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,§
*
Division of Rheumatology, Department of Medicine, and
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
Department of Pathology, University of Chicago, Chicago, IL 60637; and
§
Veteran’s Administration Medical Center, St. Louis, MO 63106
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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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We and others have generated Cr2 gene-targeted mice deficient in the expression of mouse CR1 and CR2 (14, 15). These mice demonstrate an impairment in the Ag-specific IgG response to T cell-dependent Ags. Nevertheless, in the absence of CR1 and CR2, several features of the B cell response remain intact. Although Ag-specific IgM and IgG titers are decreased as compared with controls, they are still detected and they increased following secondary immunization. In addition, Cr2-/- mice show a dose-dependent increase in Ag-specific IgG following i.v. immunization with different amounts of SRBC and (4-hydroxy-3-nitrophenyl)acetyl conjugated to keyhole limpet hemocyanin (NP-KLH). Moreover, germinal centers are present, although their small size and their decreased number indicate abnormalities in their development.
It is not clear from the above observations whether the decrease in the size and number of the Cr2-/- germinal centers is just the result of the activation and subsequent migration of a lower number of Ag-specific B cells into these specialized follicular structures and that, once within germinal centers, these B cells mature normally. Alternatively, there could be additional abnormalities in the maturation of germinal center B cells associated with the CR1 and CR2 deficiency. For these reasons, we investigated whether the abnormality in germinal center development is associated with functional defects related to the germinal center reaction such as the establishment of affinity maturation and the generation of memory B cells. We immunized the Cr2-/- animals with different Ags in the presence or absence of adjuvants. We showed that, when immunized with noninflammatory Ags (Ags used in the absence of adjuvants), besides a decrease in the amount of Ab production found in the Cr2-/- mice, there is also a substantial defect in affinity maturation and memory B cell generation. In the presence of adjuvants, germinal center development is still compromised, as shown by their decrease in size and number. Surprisingly, inflammatory Ags (Ags used in the presence of adjuvants) completely restore affinity maturation, partially restore the amount of Ag-specific Ab produced during primary immunization, and improve the generation of memory B cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The (129Sv x C57BL/6) Cr2-/- mice were generated using standard gene-targeting techniques, as previously described (14). In some experiments, Cr2-/- mice-bred 10 generations into the C57BL/6 background were also used. They were maintained under specific pathogen-free conditions.
Immunohistochemistry
Spleens and mesenteric lymph nodes were removed at different times postimmunization and frozen quickly in OCT compound (Miles, Elkhart, IN). Sections (8 µm thick) were cut and fixed in acetone. Endogenous peroxidase was quenched with 0.2% H2O2 in methanol. For germinal center staining, a 1/100 dilution of peanut agglutinin (PNA) conjugated to biotin (Vector, Burlingame, CA), followed by alkaline phosphatase (AP) conjugated to streptavidin (Zymed, San Francisco, CA) was used. The spleen sections stained with PNA were then counterstained with a 1/100 dilution of rat anti-mouse IgD (Southern Biotechnology Associates, Birmingham, AL) polyclonal antiserum, followed by a 1/10 dilution of rabbit anti-rat IgG conjugated with HRP (Southern Biotechnology). Bound AP and HRP were detected with AP reaction (Vector) and diaminobenzidine.
The germinal center number was calculated by counting the PNA-positive germinal centers seen under x40 magnification. Three animals per group were used. Four different discontinuous spleen sections were analyzed from each animal so that the average amount of germinal centers in twelve different slides was determined for each experimental group.
For immune complex (IC) staining, 200 µl of HRP/rabbit anti-HRP (HRP/rabbit anti-HRP) (Dako, Carpenteria, CA) IC was injected i.v. into C57BL/6 Cr2+/+ or Cr2-/- mice, and 24 h later, spleens were collected and stained for rabbit Ig. Spleens were collected from naive animals, or from mice immunized 5 days before IC injection with either 50 µg of NP-KLH in PBS, or 50 µg of NP-KLH precipitated in alum.
