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CUTTING EDGE |
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94306
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD1 is a nonpolymorphic, class I MHC-like, non-MHC encoded molecule
that associates noncovalently with
ß2-microglobulin (10). CD1
molecules have been demonstrated to be Ag-presenting molecules for
glycolipid and hydrophobic peptides (11, 12, 13). All murine B
cells express CD1 on the cell surface (14), and there is a
subset of splenic B cells that expresses high levels of CD1
(CD1high B cells) and accounts for about 20% of
total splenic B cells. CD1high B cells in
nonautoimmune mice have been demonstrated to be predominantly marginal
zone B cells (15, 16, 17). We previously showed that BALB/c
anti-CD1 TCR transgenic T cells that secrete high levels of IFN-
and IL-10, but low levels of IL-4, can activate syngeneic B cells in
vitro to secrete IgM and IgG by cross-linking CD1, and the transgenic T
cells induced lupus in BALB/c nu/nu recipients with high levels of
serum anti-dsDNA Abs and glomerulonephritis (18). This
indicates that T and B cell interactions via CD1 can play an important
role in the pathogenesis of lupus (18).
In the current study, the role of CD1 in the development of lupus in NZB/NZW mice was examined. The results show that IgM+CD1high B cells from the NZB/NZW spleen spontaneously secreted IgM and IgM anti-dsDNA autoantibodies at levels 5- to 25-fold higher than CD1int/low B cells. Anti-CD1 T cells were present in the spleen of NZB/NZW mice also. In vivo anti-CD1 mAb treatment reduced the peak levels of serum IgG and IgG anti-dsDNA Abs, delayed the onset of proteinuria, and prolonged the survival period. Our results suggest that CD1 is expressed on the precursors of IgM and IgG autoantibody-secreting B cells and that the interaction between the CD1high B cells and anti-CD1 T cells may play an important role in the pathogenesis of hereditary lupus in NZB/NZW mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 female mice were obtained from the Department of Comparative Medicine, Stanford University breeding facility. NZB/NZW female mice were purchased from The Jackson Laboratory (Bar Harbor, ME).
mAbs, immunofluorescent staining, flow cytometric analysis, and sorting
Single-cell suspensions of spleen cells or bone marrow cells
obtained from the femur and tibia were prepared and stained with mAbs
as described previously (19, 20, 21, 22). Stainings were performed
in the presence of anti-CD16/32 (2.4G2; PharMingen, San Diego, CA)
at saturation to block FcRII/III receptors, and propidium iodide
(Sigma, St. Louis, MO) was added to staining reagents to exclude dead
cells. Erythrocytes were excluded by light scatter gating. FACS
analysis and sorting were performed with a FACS Vantage (Becton
Dickinson, Mountain View, CA), and data were analyzed using FlowJo
software (Becton Dickinson) (21). The purity of sorted
cells was >98%. The following conjugated mAbs were used for staining:
FITC- and PE-anti-B220 (RA3-6B2), FITC-anti-IgM (R6-60.2),
PE-anti-CD1(1B1), biotinylated anti-CD1 (1B1), PE-streptavidin
purchased from PharMingen. Biotinylated anti-CD1 (3C11) was
purified and conjugated as described previously (18).
In vitro secretion of IgM and IgG
Sorted splenic T and/or B cells were incubated in 96-well flat-bottom plastic plates in complete RPMI 1640 medium with 10% FBS for 1–5 days at 37°C in 5% CO2. At the end of the culture period, supernatants were harvested and the concentrations of IgM and IgG were measured with the ELISA using affinity-purified goat anti-mouse heavy chain-specific Abs as described below.
ELISA of total IgM and IgG and anti-dsDNA IgM and IgG
Measurements of total IgM and IgG in culture supernatants or sera were performed using an ELISA with goat anti-mouse IgM plus IgG (H + L chain) Abs (Southern Biotechnology Associates, Birmingham, AL) to capture mouse IgM and IgG, and alkaline phosphatase-labeled affinity-purified goat Abs specific for mouse Ig isotypes (Southern Biotechnology Associates) for detection as described previously (18).
IgM and IgG anti-dsDNA Abs were captured using deproteinized calf thymus DNA as described previously (9), and ELISA was performed as described above. Anti-dsDNA titers are expressed as units per milliliter using a reference-positive standard of pooled serum from 6- to 7-mo-old NZB/NZW mice. A 1:100 dilution of this standard serum was arbitrarily assigned a value of 100 U/ml.
