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* Departments of Pathology and Pediatrics, Center for Blood Research,
Department of Microbiology and Molecular Genetics, Harvard Medical School, and
Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Ab responses in the spleen play an essential role in host defense against encapsulated bacteria (2). Accordingly, patients with anatomic or functional asplenia are highly susceptible to infections with these organisms (3, 4). Protection against neonatal type III GBS infections is associated with the presence of Abs specific for the type III GBS capsular polysaccharide (III-PS). Pure polysaccharides are characterized as thymus-independent type 2 (TI-2) Ags. These Ags can induce a primary immune response without the help of T cells, but the presence of T cell factors enhances the IgG response.
Despite the clinical significance of bacterial polysaccharides, the
mechanisms underlying immune responses to polysaccharide Ags have not
yet been fully elucidated. It has been suggested that the cells within
the splenic marginal zone (MZ) play an important role in responses to
TI-2 Ags. The MZ is a specialized compartment containing a
subpopulation of B lymphocytes, i.e., MZ B cells, dendritic cells, and
MZ macrophages (5). One hypothesis implicates MZ B cells
in the induction of humoral responses to TI-2 Ags. MZ B cells are
distinguished from follicular B cells by cell surface phenotype (e.g.,
IgMhigh, CD21high,
IgDlow, CD23low). Lane et
al. (6) reported that the immune response of recovering
x-irradiated mice to TI-2 Ags correlated with the reappearance of B
cells in the MZ. Furthermore, responsiveness to polysaccharide Ag
develops in children at 
2 years of age—a timing that coincides with
the maturation of MZ B cells (7, 8). A recent study with
Pyk-2-deficient mice lacking MZ B cells showed a reduction in IgM and
IgG responses to trinitrophenyl (TNP)-Ficoll (a model TI-2 Ag)
as well as abrogated Ag localization to MZ B cells. However, studies of
CD19-deficient mice, which also have reduced numbers of MZ B cells,
have revealed normal-if not elevated-responses to haptenated Ficoll
(9, 10). An alternative hypothesis is that MZ macrophages
are essential in early uptake of TI-2 Ags. Macrophages within the MZ
take-up and retain carbohydrate macromolecules such as Ficoll
(11). However, the importance of macrophage uptake remains
unclear because in vivo elimination of MZ macrophages appears not to
alter the response to TNP-Ficoll (12).
Binding of Ficoll by MZ B cells in naive wild-type (WT) mice has been shown to be dependent on C3 and on CD21/CD35 (complement receptors (CR) 1 and 2; CR1/CR2) (13), whereas uptake by MZ macrophages takes place independent of C3 (3). Despite this differential complement dependence for Ag uptake by MZ cells, a role for complement in the humoral response to TI-2 Ags remains controversial. Early studies by Pepys (14) showed that complement depletion with cobra venom factor (CVF) had no effect on the primary response to polyvinylpyrrolidone 360. Studies by Markham et al. (15) demonstrated that complement depletion with CVF abrogated the Ab response to pneumococcal type 14 polysaccharide but did not affect the response to the sialic acid-containing III-PS. In contrast, studies by Pryjma and Humphrey (16) identified a reduced immune response to pneumococcal type 3 polysaccharide in CVF-treated mice. Moreover, Griffioen et al. (17) documented enhanced Ab responses to pneumococcal polysaccharide upon conjugation to C3d. Humans deficient in complement exhibit increased susceptibility to infections by encapsulated bacteria, possibly because of impaired humoral immunity and lack of effector function (18).
