spontaneously developed SLE in
association with pathogenic, high affinity IgG anti-DNA antibodies, H-2z/z homozygous mice, which differ from the
former at only one locus or a cluster of loci, did not, but instead
developed abnormal proliferation of B-1 cells both in the peripheral
blood and in lymphoid tissues. Such B-1 cells showed an age-dependent
oligoclonal to monoclonal expansion, giving rise to
B-CLL.37 B-CLL also developed in H-2z/z
homozygous NZB and NZW, hence a gene or a cluster of genes located in
the vicinity of NZW H-2z was suggested to play a
critical role in the process of leukemogenesis.
In these studies, we also noted that the H-2-congenic B10.NZW
strain carrying homozygous H-2z
haplotype38 did not manifest as much increase in peripheral B-1 cell frequencies as that seen in
H-2z-homozygous NZW and NZB, and B-CLL did not
occur. Thus, it is clear that, in addition to the
H-2z-linked gene,
non-H-2z-linked gene(s) also controls
abnormal proliferation and subsequent leukemogenesis of B-1 cells in
New Zealand mouse strains. Taking advantage of
H-2-congenic strains and their crosses and of analyses using microsatellite markers as tools for genome-wide linkage studies,39 we did chromosomal mapping of susceptibility
alleles and analyzed their patterns of inheritance.
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MATERIALS AND METHODS |
Mice.
NZW and B10.D2 mice were originally obtained from the Shizuoka
Laboratory Animal Center (Shizuoka, Japan). NZW.H-2d strain
was established by selective backcrossing of the (NZB x NZW) F1 hybrid
to NZW for 12 generations.35 B10.NZW mice were kindly
donated by Dr J. Klein, Max-Planck-Institute for Biology, Tubingen,
Germany.38 The F1 hybrid mice between strains NZW, B10.D2,
and B10.NZW and the (NZW x B10.NZW) x B10.NZW backcross progeny were
bred and maintained in our animal facility. Genotyping of backcross
progeny was performed as described below. Only female mice were used in
the present studies.
Cell counts and cytologic examination.
Peripheral blood was taken from the periorbital sinus. White blood cell
counts were performed using a MEK-6158 Automatic Blood Cell Counter
(Nihon Koden, Tokyo, Japan) according to the manufacturer's instructions. White blood cell-rich populations were separated from 40 µL of heparinized blood using a density gradient lymphocyte separator
M-SMF (Japan Immuno Research Laboratories Co, Ltd, Takasaki, Japan).
Leukocyte film for cytologic examination was prepared using the
Cytospin 3 Cell Preparation System (Shandon Scientific Ltd, Cheshire,
UK) and stained with Giemsa.
Flow cytometry.
Peripheral blood was taken from the periorbital sinus, followed by
lysis of red blood cells with ammonium chloride. For flow cytometric
analysis, aliquots of 5 to 10 × 105 cells in 20 µL
of phosphate-buffered saline (pH7.4) supplemented with 0.2% bovine
serum albumin and 0.05% NaN3 were incubated with fluorescein isothiocyanate (FITC)-labeled rat antimouse CD5 (clone 53-7.3) monoclonal antibodies and biotinylated rat antimouse CD45R (B220) (clone RA3-6B2) antibodies, followed by phycoerythrin
(PE)-avidin (Becton-Dickinson, Mountain View, CA). All incubations were
run for 30 minutes at 4°C. The stained cells were examined using
FACStar (Becton Dickinson), equipped with the FITC/PE
filter system.
Genotyping of mice.