Immunization of mice
NP conjugated to either KLH or human serum albumin (HSA) was used (Biosearch Technologies, Novato, CA). Mice were immunized i.p. with 100 µl of PBS containing 50 µg NP14-KLH alone, with CFA, or precipitated in alum, at day 0, and were then boosted at day 60. Alternatively, mice were immunized with 50 µg NP15-HSA precipitated in alum together with 109 killed Bordetella pertussis organisms (Michigan Department of Health). Serum was obtained before and at the indicated intervals after the first immunization. For germinal center staining, mice were immunized with NP-KLH, as above, and 10 days postimmunization, the spleens were collected for further analysis.
ELISA
Serum anti-NP levels were measured by coating Immulon 4 plates (Dynatech Laboratories, Chantilly, VA) with 5 µg/ml of NP-conjugated BSA (Biosearch Technologies) in PBS. The detecting Ab was 100 µl of a 0.2 µg/ml AP-conjugated goat anti-mouse IgM or AP-conjugated goat anti-mouse IgG Ab (Southern Biotechnology) added for 1 h, followed by AP substrate p-nitrophenyl phosphate (Sigma, St. Louis, MO) at 1 mg/ml. The mean OD at 405 nm from triplicate wells was compared with a standard curve of titrated immune serum to calculate the relative units (RU) (11, 14). Affinity maturation was calculated by measuring the Ag-specific Ab RU using ELISA plates coated with either NP13-BSA (13 molecules of NP per molecule of BSA) or NP3-BSA (3 molecules of NP per molecule of BSA) (16). The NP13-BSA ELISA detects low and high affinity Abs, and the NP3-BSA ELISA detects high affinity Abs. The ratio of the RU detected with the NP3-BSA ELISA vs the RU detected with the NP13-BSA ELISA provides an estimate of the average affinity of the Ab response.
Somatic hypermutation studies
C57BL/6 Cr2-/- or Cr2+/+ mice were immunized with 50 µg of NP-KLH in the presence of CFA at day 0, followed by the same antigenic dose in the presence of IFA at days 30 and 40. Ten days after the last immunization, total spleen RNA was extracted using RNAgents (Promega, Madison, WI). RT-PCR for amplification of the VH186.2 gene and subsequent sequencing was performed as described previously (16, 17, 18).
FACS analysis
Cy-Chrome-conjugated anti-mouse B220 and FITC-conjugated anti-mouse GL7 were obtained from PharMingen (San Diego, CA). For FACS analysis, single cell suspensions were prepared from spleen. Ab (1 µg) was added to 1 x 106 cells for 60 min in 100 µl of PBS/1% BSA at 4°C. Flow cytometry was performed on a FACScan (Becton Dickinson, San Jose, CA). The percentage of B220+, GL-7+ B cells was calculated to estimate the prevalence of germinal center B cells (16).
Adoptive transfer of B cells
Cr2+/+ or Cr2-/- mice were immunized i.p. with 50 µg of NP-KLH precipitated in alum. After 60 days, splenocytes were recovered and transferred i.v. to naive (sv129 x C57BL/6) wild-type (WT) mice that were sublethally irradiated (550 rad) the day before. These mice were then immunized with 50 µg of NP-KLH in PBS i.p., and the serum was collected 10 days after immunization for analysis of the anti-NP IgG titers.