Much of our knowledge about humoral immunity to TI-2 Ags comes from studies conducted with nonphysiological Ags. To investigate the role of complement in humoral immunity to a clinically relevant polysaccharide, we immunized mice deficient in C3 or CD21/CD35 with purified III-PS. These mice had impaired IgM and IgG responses to III-PS; the impairment was characterized by a negligible uptake of Ag by follicular dendritic cells (FDCs) and MZ B cells. These observations suggest that humoral responses to a clinically relevant TI-2 Ag-containing sialic acid depend on complement-tagged Ag trapping and processing by MZ B cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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WT, C3-deficient (C3null), and
CD21/CD35-deficient (Cr2null) mice were
maintained on a C57BL6/129Sv mixed background. T cell-deficient (CD3
transgenic (tg)) tg mice and WT controls were maintained on a C3H
background. All mice were used at 6–10 wk of age. Mice were housed in
a specific pathogen-free barrier animal facility at Harvard Medical
School (Boston, MA).
Preparation of III-PS and conjugates
Type III GBS strain M781 was the source of the purified polysaccharide. III-PS was conjugated to human serum albumin (HSA; Sigma-Aldrich, St. Louis, MO) and to biotin hydralazine (Pierce, Rockford, IL) by reductive amination (19). The conjugated polysaccharide retained the specificity of the pure polysaccharide, as shown by ELISA inhibition.
Immunization protocol
On day 0, mice were injected i.p. with 8 µg of III-PS in saline or with saline only. Mice were bled 3 days before and 11 days after immunization. Levels of type III-specific IgM and IgG were quantified by ELISA. To assess III-PS localization in spleens, mice were injected i.v. with 50 µg of biotinylated III-PS at different time points before harvest (15 min, 30 min, 1 h, 2 h, or 16 h). Harvested spleens were either snap-frozen for cryosectioning or mechanically dissociated in preparation for FACS analysis and/or ELISPOT).
Reconstitution with III-PS-specific IgG and IgM
Sera from naive mice and from mice immunized i.p. with three 2-µg doses of III-PS covalently linked to tetanus toxoid (III-PS-TT absorbed to 0.5 mg AlOH2) were separated into IgG- and IgM-containing fractions over a protein G column using an Immunopure (G) IgG Purification kit (Pierce) per instructions from the manufacturer. The fractions were desalted over a PD10 column (Amersham Pharmacia Biotech, Piscataway, NJ) and calibrated with PBS (pH 7.4). The fractions from immunized mice contained 5.9 and 4.3 µg/ml of III-PS-specific IgG and IgM, respectively; those fractions from naive mice contained 0.005 and 0.023 µg/ml, respectively. WT and C3null mice received an i.v. injection of IgG or IgM (200 µl each) from immunized and naive mice 2 h before injection of biotinylated III-PS.
ELISA for III-PS-specific Ab
Levels of III-PS-specific Abs were quantitated by ELISA, as described previously (20). The limits of IgM and IgG Ab detection were 20 and 5 ng/ml, respectively.
ELISPOT assay for III-PS-specific Ab-secreting cells (ASCs)
The frequency of ASCs in spleens was determined by ELISPOT assay. In brief, 24-well plates (Falcon, San Diego, CA) were coated overnight with III-PS conjugated to HSA (III-HSA; 5 µg/ml). Wells were blocked with 1% BSA in PBS, splenocytes diluted in DMEM (Life Technologies, Grand Island, NY) were added (5 x 106, 1 x 106, or 0.5 x 106 cells per well), and preparations were incubated for 12–18 h at 37°C. Plates were washed in 0.1% BSA, then coated for 4 h at room temperature with goat anti-mouse IgM or IgG conjugated to alkaline phosphatase (Sigma-Aldrich). Plates were developed with X-phosphate/5-bromo-4-chloro-indolyl-phosphate (BCIP; Boehringer Mannheim, Indianapolis, IN) in 2-amino-2-methyl-1-propanol (AMP; Sigma-Aldrich) agarose solution. Spots were counted with a Leica microscope (Deerfield, IL).