In vitro proliferative responses
Sorted splenic T cells (Thy1.2+B220-) were incubated (1 x 105 cells/well) together with graded numbers (1–25 x 103 cells/well) of irradiated (5000 rad) stimulator cells. The latter were either the A20 B cell line derived from BALB/c mice or CD1-transfacted A20 B cells obtained from Dr. M. Kronenberg (La Jolla Institute of Allergy and Immunology, La Jolla, CA) (23). Cells were cultured in 10% FCS complete RPMI 1640 medium in 96-well round-bottom plastic plates for 72 h at 37°C in 5% CO2. [3H]Thymidine (1 µCi/well) was added 24 h before cells were harvested. [3H]Thymidine (New England Nuclear, Boston, MA) incorporation was measured in a liquid scintillation counter (Betaplate; Wallac, Turku, Finland). All assays were performed in triplicate wells with responder or stimulator cells alone or together.
In vivo treatment of anti-CD1 and control mAbs
Anti-CD1 mAb (rat IgG2b) was purified from the hybridoma 1B1 (a
gift from Dr. M. Kronenberg) and anti-human lymphoma-Id mAb (rat
IgG1) was purified from hybridoma R9A9 (a gift from Dr. R. Levy,
Stanford University). Hybridoma supernatants were purified using
recombinant protein G-agarose columns (Life Technologies, Grand Island,
NY), and eluates were injected i.p. into NZB/NZW mice. Proteinuria was
measured on a 1–4+ scale using a colorimetric assay for albumin
(Albustix; Miles, Elkhart, IN). Mice were considered to have
proteinuria if at least two consecutive urine samples were 
2+ (100
mg/dl) (18). Serum levels of IgM and IgG and
anti-dsDNA were measured with the ELISA as described above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We compared the percentage of CD1high B
cells in the spleen of lupus-prone NZB/NZW and nonautoimmune C57BL/6
mice at 3 and 6 mo of age. As shown in Fig. 1
, A and B, the
spleen of C57BL/6 mice contained a subset of
CD1high B cells, which accounted for about 7% of
live nucleated spleen cells and about 20% of total spleen B cells, as
judged by staining for CD1 receptors (using 3C11 and 1B1 mAbs) vs B220
receptors. The C57BL/6 CD1high B cells were
almost all IgM+ cells when anti-IgM mAb was
used instead of anti-B220 mAb (Fig. 1C). The percentage of
CD1high B cells in the spleen of 6-mo-old NZB/NZW
mice with nephritis (proteinuria, 3+) was similar to that of the age-
and sex-matched C57BL/6 mice. Almost all NZB/NZW
CD1high B cells were IgM+
(Fig. 1, D–F). The percentages of
CD1high B cells in the spleen of C57BL/6 (Fig. 1, G–I) and NZB/NZW (Fig. 1, J–L) mice at 3 mo
were similar also.
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Splenic B cells from 6-mo-old NZB/NZW mice spontaneously secrete
large amounts of autoantibodies in vitro (4, 24). To
examine the role of CD1high B cells in secretion
of autoantibodies, B cells from 3- and 6-mo-old NZB/NZW mice without
proteinuria or 6-mo-old mice with proteinuria were studied. The highest
percentage of B220+ B cells in the spleen was
found in the 6-mo-old mice without proteinuria (data not shown). An
example of the studies of splenic B cells from a group of the latter
mice is shown in Fig. 2. Cells were
sorted into B220+CD1high,
B220+CD1int, and
B220+CD1low populations
using a nonactivating anti-CD1 mAb (1B1) (Fig. 2A). The
cells of each population were cultured (5 x
105 cells/well) in vitro with or without
syngeneic cocultured T cells (1.25 x 105)
for 5 days. Thereafter, the supernatants were assayed in duplicate for
the concentrations of total IgM and IgG and IgM and IgG anti-dsDNA
Abs. As shown in Fig. 2, B and C,
CD1high B cells produced large amounts IgM (about
14 µg/ml) and IgM anti-dsDNA Abs (about 30 U/ml) even without T
cells in coculture. This was five times higher than that secreted by
CD1int B cells (p < 0.001,
two-tail Student’s t test) and 25 times higher than that
secreted by CD1low B cells (p <
0.001, two-tail Student’s t test). Add-back of syngeneic T
cells significantly enhanced the IgM and IgM anti-dsDNA Ab
secretion by the CD1high B cells
(p < 0.01, two-tail Student’s t test). IgG
secretion (<100 ng/ml) by the three subsets of B cells was too low to
be compared. These results indicate that the IgM autoantibodies
spontaneously secreted by splenic B cells of 6-mo-old NZB/NZW mice
without proteinuria are predominantly derived from the
CD1high B cell population. Studies using 6-mo-old
NZB/NZW mice with proteinuria and 3-mo-old mice without proteinuria
also showed that the CD1low B cells secreted
little IgM autoantibody, and most was secreted by
CD1int and CD1high B cells
(data not shown). In addition, sorted C57BL/6
CD1high B cells secreted about 40 times less IgM
(mean ± SE, 0.3 ± 0.1 µg/ml) as compared with that
secreted by NZB/NZW CD1high B cells (mean ±
SE, 14 ± 0.5 µg/ml).