Statistical analysis
Values are expressed as mean ± SEM. Levels of statistical significance were determined using the Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The observations detailed above raised the question of whether the
abnormalities in the Cr2-/- germinal
center development were also associated with defects in affinity
maturation and memory B cell generation. To evaluate the extent of
affinity maturation, mice were challenged i.p. with NP-KLH in PBS, and
the Ag-specific IgG titer was measured as a function of time. The level
of anti-NP Ab and the relative affinity for NP were determined
using different NP-BSA substrates (16). As expected,
Cr2-/- mice immunized with NP-KLH in PBS
had a 6-fold decrease in the levels of total anti-NP IgG titers
(Fig. 1
A)
(Cr2+/+ 626 ± 127 RU;
Cr2-/- 110 ± 29 RU by day 30,
p < 0.005) and high affinity anti-NP IgG titers
(Fig. 1B) (Cr2+/+ 306 ± 113 RU,
Cr2-/- 40 ± 12 RU by day 30,
p < 0.05), as compared with controls at the peak of
the response. Secondary immune responses were also markedly compromised
(Fig. 1C) (Cr2+/+ 28,726 ±
2,651 RU; Cr2-/- 471 ± 160 RU,
p < 0.005). In addition, although there was affinity
maturation in the Cr2-/- mice, the degree
of affinity maturation was substantially lower as compared with the WT
littermates (Fig. 1D; for all values p <
0.05).
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C3 has been shown to act as a natural adjuvant in the generation
of humoral immune responses (19). The ligand for CR2, the
C3d,g fragment, enhances the Ab response to hen egg lysozyme
severalfold when C3d,g is covalently attached to the Ag. Furthermore,
other models of murine immunodeficiencies generated by gene targeting
can be compensated by using Ags precipitated in alum (20).
Based on these observations, we explored the possibility that the use
of adjuvants could rescue the abnormal immune response in the
Cr2-/- mice.
Cr2-/- mice were immunized i.p. with 50
µg of NP-KLH precipitated in alum, and their immune response was
followed as a function of time. As shown in Fig. 2, the total Ag-specific IgG response
(Fig. 2A) (Cr2+/+ 2180 ± 640
RU; Cr2-/- 980 ± 200 RU by day 20,
p = 0.1465) and the high affinity Ag-specific IgG
response (Fig. 2B) (Cr2+/+ 910
± 250 RU; Cr2-/- 390 ± 60 RU by day 20,
p = 0.0625) were almost comparable with the WT mice
with only about a 2-fold decrease in the average Ab titer as compared
with the control mice. This 2-fold decrease in the average Ab titer was
not statistically significant. Secondary immune responses paralleled
this difference (Fig. 2C) (p =
0.28). Similar results were obtained using NP-KLH and NP-HSA
precipitated in alum in the presence of B. pertussis (data
not shown). Moreover, affinity maturation was similar in the
Cr2+/+ and
Cr2-/- mice (Fig. 2D). This
effect was independent on the mouse strain or the type of adjuvant
used. There was a decrease, but not statistically significant
difference between the immune response in the
Cr2-/- mice on a C57BL/6 background
immunized with NP-KLH precipitated in alum in the presence of B.
pertussis and the immune response of
Cr2+/+ mice
(Cr2+/+ 181 ± 10 RU,
Cr2-/- 169 ± 8 RU, p =
0.5383 for total Ab titers; Cr2+/+ 127 ±
40 RU, Cr2-/- 117 ± 37 RU,
p = 0.8991 for high Ab titers) (Fig. 3, A and B). There
was also a decrease, but not statistically significant difference
between the immune response in the Cr2-/-
mice on a C57BL/6 background immunized with CFA, and the immune
response of Cr2+/+ mice
(Cr2+/+ 133 ± 18 RU,
Cr2-/- 98 ± 30 RU, p =
0.1798 for total Ab titers; Cr2+/+ 78 ± 23
RU, Cr2-/- 42 ± 1 RU, p
= 0.1792 for high Ab titers) (Fig. 3, D and E).
Moreover, affinity maturation was restored (Fig. 3, C and
F). Thus, the use of inflammatory Ags markedly offsets the
reduction in Ab production and largely compensates for the decrease in
affinity maturation seen in the Cr2-/-
animals immunized in the absence of adjuvants.
