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*
Department of Pathology, Center for Blood Research and
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
Massachusetts Institute of Technology, Cambridge, MA 02139; and
§
Department of Immunology, Duke University Medical Center, Durham, NC 27710
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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is critical for resolution of acute septic peritonitis,
questions remain as to how mast cells are activated upon peritoneal
bacterial infection. Clues to how this may occur have been derived from
earlier studies by Prodeus et al. in which complement proteins C3 and
C4 were shown to be required for survival following cecal ligation and
puncture (CLP), a model for acute septic peritonitis. To evaluate the
mechanism for mast cell activation in the CLP model, complement
receptor CD21/CD35-deficient mice (Cr2null) were examined
in the present study. Along with CD19-deficient (CD19null)
mice, these animals exhibit decreased survival following CLP compared
with wild-type littermates. Injection of IgM before CLP does not change
survival rates for Cr2null mice and only partially improves
survival of CD19null mice, implicating CD21/CD35 and CD19
in mast cell activation. Interestingly, early TNF- release is also
impaired in Cr2null and CD19null animals,
suggesting that these molecules directly affect mast cell activation.
Cr2null and CD19null mice demonstrate an
impairment in neutrophil recruitment and a corresponding increase in
bacterial load. Examination of peritoneal mast cells by flow cytometry
and confocal microscopy reveals the expression and colocalization of
CD21/CD35 and CD19. Taken together, these findings suggest that the
engagement of complement receptors CD21/CD35 along with CD19 on the
mast cell surface by C3 fragments may be necessary for the full
expression of mast cell activation in the CLP
model. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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from mast cells is essential for the recruitment of neutrophils
and clearance of bacteria from the peritoneal cavity. Thus, mast cells
are not only involved in IgE- and IgG-driven anaphylaxis but also in
innate immune responses (3, 4). However, the mechanism(s)
that result in PMCs activation in this context remain(s) elusive.
A major pathway for mast cell activation is mediated by Fc receptors.
In the case of Fc
RI, ligation of the multichain receptor is
accomplished by cross-linking bound IgE with multivalent allergens,
resulting in the release of mediators such as histamine, proteases, and
cytokines from PMCs (reviewed in Ref. 5). Fc
RI and
FcRIII share the receptor subunit with the FcRI and thus also
share some of the same downstream signaling components. These receptors
may be triggered by immune complexes to induce mast cell degranulation
(6). In particular, FcRIII on mast cells has been shown
to be a critical participant in the immune complex-based disease state
called the Arthus reaction (7, 8).
In the absence of preexisting immunity, resolution of acute septic
peritonitis has been shown to require natural IgM and the complement
system (9). Specifically, compared with wild-type (WT)
littermates, C3null and
C4null mice exhibit lower survival rates
following CLP that correlate with a significant decrease in the level
of TNF- in peritoneal lavage fluid (3). Boes et al.
(9) have demonstrated that natural IgM is required for
survival following CLP by reconstituting secreted IgM-deficient mice
with IgM purified from WT mice. Because IgM is a potent activator of
complement, it may function to bind enteric bacteria and subsequently
activate the classical complement cascade, thus opsonizing the
bacterial surface with C3d fragments that, in turn, activate complement
receptor-bearing cells.
These findings raise the question of how complement mediates activation of PMCs. Mast cells have the capacity to bind directly to the FimH minor subunit of type 1 fimbriae present on enteric bacteria such as Escherichia coli (1). This interaction may contribute to CLP-induced mast cell activation, because neutrophil influx was found to be impaired upon infection with E. coli bearing a recombinant plasmid encoding FimH- Klebsiella pneumoniae fimbrae (1). Although a direct interaction between resident peritoneal bacteria and PMCs is likely important, the results described with the C3null and C4null mice demonstrate that additional molecules are involved.