Genomic DNA was extracted from murine tail skins using standard
techniques. Chromosomal markers consisting of simple-sequence length
polymorphisms were identified by polymerase chain reaction (PCR).39 The primers were purchased from Research Genetics
(Huntsville, AL). PCRs were performed in the presence of
radioactively-labeled primers with [ -32P] adenosine
triphosphate (ATP), using T4 kinase (Takara Shuzo, Kyoto, Japan)
according to the manufacturer's instruction. A 40-ng aliquot of
genomic DNA was amplified in 10 µL of PCR solution containing Taq
polymerase (Takara Shuzo). A three temperature PCR protocol (94°C,
55°C, and 72°C, 25 to 30 cycles or 94°C, 50°C, and
72°C, 35 cycles) was conducted in a Geneamp 9600 Thermal Cycler (Perkin Elmer Cetus, Norwalk, CT). PCR products were diluted twofold with loading buffer consisting of xylene cyanol and bromophenol blue
dyes in 100% formamide and were run on 7% polyacrylamide gels. After
electrophoreses, gels were dried and examined using a Bio-imaging
analyzer BAS 2000 (Fuji Film, Tokyo, Japan).
Statistics.
The linkage of a particular locus with increased peripheral frequency
of B-1 cells was estimated using  2 analysis with a
standard (2 × 2) contingency matrix. Interval mapping was done
using MAPMAKER/EXP and MAPMAKER/QTL40 to identify chromosomal locations of quantitative trait loci (QTL). The likelihood ratio statistic (base-10 lod score) of  1.9 and 3.3 was used as
thresholds for statistically suggestive and significant linkage, respectively, and support intervals were determined according to Lander
et al.41,42 Analysis of variance (ANOVA) was used to
determine the difference in B-1 cell frequencies among each group with
different combinations of susceptibility alleles.
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RESULTS |
Involvement of both H-2z-linked and nonlinked genes in
aberrant B-1 cell proliferation in peripheral blood of New Zealand
mice.
Table 1 compares age-associated changes in
the proportion of peripheral blood CD5+ B (B-1) cells per
total B cells in mouse strains with different genetic backgrounds, NZW
(H-2z/z), NZW.H-2d
(H-2d/d), B10.NZW (H-2z/z),
B10.D2 (H-2d/d), (NZW x B10.NZW) F1
(H-2z/z), (NZW x B10.D2) F1 (H-2z/d),
and (NZW x B10.NZW) F1 x B10.NZW backcross mice at 8, 12, and 16 months
of age. H-2z-homozygous NZW mice at any given age
showed much higher B-1 cell frequencies compared with
NZW.H-2d mice, a finding consistent with our earlier
observation that the H-2z-linked gene(s),
provisionally designated Bpal-1 (B1 cell
proliferation-associated locus), acts as one major predisposing genetic
element for abnormal proliferation of B-1 cells.36,37
Because, the H-2-congenic NZW.H-2d strain was
established by selective backcrossing of (NZW x NZB) F1 to NZW for 12 generations,35 Bpal-1 is estimated to be located within or in close proximity of the H-2 complex. Compared with findings in H-2z/z-homozygous NZW, however, B-1
cell frequencies in H-2z/z-homozygous B10.NZW mice
at any given age were much less, indicating that an additional
non-H-2-linked NZW gene or genes are also involved.
Comparison of data shown in Table 1 indicate several inheritance
patterns of the H-2z-linked and nonlinked
susceptibility alleles: (1) because B-1 cell frequencies were higher in
strains bearing either one of the H-2-linked or nonlinked
genes (B10.NZW and NZW.H-2d/d, respectively) than those
found in the B10.D2 strain, which lacks both genes, each gene can act
to propagate B1 cells in an independent manner; (2) because
H-2z/d-heterozygous (NZW x B10.D2) F1 at any given
age had lower B-1 cell frequencies than did H-2z/z
homozygous (NZW x B10.NZW) F1 mice and because
H-2z/z homozygous (NZW x B10.NZW) F1 had higher B-1
cell frequencies than did H-2z/z homozygous
B10.NZW, the H-2z-linked and the
non-H-2z-linked genes both appeared to be
inherited in an incomplete dominant fashion; and (3) because the NZW
strain, which carries all susceptibility alleles, has the highest
frequencies of B-1 cells compared with others bearing fewer or none
such as (NZW x B10.NZW) F1, (NZW x B10.D2) F1 and B10.D2, the extent of
B-1 cell frequencies in the progeny appeared to depend on additive
effects of the sum of each H-2z-linked and
non-H-2z-linked susceptibility allele.