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Initial B cell responses during a T cell-dependent humoral immune response occur at the margins of the T cell zone (21). Later, some Ag-primed B cells migrate to the follicles, forming groups of rapidly dividing cells known as germinal centers (22, 23). Germinal centers are the principal sites for the generation and selection of high affinity Ag-specific B cells.
In the Cr2-/- mice, germinal centers are
still generated, but they are strikingly different from those found in
the WT animals. When immunized in the absence of adjuvants, the
Cr2-/- mice have reduced numbers of
germinal centers and their size is markedly decreased (Fig. 4, A and B; see
Refs. 11, 14). To determine the effect of adjuvants on
germinal center formation in the Cr2-/-
mice, we immunized these mice with NP-KLH precipitated in alum and
subsequently examined their spleens and mesenteric lymph nodes for
germinal center development. PNA staining of tissue sections revealed
that both the number and size of germinal centers are markedly reduced
as compared with their WT counterparts (Fig. 4C–F) (Table I). This observation is further supported
by analyzing the frequency of B220+,
GL-7+ B cells using flow cytometry. Confirming
the histologic determinations, germinal center B cells increased from
background levels of 0.69% in naive animals to 6.21% in normal
animals 10 days after immunization, but only to 2.86% in the
Cr2-/- mice (Fig. 5). Similar results were obtained by
immunizing with NP-KLH and NP-HSA precipitated in alum in the presence
of B. pertussis, or C57BL/6
Cr2-/- mice immunized with NP-KLH
precipitated in alum, or in the presence of CFA (data not shown). In
addition, this defect in germinal center formation persists throughout
the course of the primary immune response (Table I), and is not
corrected even after multiple immunizations (data not shown). Thus,
although optimal affinity maturation is restored by the use of
adjuvants, germinal center development is still abnormal.
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Ag-induced somatic hypermutation in the DNA coding for the Ig V
regions in Ag-stimulated B cells is the main mechanism by which optimal
affinity maturation is achieved. It has been previously shown that, in
the C57BL/6 mouse strain, the immune response against NP is dominated
by Abs encoded by the heavy chain V region gene
VH186.2 in association with the 
1
light chain (16, 17, 18). Well-characterized specific somatic
hypermutations are induced in the
VH186.2 gene during the NP-specific
immune response that increases the affinity of the B cell receptor for
NP. To determine whether this mechanism was responsible for the
increased affinity maturation in the
Cr2-/- mice, we analyzed the
characteristics of the Ag-induced mutations in the
Cr2-/- C57BL/6 mice as compared with WT
littermate controls.
We immunized the Cr2+/+ C57BL/6 and
Cr2-/- C57BL/6 with NP-KLH in the
presence of adjuvants. In both groups of mice, we saw mutations that
showed a preference for transitions rather than transversions and a
tendency of mutations at AGC/T sequences (Fig. 6). These results are consistent with
those previously reported (16, 17, 18). Furthermore, change of
Trp to Leu at codon 33 in the first complementarity-determining region
(CDR) was observed in 8 of 15 independent clones derived from WT mice
and in 12 of 15 independent clones derived from
Cr2-/- mice. This particular mutation has
been shown to result in the acquisition of high affinity for NP.
Mutation frequency was comparable between WT mice (6.1 per clone) and
Cr2-/- mice (6.2 per clone). If somatic
mutation occurred randomly, the expected R/S ratio (ratio of
replacement (R) to silent (S) mutations) in the CDR would be 4.9,
and that ratio in the framework regions would be 2.6, as previously
described (16, 17, 18). Elevated ratio of R/S in the CDRs, but
not in the framework regions, suggested Ag-driven somatic mutation. The
R/S ratio in the framework region was comparable with the expected (WT
R/S ratio is 2.8, Cr2-/- R/S ratio is 2).
In contrast, the ratio in the CDRs was much higher than expected in
both WT (R/S ratio of 10.8) and Cr2-/-
(R/S ratio of 6.7) mice (Table II). These
experimental results suggest that Ag-driven somatic hypermutation
occurs in Cr2-/- mice, despite the
abnormalities in germinal center development observed in these
animals.