The observation that the enhancement of TNF- levels in the
peritoneal cavity after CLP is impaired in the absence of complement
proteins C3 or C4 suggests either an indirect or a direct role for
these molecules in mast cell activation. The production of C3a and C5a
anaphylatoxins could account for PMC degranulation via C3a and C5a
receptors. Alternatively, complement receptors CD11b/CD18 (CR3) may
also play a role in complement-mediated PMC activation
(10). Two well-characterized receptors that bind
byproducts of C3 activation, as well as C4b, are CD35 and its
alternatively spliced variant CD21. CD21/CD35 are expressed on
follicular dendritic cells, neutrophils, monocytes, and B lymphocytes.
CD35 also functions as an immune adherence receptor on human RBC and it
is important in clearance of immune complexes from the circulation
(11). Although its function is not clearly delineated on
phagocytic cells, CD35 appears to be involved in binding and
internalization of Ag (12, 13). On B lymphocytes, CD21
forms a coreceptor with CD19 and TAPA-1. Together, these form a
coreceptor complex which, when cross-linked with the B cell receptor
via complement-bound Ag, lowers the threshold of activation for the B
lymphocyte 10- to 100-fold (14). Furthermore,
co-cross-linking induces the expression of activation markers such as
B7-1 and B7-2 on murine splenic B cells (15), and is
critical for B cell responses in vivo (16, 17). Given the
importance of coreceptor signaling in B lymphocyte responses (14, 18, 19, 20), it was therefore postulated that both CD21/CD35 and
CD19 might also play a role in PMC activation.
To determine whether CD21/CD35 receptors are involved in PMC
activation, and whether they form a signaling receptor complex along
with CD19, CD21/CD35-deficient (Cr2null) and
CD19-deficient (CD19null) mice were evaluated in
the CLP model. Both groups of deficient animals were highly sensitive
to peritoneal infection, as survival levels at 48 h were 13.3 and
7.4% for Cr2null and
CD19null mice, respectively, compared with 50.9%
survival for WT littermate controls. TNF- release and neutrophil
recruitment were similarly impaired in Cr2null
and CD19null mice, and these receptors were
detected on WT PMCs. The expression of CD21/CD35 and CD19 on peritoneal
mast cells may therefore represent a novel link between the complement
system and mast cell activation in innate immune responses to bacterial
infections.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice deficient in CD21/CD35 (Cr2null) were constructed as described using the approach of homologous recombination in embryonic stem cells (21). Mice deficient in CD19 (CD19null) with a genetic background of 129Sv/C57BL/6 were prepared as described previously (22). WT controls were matched for age, gender, and MHC and had a genetic background 129Sv/C57BL/6 similar to that of the Cr2null and CD19null mice. All animals were maintained in a specific pathogen-free facility. Mice were monitored frequently for signs of morbidity or mortality. Studies were performed according to the National Institutes of Health and institutional guidelines for animal use and care.
Cecal ligation and puncture
CLP was performed on 6- to 8-wk-old male mice as described previously (23, 24). Briefly, after inducing an appropriate level of anesthesia with avertin (0.015 ml of a 2.5% solution per g body weight), a 0.5-cm midline incision was made in the peritoneum and the distal two-thirds of the cecum was ligated and punctured once with an 18.5-gauge syringe needle. The incision was closed with wound clips, and the mice were resuscitated with 1 ml of sterile saline injected s.c.
IgM purification and reconstitution
Polyclonal IgM was isolated from normal mouse serum (Sigma, St. Louis, MO) as described elsewhere (9). Briefly, sera was precipitated with ammonium sulfate, dialyzed, filtered through a 0.45-µm filter, and applied to a 5-ml protein G-Sepharose column (Sigma) to remove IgG. The flow-through was applied to an anti-IgM-Sepharose column (Zymed Laboratories, South San Francisco, CA). Bound IgM was eluted with 0.1 M glycine/0.15 M NaCl (pH 2.5), and neutralized with 1 M Tris (pH 8.0). Purity and concentration were verified by reducing and nonreducing SDS-PAGE. Gels were developed using Coomassie blue staining and Western blotting with anti-IgM HRP-conjugated Abs. Purified samples were compared with a monoclonal IgM standard (Sigma). In reconstitution experiments, mice were given 0.4 mg i.v. of polyclonal IgM in 0.2 ml PBS 4 h before CLP.