Mapping of non-H-2z-linked susceptibility alleles for
aberrant B-1 cell proliferation.
To map the non-H-2z-linked NZW locus or loci for
abnormal proliferation of B-1 cells, (NZW x B10.NZW) F1 x B10.NZW
female backcross mice, all bearing homozygous
H-2z/z, were generated and genotyped using
microsatellite markers. Of a total of 504 markers screened, 192 markers
were polymorphic between the two parental strains and 103 markers were
selected for further studies (Fig 1).
Figure 2 illustrates histograms of the distribution of
blood B-1 cell frequencies in NZW, B10.NZW, the F1 hybrid and the F1 x
B10.NZW backcross mice at 8 and 16 months of age. When cut-off points
were determined based on criteria that B-1 cell frequencies of over 5%
and 10% were regarded as abnormal levels at age 8 and 16 months,
respectively, 2 analyses using 127 to 140 backcross mice
showed that NZW/B10.NZW (NB) genotype at loci on each chromosome 13 and
17 was significantly associated with abnormal proliferation of B-1
cells (Table 2).
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| Fig 1.
Polymorphic microsatellite markers used in this study.
Linkage relationships for the 103 polymorphic markers were determined
by analysis of 140 (NZW x B10.NZW) F1 x B10.NZW backcross mice. Genetic
maps for each chromosome were prepared using MAPMAKER/EXP.
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| Fig 2.
Histograms of proportions of CD5+B (B-1)
cells in total peripheral B cells in NZW, B10.NZW, (NZW x B10.NZW) F1
and (NZW x B10.NZW) F1 x B10.NZW backcross mice at 8 and 16 months of
age. Cut-off point used in 2 test is indicated by an arrow.
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Interval mapping of data from backcross mice at 8 and 16 months of age
using MAPMAKER/QTL showed that the locus on chromosome 13, provisionally designated Bpal-2, is located on the centromeric portion and is either significantly or suggestively linked to D13MIT136, D13MIT61, and D13MIT13. However,
second peaks were always identified within each MAPMAKER/QTL
analysis. In mice aged 8 months, the locus was most closely linked to
D13MIT136 and, in mice aged 16 months, it was closely linked
to D13MIT13 (Table 2 and Fig 3).
The existence of these two peaks and the large size of the one-log
confidence support interval (29 centiMorgans) obtained by
analysis in mice aged 8 months suggest the possible existence of two
susceptibility loci in this region (Fig 3). As numbers of recombinants
between D13MIT136 and D13MIT13 were few, we could not
confirm this possibility.
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| Fig 3.
MAPMAKER/QTL scans on chromosomes 13 and 17 for aberrant
B-1 cell proliferation in blood of 127 to 140 (NZW x B10.NZW) F1 x
B10.NZW backcross mice. Lod score curves (bold lines, 8 months of age;
dotted line, 16 months of age) are shown on the right with scale on the
top. Map positions of markers are arranged from centromere to telomere
on the left side of the chromosome line. An "error" bar
represents the one-lod support interval of Bpal-2. Candidate
genes within the support interval are also listed.