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F). We
tested whether both IgM and IgG autoantibodies were secreted by
IgM+ B cells as compared with all
B220+ B cells from these mice. As shown in Fig. 3, while sorted
B220+ cells produced large amounts (about 5.5
µg/ml) of both IgM and IgG, IgM+ cells produced
large amounts (about 5.2 µg/ml) of IgM, but <0.5 µg/ml of IgG.
Sorted residual B220+IgM-
cells were the source of IgG (data no shown). There were insufficient
CD1highIgM- spleen cells
to assay for spontaneous IgG secretion (Fig. 1F).
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To determine whether anti-CD1 T cells were present in the
spleen of 3-mo-old NZB/NZW mice, sorted splenic T
(Thy-1+) cells were obtained from the latter mice
and incubated with either the CD1-transfected A20 (A20/CD1) B cell line
derived from BALB/c mice or the nontransfected A20 B cell line. As
shown in Fig. 4, the sorted T cells
proliferated vigorously in response to stimulation by A20/CD1 cells,
but not to the A20 cells (Fig. 4C). A20 cells did not
express CD1, but A20/CD1 cells expressed high levels of CD1 (Fig. 4, A and B). T cells from the spleens of C57BL/6
mice were not tested in this proliferation assay, because A20 cells
(H-2d) and C57BL/6 (H-2b) T
cells are MHC mismatched, whereas NZB/NZW
(H-2d/z) T cells are not stimulated to
proliferate by the shared H-2d MHC of the
BALB/c-derived cell line. In addition, the proliferation of the NZB/NZW
T cells to A20/CD1 cells was about 2-fold higher than that of BALB/c
(H-2d) T cells (data not shown).
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Since anti-CD1 T cells were found in the spleen of NZB/NZW
mice and CD1high B cells secreted IgM
autoantibodies, it was possible that the T cells stimulated the
secretion of IgM autoantibodies via CD1. Thereafter, the stimulated B
cells could switch the autoantibody isotype from IgM to IgG associated
with the development of disease. To interfere with B cell signaling via
CD1 in a preliminary study, groups of 8-wk-old NZB/NZW mice were
injected i.p. five times over a 30-day period with 250 µg/mouse rat
IgG anti-CD1 (1B1) mAb or control irrelevant rat IgG mAb (days 0,
3, 5, 15, and 30). Thereafter, the mice were monitored for levels of
serum IgG and IgG anti-dsDNA, proteinuria, and survival (Fig. 5). The anti-CD1 mAb was rat IgG2b, a
complement-binding isotype, and the control mAb was rat IgG1, a
noncomplement-binding isotype (25, 26). The control
isotype was unlikely to worsen renal disease by the deposition of
aggregate-complement complexes in the glomeruli.
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, A and B).
At the age of 24 wk, the mean serum IgG level (about 3000 µg/ml) of
mice given anti-CD1 mAbs was three times lower than that (9000
µg/ml) of the mice given control rat IgG (p < 0.01,
two-tail Student’s t test). The mean serum IgG
anti-dsDNA Ab level at the same time point (about 1000 U/ml) was
eight times lower than that (8000 U/ml) of mice given control rat IgG
(p < 0.01, two-tail Student’s t test).