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The effects of adjuvants during an immune response are multiple,
and it will be extremely complex to determine what specific
adjuvant-induced event is responsible for the normalization of the IgG
response and the complete restoration of affinity maturation.
Nevertheless, because one of the functions of the CR1 and CR2 is to
retain Ag within the FDC network, we investigated the possibility
that adjuvants could be promoting changes within the FDC that improve
their ability to mediate Fc
-receptor Ag trapping
(24).
To study this possibility, we injected rabbit IC i.v. into
Cr2+/+ or
Cr2-/- C57BL/6 mice, and 24 h later
determined the presence of these Ag-Ab complexes in the spleen of these
animals. In WT nonimmunized animals, IC are retained within FDC (Fig. 7A). This has previously been
shown to be mainly CR dependent (11, 24). In contrast,
minimal splenic IC trapping is noted in nonimmunized
Cr2-/- mice, with the majority of
follicles lacking IC retention (Fig. 7B). This small
quantity of IC trapping in the Cr2-/-
animals is Fc dependent because it can be blocked by anti-Fc
Abs (data not shown, 24). These data support previous
experimental observations by us and others, suggesting that, previous
to immunization and during the early stages of the primary immune
response, the main mechanism of Ag retention within the follicles is
through CR1 and CR2. Surprisingly, IC trapping in WT mice is increased
if, 5 days before IC injection, the mice are immunized with either
NP-KLH alone, or NP-KLH precipitated in alum (Fig. 7, C and
E, respectively). Interestingly, no increase in
Fc-mediated IC trapping is noted in
Cr2-/- animals immunized with either
NP-KLH alone (Fig. 7D), or NP-KLH precipitated in alum (Fig. 7F), as compared with nonimmunized
Cr2-/- mice. No increase is also noted in
Cr2-/- animals 10 days after immunization
when germinal centers are present (data not shown). These observations
suggest a direct effect of immunization, independent on the use of
adjuvants, in CR-mediated follicular Ag localization in WT mice. In
addition, it implies that neither immunization nor the use of adjuvants
promotes changes within the FDC of Cr2-/-
mice that improve their ability to mediate Fc-receptor Ag
trapping.
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Germinal centers are important for the development of memory B
cells. In the absence of adjuvants, secondary immune responses in the
Cr2-/- mice are substantially
affected (Fig. 1
C). Similar results have been reported
previously (11, 14). This observation, combined with the
compromised affinity maturation and the abnormal morphological
appearance of germinal centers, demonstrated a defect in memory B cell
generation. The rescue of the IgG primary and secondary response and
the complete recovery of affinity maturation by adjuvants raised the
question of whether memory B cell generation was accordingly
reconstituted in the Cr2-/- mice. To
further examine this issue, we performed adoptive transfer experiments
in which 60 days postimmunization with NP-KLH in alum,
Cr2-/- or
Cr2+/+ B cells were transferred i.v. into
naive WT irradiated mice (25). The recipient mice were
then reimmunized with NP-KLH in PBS, and the Ag-specific IgG titers
were examined. Irradiated mice that either did not receive any B cells,
or received only naive B cells, exhibited no response after antigenic
challenge (data not shown). By contrast, mice that received
postimmunized Cr2+/+ or
Cr2-/- B cells both exhibited a very
strong immune response (Cr2+/+ 330 ± 113
RU, Cr2-/- 124 ± 37 RU,
p = 0.2354). Although the Ag-specific Ab titer is
slightly lower in the Cr2-/- mice, this
difference is not statistically significant. Thus, these data indicate
that memory B cell generation in the
Cr2-/- mice is present when adjuvants
are used.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B), and the strong Ab response after
adoptive transfer of primed B cells. This is of particular significance
because it shows that, in the presence of adjuvants, CR1- and
CR2-dependent Ag trapping within follicles is not necessary for memory
B cell generation. Interestingly, even in the presence of adjuvants,