Immunofluorescence analysis of splenic sections
For immunofluorescence analysis, 7-mm cryosections of spleen were cut, fixed, and stained as described previously (21). At least 10 sections per spleen were analyzed. Biotinylated Ag was detected with fluorescence-labeled streptavidin (streptavidin-Cy-Chrome, BD PharMingen (San Diego, CA); or streptavidin-Alexa 568 Fluor, Molecular Probes (Eugene, OR). The following Abs were used for staining: rat anti-mouse FDC-M1, anti-mouse IgM-Cy5 (clone 341.12), peanut lectin agglutinin (PNA)-FITC (EY Laboratories, San Mateo, CA), anti-mouse CD3-PE (BD PharMingen), anti-mouse IgD-FITC (Southern Biotechnology Associates, Birmingham, AL), anti-mouse IgM-PE (BD PharMingen), and anti-human C3d-FITC (DAKO, Carpinteria, CA). Pictures were taken with a Bio-Rad MRC confocal microscope (Hercules, CA) using Bio-Rad Radiance 2000 software.
FACS analysis
Single-cell suspensions of splenocytes were stained with rat anti-mouse Abs CD11b-PE, CD24-PE, and CD23-FITC (BD PharMingen). III-PS biotin was detected with streptavidin-allophycocyanin (Molecular Probes). Cells were analyzed with a FACSCalibur (BD Biosciences, Mountain View, CA) flow cytometer.
Statistical analysis
Statistical analysis was performed with Prism software,
version 2.0b (GraphPad Software, San Diego, CA). The Student
t test for unequal variances was used to compare means, and
the 
2 test was used to compare frequencies for different
experimental groups. A two-tailed p value of <0.05 was
considered significant.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To analyze the role of complement in primary Ab responses to
III-PS, we immunized WT, C3null, and
Cr2null mice i.p. with 8 µg of III-PS and
collected serum samples at multiple time points after immunization.
III-PS-specific Ig were quantified by ELISA (Fig. 1
, a and b). Before
day 11 no significant IgM response was observed in either
complement-deficient or WT mice (data not shown). However, the day 11
IgM response of immune WT mice to the polysaccharide Ag was
significantly greater than that of saline-injected WT mice (6493
± 2418 ng/ml vs 190 ± 25 ng/ml; p < 0.05). By
contrast, the primary IgM response was impaired in the deficient mice.
Notably, IgM Ab levels in deficient mice were in a range similar to
that measured in saline-injected WT mice (311 ± 43 ng/ml for
C3null mice and 80 ± 18 ng/ml for
Cr2null mice; Fig. 1a). The IgG
isotype switch observed in immunized WT mice (366 ± 173 ng/ml)
did not occur in immunized C3null mice (4 ±
0.3 ng/ml), immunized Cr2null mice (5 ± 3
ng/ml), or saline-injected WT mice (6 ± 1 ng/ml)
(p < 0.01 for all groups; Fig. 1b).
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c). Consistent with the low Ab
levels, only negligible numbers of IgM ASCs were observed in
C3null, Cr2null, and
saline-injected WT mice as opposed to immunized WT mice; specific
values (per 5 x 106) were 56 ± 22 for
immunized WT mice, 5 ± 1 for immunized
C3null mice, 7 ± 3 for immunized
Cr2null mice, and 4 ± 0.5 for
saline-injected WT mice (p < 0.01 for all
groups). Negligible numbers of IgG ASCs were observed in all four
groups (data not shown). Germinal center (GC) response and complement-mediated retention of III-PS within GCs
Humoral responses are dependent on histologically defined areas
within splenic follicles called GCs. Although GC formation is usually
described in immune responses to thymus-dependent Ags, recent studies
have demonstrated that GCs can also develop in response to TI Ags such
as dextran B512 (22, 23). To investigate GC formation in
response to III-PS, we harvested spleens and prepared splenic sections
on day 13 after primary immunization. Although the number of splenic
follicles did not differ among the four groups, the number of GCs
(PNA+ clusters) was significantly lower in
immunized Cr2-deficient mice and saline-injected WT mice than in
immunized WT mice (Table I). Notably,
PNA-positive GCs were observed in C3-deficient mice despite an impaired
Ab response and an absence of specific Ag staining in the follicles.
The GCs probably represent an ongoing response to environmental
Ags.