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On the other hand, the non-H-2-linked locus on chromosome 17 showed a suggestive association in lod scores with D17MIT222 in
MAPMAKER/QTL analysis of 8 months old mice. Although the lod scores were not in the range of significant values, the existence of
QTL close to this locus was suggested in ANOVA, as based on four groups
of backcross progeny, classified according to combinations of genotypes
for D13MIT136 (Bpal-2) and D17MIT222, ie, group
A, B10.NZW/B10.NZW (BB) genotype for both D13MIT136 and
D17MIT222; groups B and C, either one of the two loci is
NZW/B10.NZW (NB) and the other is BB; and group D, NB for both loci
(Fig 4). Among these four groups, the
extent of B-1 cell frequencies was in the order of group D, groups B
and C, and group A, indicating that the frequencies are increased in a
manner depending on the number of the corresponding NZW susceptibility
alleles. The differences were statistically significant in mice at 8 and at 16 months of age (P < .0001 at 8 months, and P < .01 at 16 months) by ANOVA. Thus, in addition to the effects of
Bpal-1 (H-2-linked) and Bpal-2, the third
non-H-2-linked locus on NZW chromosome 17, tentatively designated Bpal-3, is also likely to play a role in the
abnormal proliferation of B-1 cells.
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| Fig 4.
ANOVA among groups classified by combined genotyping.
(NZW x B10.NZW) F1 x B10.NZW backcross mice were subdivided into four
groups (A to D) according to combined genotyping of loci,
D13MIT136 (Bpal-2) and D17MIT222. Symbol
`+', genotyped as NB (heterozygous for NZW and B10.NZW) and
` ', genotyped as BB (homozygous for B10.NZW). P values
of post hoc test (Fisher's Protected Least Significant Difference
test) were as follows: at 8 months old; A versus C, P < .05;
A versus D, P < .0001; B versus D, P < .0001; C
versus D, P < .005; at 16 months old; A versus D, P < .0005; B versus D, P < .005; C versus D, P < .05.
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Development of B-CLL in backcross progeny.
At the age of 23 months, a time when 70% of NZW mice had developed
B-CLL, as determined by blood smear samples, 12% of the (NZW x
B10.NZW) x B10.NZW backcross mice developed leukemia, and this was
associated with age-related abnormal increase in the frequency of B-1
cells in the blood. Figure 5 shows a
representative result of age-associated changes in frequencies of B-1
cells in the blood, as determined by fluorescence-activated cell
sorting (FACS) analysis and in cytospinned leukocyte films in a (NZW x B10.NZW) x B10.NZW backcross mouse at ages 8, 16, and 23 months. FACS
profiles showed that proportions of B-1 cells per total B cells were
progressively increased in this mouse with aging (11%, 44%, and 97%
at 8, 16, and 23 months of age, respectively). In the leukemic stage in
the mouse 23 months of age, total leukocyte counts were markedly high
(35,500/mm3). Morphologically, most lymphocytes in the
peripheral blood in the 8-month-old mouse were small and had condensed
nuclear chromatin and a scant cytoplasm. At 16 months of age, there
occasionally appeared relatively larger lymphocytes with a basophilic
cytoplasm, some of which had irregular nuclei with irregular networks
of chromatin. The majority of blood lymphocytes at the leukemic stage were composed of lymphoid cells with a basophilic cytoplasm and nuclei
with a coarse granular chromatin. Smudged cells and broken lymphocytes
were frequent (data not shown). Surface markers of leukemic cells were
positive for surface IgM, CD2, CD5, CD19, and MHC class II and negative
for CD25 and CD38, with patterns similar to those seen in human B-CLL
cells.43
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| Fig 5.
Representative flow cytometry profiles and blood films of
peripheral blood lymphocytes from a single (NZW x B10.NZW) F1 x B10.NZW
backcross mouse carrying all Bpal-1, -2 and -3 alleles,
at 8, 16, and 23 months of age. CD5+ B-1 cells are boxed.
Cytospinned lymphocyte films were stained with Giemsa. Proportions of
B-1 cells in total peripheral B cells and total white blood cell counts
were 11% and 7,200/mm3 in mice at 8 months, 44% and
7,000/mm3 at 16 months, and 97% and 35,500/mm3
at 23 months of age, respectively.