germinal centers are still diminished in size and number (Figs. 4 and 5; Table I). Fischer et al. (26) have shown that this abnormality in Cr2-/- germinal center development is related to problems in B cell entry, retention, and survival within these specialized follicular structures. Using a hen egg lysozyme-specific B cell transgenic model, these investigators demonstrated that, when stimulated with the corresponding Ag in the absence of adjuvants, the ability of Cr2-/- hen egg lysozyme-specific transgenic B cells to populate and survive within germinal centers was reduced as compared with Cr2+/+ controls. Several reasons explain this failure of Cr2-/- B cells in migrating to the follicle and forming germinal centers. The lack of CR2 on B lymphocytes may reduce the number of activated B cells due to absence of CD19/CR2/CD81-related costimulatory signals (27). Once within germinal centers, the same CD19/CR2/CD81 costimulatory signals that may promote B cell retention and maturation could be compromised. In addition, lack of CR1- and CR2-mediated Ag retention by FDC may compromise signals needed for increased B cell proliferation, decreased threshold for cytokines, and protection from premature apoptosis (28, 29, 30).
Interestingly, even in the absence of adjuvants, some degree of affinity maturation is still detected in the Cr2-/- mice. One explanation is that reduced levels of affinity maturation may occur even in the absence of germinal centers. It has previously been shown that limited affinity maturation can occur in Ab-forming cells that accumulate in the bone marrow of WT mice by a process previously described as post-germinal center intraclonal competition (16). This limited affinity maturation can develop in the absence of germinal centers, and can be explained by Ag-driven clonal competition and selection between these bone marrow Ab-forming cells.
In contrast to the limited affinity maturation described above, optimal affinity maturation occurs within germinal centers and is the result of somatic hypermutations in the Ag-binding area of the B cell receptor, followed by selection of high affinity clones (31). Surprisingly, optimal affinity maturation is restored in the Cr2-/- mice by the use of adjuvants without substantial improvement in the size and number of germinal centers. Ag-specific IgG responses and production of memory B cells are also partially compensated by using inflammatory Ags. This observation clearly indicates that these processes may operate independently of germinal center development. In addition, these results suggest that the decreased entry and retention of B cells within germinal centers are not the only determinant affecting optimal affinity maturation and memory B cell generation (26).
Because affinity maturation and memory B cell generation can occur independently of normal germinal center development, what is the role of these specialized structures in the humoral immune response? The answer to this question is probably related to the nature of Ag stimulation. In the presence of weak Ags, the formation of a strong germinal center reaction can accelerate the generation of high affinity Abs by providing an environment that optimizes B cell maturation. As shown in this work, some of the mechanisms that improve this B cell maturation process are dependent on the expression of CR1 and CR2 (28, 29, 30). In this respect, these CRs play a particularly important role in optimizing the effect of weak Ags. A strong antigenic challenge can clearly compensate for the absence of normal germinal center development (17, 32). This is particularly the case when multiple immunizations are done, specially with high doses of Ag, or when adjuvants are used.
In this context, it is interesting to consider the role of adjuvants in
the Cr2-/- immune response
(33). Adjuvant could increase the recruitment and
activation of inflammatory cells to areas in which activated B
lymphocytes are located. These cells could secrete cytokines that lower
the threshold for B cell activation or aid in their maturation process.
These inflammatory cells could enhance T cell activation and T cell
help by serving as APCs. Adjuvants could also concentrate and prolong
Ag retention in areas in which B cell activation is occurring, and thus
substitute for the lack of CR1- and CR2-mediated Ag trapping within
FDC. In addition, adjuvants could promote changes within the FDC that
improve their ability to interact with B cells. However, we have shown
in this work that increased Fc-mediated trapping is not a mechanism
by which we could explain the role of adjuvants in the restoration of
the affinity maturation and the normalization of the immune response in
the Cr2-/- mice.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hector Molina, Washington University School of Medicine, Rheumatology-Box 8045, 660 South Euclid Avenue, St. Louis, MO 63110.