More than 4 wk later, the differences in the mean levels of serum IgG
and IgG anti-dsDNA Abs of the two groups were reduced, but still
remained significantly different (p < 0.05, two-tail
Student’s t test). The serum levels of IgM and IgM
anti-dsDNA Ab of the two groups increased during the observation
period; however, the mean levels were not significantly different at
all time points (p > 0.4, data not shown). Bleeding
for serum samples was not done after 28 wk of age due to the increasing
morbidity and mortality after that time point, especially in the
control group. The brief course of anti-CD1 mAb treatment also
delayed the onset of proteinuria and prolonged the survival of the mice
by 4–8 wk (Fig. 5, C and D). The differences in
the onset of proteinuria (p < 0.05, log rank test) and
in survival (p < 0.01, log rank test) were both
significant. Thus, anti-CD1 mAb treatment delayed disease
progression by at least the duration (4 wk) of the treatment period in
this small preliminary study. To determine whether administration of anti-CD1 mAb depleted CD1high B cells, a single injection of 250 µg/mouse was given to three mice, and 1 wk later, the spleen cells were assayed for the expression of CD1 on B cells. As reported previously (27), the staining pattern of CD1 vs B220 receptors and the absolute number of CD1high B cells was unchanged after the administration of the 1B1 mAb (data not shown). Thus, the anti-CD1 mAb neither down-regulated CD1 expression on B cells nor depleted CD1high B cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD1high B cells in the spleen of nonautoimmune C57BL/6 mice are predominantly CD21high marginal zone B cells (15, 16, 17), and they spontaneously secreted little IgM in vitro. Although the CD1high B cells in the spleen of C57BL/6 mice had little contribution from CD5+ B (B-1) cells (15), our recent studies indicate that splenic NZB/NZW CD1high B cells between ages 3 and 6 mo have a markedly increased contribution from CD5+ B (B-1) cells, and these CD1highCD5+ B cells are responsible for the majority of spontaneous IgM secretion (J. Tung, N. Baumgarth, L. S. Herzenberg, and S. Strober, manuscript in preparation). This is consistent with our previous studies showing that CD5+ B cells in the spleen of NZB/NZW mice are the predominant source of spontaneous IgM secretion (24).
The presence of anti-CD1 T cells in the spleen of NZB/NZW mice was
shown by experiments in which T cells from the NZB/NZW spleen
proliferated vigorously to CD1-transfected A20 B cells, but not to the
parental nontransfected A20 B cells. Anti-CD1 mAb treatment was
administered in vivo to interfere with the interaction between
anti-CD1 T cells and CD1high B cells. The
administration of the anti-CD1 mAb markedly reduced the peak levels
of serum IgG and IgG anti-dsDNA Ab, but did not reduce the levels
of serum IgM and IgM anti-dsDNA Ab. These results suggest that IgM
anti-dsDNA Ab-secreting CD1high B cells may
be the precursors of IgG anti-dsDNA Ab-secreting B cells, and the
interaction of anti-CD1 T cells and the
CD1high B cells via CD1 may play an important
role in the isotype switch of anti-dsDNA Abs from IgM to IgG. This
notion is consistent with the report that Th1-like anti-CD1 TCR
transgenic T cells induced lupus with high levels of serum
anti-dsDNA IgG2a (18). It is of interest that
IL-4-producing NK T cells that express the invariant
V
14J281 TCR are
selectively reduced in NZB/NZW mice (28). Our recent
studies found that NK T cells in the bone marrow of NZB/NZW mice
produced large amounts of IFN- but small amounts of IL-4 as compared
with that of C57BL/6 mice (D. Zeng and S. Strober, manuscript in
preparation). This indicates that there may be an intrinsic cytokine
abnormality in anti-CD1 T cells in NZB/NZW mice that augments the
autoantibody isotype switch from IgM to IgG2a.
The mechanisms of in vivo anti-CD1 mAb amelioration of the development of lupus are not clear as yet. The administration of anti-CD1 mAb did not reduce the serum levels of IgM and IgM anti-dsDNA Ab, and did not deplete the CD1high B cells in the current study and in a previous report (27). It is most likely that the effect is due to blocking the interaction between anti-CD1 T cells and the CD1 ligand on CD1high B cells and possibly on CD1high macrophages and dendritic cells, thereby blocking the isotype switch of autoantibody from IgM to IgG. In conclusion, our results suggest that the interaction between anti-CD1 T cells and CD1high B cells may play an important role in the development of hereditary lupus in NZB/NZW mice.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Samuel Strober, Division of Immunology and Rheumatology, Stanford University School of Medicine, 300 Pasteur Drive, Room S105B, Stanford, CA 94305.
Received for publication January 20, 2000. Accepted for publication March 14, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14+ NK T cells associated with disease development in autoimmune-prone mice. J. Immunol. 156:4035.[Abstract]
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M. Batten, J. Groom, T. G. Cachero, F. Qian, P. Schneider, J. Tschopp, J. L. Browning, and F. Mackay Baff Mediates Survival of Peripheral Immature B Lymphocytes J. Exp. Med., November 20, 2000; 192(10): 1453 - 1466. [Abstract] [Full Text] [PDF]
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P. A. Sieling, S. A. Porcelli, B. T. Duong, F. Spada, B. R. Bloom, B. Diamond, and B. H. Hahn Human Double-Negative T Cells in Systemic Lupus Erythematosus Provide Help for IgG and Are Restricted by CD1c J. Immunol., November 1, 2000; 165(9): 5338 - 5344. [Abstract] [Full Text] [PDF]
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