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and Table I). Immunofluorescence
analysis of splenic sections revealed a high percentage of
III-PS-positive GCs in immunized WT mice (47% ± 10%). In contrast, a
negligible number of splenic follicles stained positive for the
capsular polysaccharide in immunized deficient mice and saline-injected
WT mice. As expected, III-PS colocalized with M1+
FDCs within GCs of immunized WT mice (Fig. 2, a and
b). However, no III-PS was detected in GCs of immunized
deficient mice or in saline-injected WT controls (Fig. 2, c–h, and Table I) despite the presence of a network of FDCs
in each group. Localization of III-PS to GCs does not in itself define
specificity of GC B cells, it does, however, provide a relative measure
of the humoral response to the specific Ag.
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tg mice, which are deficient in T and NK
cells, with III-PS (24). CD3 tg mice had normal IgM
responses; mean anti-III-PS IgM levels ± SEM were 1000
± 300 ng/ml for WT mice and 1500 ± 400 ng/ml for CD3 tg mice.
In contrast, anti-III-PS IgG levels were negligible in CD3 tg
mice (9 ± 0.5 ng/ml vs 263 ± 84 ng/ml for WT mice;
p < 0.01). The absence of GCs in T and NK
cell-deficient mice was consistent with an impaired IgG response
(13 ± 2 and 0.4 ± 0.3 GCs for WT and CD3 tg mice,
respectively; p < 0.01). III-PS deposition was not
observed in the splenic follicles of CD3 tg mice, whereas WT mice
had detectable III-PS in 27.8% ± 5.4% of GCs. Therefore, the
presence of T cells enhances IgG production and the GC response, even
though III-PS is considered a TI Ag. We cannot rule out a role for NK
cells in response to III-PS, as they can modulate TI-2 responses
(25). In contrast, the IgM response to III-PS appears to
be T- and NK-cell independent. Localization and deposition of III-PS in the MZ
The splenic MZ is an important site in defense against
encapsulated bacteria. Detection and uptake of particulate Ags are
enhanced by the macrophages lining the MZ sinuses (12).
Moreover, the MZ region includes B cells that bear specific receptors
for bacterial Ags, including bacterium-specific carbohydrate Ags
(26). To investigate which cell types in the MZ of the
spleen are responsible for the uptake of III-PS and to determine
whether clearance is complement-dependent, we injected biotinylated
III-PS i.v. into immune and nonimmune mice of each group and harvested
the spleens at various time points. Ag uptake in the MZ was assessed by
confocal microscopy and FACS analysis. Analysis of splenic sections
from nonimmune mice identified III-PS staining within the MZ of all
three groups (Fig. 3, a,
d, and g). Ag deposition colocalized with
CD11b+ cells in naive mice, a result suggesting
uptake by macrophages (data not shown). In immune WT mice, III-PS
localized to MZ B cells and FDCs within GCs (Fig. 3b). A
significant finding was the lack of Ag staining in splenic sections
from immunized C3- and Cr2-deficient mice (Fig. 3, e and
h). These results suggest that Ag uptake by MZ B cells is
dependent on C3 and CD21/CD35 in immune mice, whereas uptake of III-PS
by macrophages in naive mice is complement-independent.
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, c,
f, and i). As predicted, C3 protein and III-PS
colocalized to FDCs within GCs and MZ B cells in immune WT mice (Fig. 3c). By comparison, low levels of C3 staining were evident
in the sinuses and blood vessels in spleens from Cr2-deficient mice,
but no C3 was detectable within the splenic follicles (Fig. 3i). No C3 protein or III-PS was found in spleens of
C3-deficient mice (Fig. 3f).