3 Abbreviations used in this paper: C3, third component of complement; AP, alkaline phosphatase; CDR, complementarity-determining region; CR, complement receptor; FDC, follicular dendritic cell; HSA, human serum albumin; IC, immune complex; KLH, keyhole limpet hemocyanin; NP, (4-hydroxy-3-nitrophenyl)acetyl; PNA, peanut agglutinin; R/S, replacement/silent; RU, relative unit; WT, wild-type.
Received for publication December 16, 1999. Accepted for publication June 21, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-deficient mice. Nature 382:462.[Medline]
(LT) supports development of splenic follicular structure that is required for IgG responses. J. Exp. Med. 185:2111.II-mediated immune-complex trapping. Immunology 80:34.[Medline]
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R. R. Reid, S. Woodcock, A. Shimabukuro-Vornhagen, W. G. Austen Jr., L. Kobzik, M. Zhang, H. B. Hechtman, F. D. Moore Jr., and M. C. Carroll Functional Activity of Natural Antibody is Altered in Cr2-Deficient Mice J. Immunol., November 15, 2002; 169(10): 5433 - 5440. [Abstract] [Full Text] [PDF]
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R. A. Barrington, O. Pozdnyakova, M. R. Zafari, C. D. Benjamin, and M. C. Carroll B Lymphocyte Memory: Role of Stromal Cell Complement and Fc{gamma}RIIB Receptors J. Exp. Med., November 4, 2002; 196(9): 1189 - 1200. [Abstract] [Full Text] [PDF]
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K. J. Marchbank, L. Kulik, M. G. Gipson, B. P. Morgan, and V. M. Holers Expression of Human Complement Receptor Type 2 (CD21) in Mice During Early B Cell Development Results in a Reduction in Mature B Cells and Hypogammaglobulinemia J. Immunol., October 1, 2002; 169(7): 3526 - 3535. [Abstract] [Full Text] [PDF]
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S. D. Fleming, T. Shea-Donohue, J. M. Guthridge, L. Kulik, T. J. Waldschmidt, M. G. Gipson, G. C. Tsokos, and V. M. Holers Mice Deficient in Complement Receptors 1 and 2 Lack a Tissue Injury-Inducing Subset of the Natural Antibody Repertoire J. Immunol., August 15, 2002; 169(4): 2126 - 2133. [Abstract] [Full Text] [PDF]
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X. Wu, N. Jiang, C. Deppong, J. Singh, G. Dolecki, D. Mao, L. Morel, and H. D. Molina A Role for the Cr2 Gene in Modifying Autoantibody Production in Systemic Lupus Erythematosus J. Immunol., August 1, 2002; 169(3): 1587 - 1592. [Abstract] [Full Text] [PDF]
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J. M. Guthridge, K. Young, M. G. Gipson, M.-R. Sarrias, G. Szakonyi, X. S. Chen, A. Malaspina, E. Donoghue, J. A. James, J. D. Lambris, et al. Epitope Mapping Using the X-Ray Crystallographic Structure of Complement Receptor Type 2 (CR2)/CD21: Identification of a Highly Inhibitory Monoclonal Antibody That Directly Recognizes the CR2-C3d Interface J. Immunol., November 15, 2001; 167(10): 5758 - 5766. [Abstract] [Full Text] [PDF]
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M. Hasegawa, M. Fujimoto, J. C. Poe, D. A. Steeber, and T. F. Tedder CD19 Can Regulate B Lymphocyte Signal Transduction Independent of Complement Activation J. Immunol., September 15, 2001; 167(6): 3190 - 3200. [Abstract] [Full Text] [PDF]
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