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DISCUSSION |
We identified three susceptibility loci responsible for abnormal
proliferation of B-1 cells, an event that forms the basis of
leukemogenesis in a B-CLL model of NZW strain. All three susceptibility alleles function independently and are inherited in an incomplete dominant fashion. The extent of B-1 cell frequencies in the peripheral blood depends on the sum of each susceptibility allele, indicating additive effects of these alleles. These features are consistent with
the polygenic inheritance of the abnormality as a threshold liability.
It is highly plausible that these susceptible alleles predispose B-1
cells to accumulate genetic alterations, thus giving rise to B-CLL.
As usual in studies of interval mapping of genes with incomplete
penetrance, support intervals associated with B-CLL
susceptibility alleles were long. Thus, further approaches for
identification of the causative gene in each interval include the
establishment of a congenic strain for support intervals, followed by
exon-trapping. Another approach would be characterization of relevant
candidate genes potentially related to the dysregulation of B-1 cell
proliferation. In this context, because Bpal-1, an
H-2z-linked susceptibility allele, retains the
effect in H-2z-congenic B10.NZW mice that have been
established by selective backcrossing of mice for 12 generations.38 the candidate gene appears to be located
within or in close proximity of the H-2 complex. A potentially
important polymorphic candidate gene for Bpal-1 may be a
structural gene of MHC class II antigens. Evidence is accumulating that
B-CLL cells use restricted repertoires of nonmutated Ig V
genes.21,22 VH genes of B-CLL are
preferentially selected from relatively small VH subgroups
and the structure of the complementarity-determining region (CDR) 3 is
biased to be longer than that of the normal counterpart,20
suggesting that an antigen-driven, strong selective force is operative
on B-1 cells during leukemogenesis. Considering that the majority of
B-1 cells can cross-react with a variety of self-antigens, which can be
processed and presented as an MHC class II-peptide complex, chronic
stimulation via a certain ubiquitous self-peptide plus class II may
serve as a selective force for the restricted repertoires, and the risk
for neoplastic transformation into B-CLL would increase. In this
regard, the H-2z haplotype of NZW strain is unique.
Our earlier studies using H-2-congenic New Zealand mouse
strains showed that the major NZW contribution to severe SLE in (NZB x
NZW) F1 mice is the H-2z-linked locus that
forms H-2d/z heterozygosity in the F1 hybrid
mice.34,35 Importance of the H-2 heterozygosity for
SLE has been confirmed in F244 and backcross45 analyses, except for one that showed a minor influence.46
The most plausible hypothesis for the difference between homozygous H-2z/z for B-CLL and heterozygous
H-2d/z for autoimmune disease in (NZW x NZB) F1
mice is that, in the latter, the formation of mixed haplotype-class II
molecules, ie, A d u,
Aud, Edu,
and Eud allows selected B-1 cells to
undergo class switch and affinity selection, giving rise to plasma
cells producing pathogenic autoantibodies.34,35 Because
Adu molecule-specific autoreactive T-cell
clones derived from aged (NZW x NZB) F1 mice were capable of inducing
IgG anti-DNA antibody production on transfer to young mice, the
Adu is thought to be the most plausible
candidate for restriction element for autoreactive T
cells.47,48 In contrast, in the former
H-2z/z homozygotes, because of the lack of genetic
element (mixed haplotype class II molecules) required for such B-1 cell
maturation, only signals for proliferation would be
functioning.14
Another candidate for Bpal-1 may be the tumor necrosis factor
(TNF) gene. Both structural and regulatory genes of TNF- and -
are mapped to the D subregion of the H-2
complex.49 It was reported that although TNF- weakly
triggers the growth of B-CLL cells,50 it does exert a
synergistic proliferative effect in combination with interleukin
(IL)-2.51 Serum levels of TNF- are increased in B-CLL