To further examine colocalization of III-PS and C3 protein on MZ B
cells, we prepared suspensions of splenic cells from immunized WT and
deficient mice and subjected these cells to FACS analysis (Fig. 3j and Table II). MZ B cells
were identified as positive for B220 and CD24 (heat-stable Ag) and
negative for CD23. No reduction in the number of MZ B cells was
apparent in C3- and Cr2-deficient mice (data not shown). Analysis of MZ
B cells harvested at various time points indicated increasing uptake of
Ag over the 120-min period after i.v. Ag injection (Fig. 3j
and Table II). The frequency of III-PS-positive MZ B cells was
significantly greater in WT mice than in deficient mice at each time
point examined. Numbers of III-PS-positive MZ B cells were negligible
in saline-injected WT mice (data not shown).
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). However, a background level of C3-positive MZ
B cells was observed in saline-injected WT controls. This result
suggests that complexes of C3 protein and Ags (probably environmental
Ags) are taken up constitutively by MZ B cells. C3 detection was judged
to be specific because negligible numbers of C3-positive cells were
observed in C3-deficient mice. Uptake of III-PS and C3 is essentially
Cr2-dependent, although some C3 and III-PS binding took place in the
absence of Cr2. Expression of other complement receptors (e.g.,
crry/p65) that bind C3b (27) or residual CD21/CD35
(28) may explain the low levels of C3 on
Cr2null MZ B cells. The results of splenic cell
analysis by confocal microscopy and FACS strongly suggest that III-PS
decorated with activated complement products efficiently localizes to
FDCs and MZ B cells by binding through CD21/CD35 complement
receptors.
An alternative explanation for the lack of III-PS uptake by MZ B cells
in C3- and Cr2-deficient mice is the failure of both strains to produce
significant levels of III-PS-specific Abs (Fig. 1). To determine
whether Ab alone or both Ab and complement are required for
opsonization of III-PS, naive WT and C3null mice
were given an i.v. injection of 1.2 µg of IgG or 1 µg of IgM
anti-III-PS Abs before receiving an injection of biotinylated
III-PS. The levels of III-PS-specific Abs detected in sera at the time
of harvest were similar in WT and C3null mice
(data not shown). FACS analysis performed on splenic cells from the two
strains revealed uptake of III-PS by MZ B cells from WT mice (4.2 and
4.9% for III-PS-specific IgG and IgM, respectively) but not by those
from C3null mice (0.7 and 0.8%, respectively)
2 h after i.v. Ag injection (Fig. 4). Therefore, uptake of III-PS by MZ B
cells requires both specific Abs and C3. Uptake of III-PS by MZ B cells
from WT and C3null mice that were given IgG and
IgM fractions from naive sera was <1% (data not shown). Notably, the
level of uptake in naive WT mice reconstituted with III-PS specific Abs
was lower than that in immunized WT mice (4.2 (IgG naive mice) and
4.9% (IgM naive mice) vs 18.4% (III-PS immunized)). One possible
explanation for the differences could be the reduced levels of
circulating III-PS-specific Abs in reconstituted WT mice.
Alternatively, actively immunized mice developed an ongoing response,
whereas passively immunized mice received only one dose of
III-PS-specific Abs. Another explanation is the possible clonal
expansion of III-PS-specific B cells in the MZ of immune mice. Evidence
of clonal expansion of MZ B cells in humans was recently reported
(29).
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In a recent report, Guinamard et al. (13) observed that the humoral response to TNP-Ficoll was dependent on an intact MZ compartment and the presence of C3 and Cr2. Injection of naive mice with TNP-Ficoll Ag resulted in rapid uptake by MZ B cells in WT mice, but only negligible uptake by MZ B cells in mice deficient in C3 or CD21/CD35. In contrast, we found that III-PS is preferentially taken up by MZ macrophages in naive mice. The mechanism of uptake is unclear but does not depend on complement, as no differences in Ag binding were observed among WT, C3null, and Cr2null mice after i.v. injection of III-PS. One possible explanation for the difference in the handling of the two Ags is that Ficoll, which is not a bacterial Ag, may directly activate complement, leading to covalent attachment of C3b and deposition on MZ B cells. Importantly, III-PS includes a terminal sialic group that can inhibit complement activation and, therefore, III-PS may be bound by carbohydrate recognition receptors (e.g., mannose receptors) expressed constitutively by MZ macrophages (30).