patients compared with findings in healthy age-matched
individuals.52 Thus, it is possible that the polymorphic TNF- gene in the H-2 complex controls the proliferation of
B-1 cells in NZW mice. However, this is less likely because production of TNF- in the NZW strain is downregulated, rather than upregulated, by the unique polymorphic NZW TNF- allele,53 and because
this NZW TNF- allele upregulates SLE in (NZB x NZW) F1
mice.53 Our recent genetic studies suggested that both
class II and NZW TNF- polymorphisms appear to be functioning as
H-2-linked prediposing genetic elements for SLE, and that the
TNF- polymorphism functions to modulate an initial process of the
autoimmune disease in these mice.54
One-log confidence interval containing Bpal-2 on chromosome 13 covers potent candidate loci, ie, encoding T-cell receptor chain (Tcrg), inhibin A (Inhba), prolactin
(Prl), and Friend murine leukemia virus (MuLV)
integration site-1 (Fim-1). Among these, Inhba deserves
attention. A homodimer of inhibin A is activin A produced in stromal
cells in the bone marrow55 and regulates differentiation
and proliferation of cells, including hematopoietic cells and leukemic
cells.56,57 We are now determining if Inhba is
polymorphic and has the potential to proliferate B-1 cells. This
segment of murine chromosome 13 is homologous to portions of human
chromosomal regions 7p15 (as for Tcrg and Inhba) and 6p23 (as for Prl).58
Among genes on the centromeric portion of chromosome 17, Igf2r
(insulin-like growth factor 2 receptor [IGF2R]) is a plausible candidate for Bpal-3.59 Evidence is accumulating
that Igf2r acts as a tumor suppressor gene in both humans and
mice. Loss of IGF2R function leads to an increased extracellular
concentration of IGF2 and a decreased level of activated TGF-, a
condition under which human hepatocytes are susceptible to malignant
transformation.60 In human breast cancers, loss of
heterozygosity was found at the locus of Igf2r.61
Overexpression of IGF2 can increase frequencies of diverse
malignancies, including lymphoma in mice.62 Thus, a
potential genetic polymorphism of the NZW Igf2r gene may be involved in leukemogenesis. To examine all of these possibilities, we
are now generating interval-specific congenic strains for
Bpal-2 and Bpal-3. Such strains will also be useful for
the analysis of epistatic effects between susceptibility alleles.
Raveché et al63,64 reported that aged NZB mice, a
spontaneous model of autoimmune hemolytic anemia, exhibit a clonal
expansion of hyperdiploid B-1 cells that resemble B-CLL. In our earlier studies, the frequencies of B-1 cells in the NZB strain
(H-2d) were much lower than found in the homozygous
H-2z/z-congenic NZB strain.36,37
However, considering the disparity in B-1 cell frequencies between the
H-2z/z-congenic NZB36,37 and the
H-2z/z-congenic B10.NZW (present study), it is highly
plausible that the NZB strain also carries certain susceptibility
alleles such as Bpal-2 and/or Bpal-3 for
abnormal proliferation of B-1 cells. In concert with effects of the
susceptibility alleles for aberrant B-1 cell
differentiation,65,66 such Bpal-2 and/or
Bpal-3 may possibly relate to the autoimmune disease seen in
NZB and (NZB × NZW) F1.
In conclusion, New Zealand mouse models provide a valuable tool for
determination of the genetic basis of not only B-CLL ontogeny, but also
autoimmune disease, in which dysregulated proliferation of B-1 cells
forms the basis of B-CLL and the associated aberrant maturational
processes of these expanded populations of B-1 cells can lead to
autoimmune disease.
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ACKNOWLEDGMENT |
We thank Dr T. Ushijima, National Institute for Cancer Research, Japan
for helpful discussion and M. Ohara for comments on the manuscript.
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FOOTNOTES |
Submitted April 15, 1998;
accepted June 30, 1998.
Supported in part by CREST (Core Research for Evolutional Science and
Technology) of Japan Science and Technology Corporation and a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.
The publication costs of this
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Abstract
Introduction