In a previous study, Markham et al. (15) reported that transient depletion of C3 by CVF had no significant effect on the day 5 IgM response to III-PS in CFA injected s.c. Moreover, they reported that 5 days following immunization, specific IgM synthesis was not dependent on an intact spleen and that no III-PS specific splenic ASCs were identified. One explanation for the apparent differences between this earlier study and our current results is that depletion of circulating C3 with CVF is not likely to affect local production of C3 by myeloid cells within the lymphoid compartment. Recent studies have demonstrated that local C3 synthesis by myeloid cells within the spleen and peripheral lymph nodes is sufficient to enhance the humoral response to protein Ags irrespective of the C3 levels in the blood (31, 32).
One model that could account for our current observations is that
phagocytic cells within the splenic MZ and other secondary lymphoid
tissues bind Ag via carbohydrate recognition, such as mannose receptor
or mannan binding protein, and transport it into the B cell follicles,
as proposed by Martinez-Pomares et al. (33).
Alternatively, myeloid dendritic cells bind III-PS and "present"
the Ag to B cells within the MZ, leading to plasmablast formation and
specific IgM release (34, 35, 36). In this scenario, the
presence of specific Ab overcomes the inhibitory effect of sialic acid
and activates classical pathway complement, resulting in C3 attachment
and more efficient uptake by MZ B cells. The high frequency with which
MZ B cells bind C3-coated complexes of III-PS in WT immune mice
suggests an efficient process of Ag localization to the MZ compartment.
MZ B cells express higher levels of CD21 than follicular B cells and
might be expected to preferentially bind C3d-III-PS complexes. Because
we find a high frequency of Ag-C3d-positive B cells, it is unlikely
that only III-PS-specific B cells bind C3d complexes (Fig. 3j). However, efficient localization to this compartment
would enhance specific interaction with cognate B cells and recent
studies have reported clonal expansion of Ag-activated MZ B cells
(29). An alternative mechanism for complement enhancement
in the current model is that C3d-coated III-PS coligates the
CD21/CD19/CD81 coreceptor and B cell receptor on MZ B cells, thereby
lowering the threshold for activation of B cells in a manner similar to
previous observations using protein Ags (37). Recent work
by Cariappa et al. (38) suggests that
Cr2null mice have increased numbers of MZ B
cells. The results reported herein demonstrate similar MZ B cell
numbers in all experimental groups. Although the generation and
localization of MZ B cells appear to be independent of CD21/CD35, MZ B
cells lacking CD21/CD35 clearly cannot capture complement-coated
III-PS.
In conclusion, the data presented in this study show that TI responses to III-PS are complement-dependent. They further suggest that complement-tagged III-PS is trapped via CD21/CD35 on MZ B cells, which, in turn, transport the Ag to FDCs within GCs. The proximity of MZ B cells to marginal sinuses and the high-level expression of CD21/CD35 by these cells appear to emphasize the importance of their function as sentinel cells for recognizing systemic bacterial infections.
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Acknowledgments |
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Footnotes |
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2 O.P. and H.-K.G. contributed equally.
3 Address correspondence and reprint requests to Dr. Dennis L. Kasper, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail address: dennis_kasper{at}hms.harvard.edu
4 Abbreviations used in this paper: GBS, group B Streptococcus; III-PS, type III GBS capsular polysaccharide; TI-2, thymus-independent type 2; MZ, marginal zone; TNP, trinitrophenyl; WT, wild type; CR, complement receptor; CVF, cobra venom factor; FDC, follicular dendritic cell; tg, transgenic; HSA, human serum albumin; ASC, Ab-secreting cell; GC, germinal center; PNA, peanut lectin agglutinin.
Received for publication May 24, 2002. Accepted for publication October 23, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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(1->6)dextran. Proc. Natl. Acad. Sci. USA 91:2502.This article has been cited by other articles:
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