Peritoneal lavage and cytospin staining
Mice were sacrificed by CO2 inhalation. The abdominal skin was then washed with 70% ethanol, the peritoneum was exposed by a midline abdominal incision, and 3.0 ml of sterile, pyrogen-free HBSS (Sigma) was injected into the peritoneal cavity via a 25-gauge needle. Cells in the lavage fluid were then cytospun onto glass slides and stained with Giemsa stain (25). Slides were examined under a light microscope at x400 magnification to quantify the neutrophils and mast cells.
TNF- assays
TNF- levels in peritoneal lavage fluids (about 2 ml recovered
from each mouse) were measured by an ELISA kit (Endogen, Woburn, MA)
according to the manufacturer’s specifications.
Quantitation of neutrophils by flow cytometry
Although TNF- measurements and CFU quantitation were
performed on peritoneal lavage fluid collected at 1 h, neutrophil
numbers were enumerated at 3 h post-CLP as their numbers were
greatly increased, thus facilitating comparison between genotypes.
Lavage fluid was analyzed for number of neutrophils by using
biotinylated Abs to the granulocyte cell surface marker Gr-1
(PharMingen, San Diego, CA), and FITC-labeled Abs specific for mouse
neutrophils (Caltag, Burlingame, CA). Dead cells staining for propidium
iodide (Sigma) were excluded from the analysis.
CFU assay
Serial dilutions of peritoneal lavage fluid were cultured overnight on MacConkey agar (Becton Dickinson, Cockeysville, MD) at 37°C, and the number of Gram-negative CFUs was counted.
Flow cytometric analysis of peritoneal mast cells
Peritoneal lavage cells from untreated WT, Cr2null, and CD19null mice were stained with anti-c-Kit-PE, anti-CD19-biotin (clone 1D3), and anti-CD21/CD35-FITC (clone 7G6) (all from PharMingen) in HBSS + 2% FBS (Sigma) for 30 min. Cells were then washed three times in HBSS/FBS followed by staining with streptavidin-CyChrome (CyC; PharMingen) for 15 min. Cells were washed two additional times in HBSS/FBS and analyzed by flow cytometry. Double stains of anti-c-Kit and either anti-CD19 or 7G6 were also performed in conjunction with propidium iodide staining as a viability indicator with similar results. Cells were kept at 4°C throughout the procedure. c-Kit-positive cells were gated to analyze the coexpression of CD21/CD35 and CD19 on peritoneal mast cells.
FACS sorting of peritoneal mast cells and confocal microscopy
Peritoneal exudate cells were stained as above, and c-Kit-positive cells were gated and collected by flow cytometric sorting. Collected cells were placed in a 5-mm petri dish and analyzed by confocal microscopy. Percentage of colocalized anti-CD19 and anti-CD21/CD35 was calculated using a ratio of number of white aggregates (colocalized stain) in the numerator with the denominator being total number of white aggregates plus green aggregates (7G6 stain) or total number of white and purple (anti-CD19) aggregates. This analysis was done over a sampling of 50 different c-Kit-positive mast cells.
Statistical analysis
Statistical analyses of most data were performed using Student’s t test with two tails and assuming unequal variances, where indicated. Statistical analysis for survival was performed using the Mantel-Cox rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The observation that the complement system was required for
protection in the CLP model suggested that complement receptors
CD21/CD35 might be involved in mast cell activation (3).
Because CD21 forms a signaling coreceptor with CD19 on B lymphocytes
(14), it was speculated that it might have a similar role
in peritoneal mast cell activation. Both CD19null
and Cr2null mice were therefore treated using the
CLP procedure, and survival was monitored over a 48-h period. The
survival for WT littermates in response to this treatment (74.1% at
24 h, 48.1% at 48 h, n = 27), was
significantly higher than that observed for the
Cr2null (33.3% at 24 h, 13.3% at 48
h, n = 30, p = 0.0012) and
CD19null mice (51.9% at 24 h, 7.4% at
48 h, n = 27, p = 0.0042) (Fig. 1
A). These results demonstrate
that mice that lack expression of CD21/CD35 and CD19 exhibit impaired
survival following CLP.
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B, i.v. injection of IgM
restores survival of RAG1null mice to nearly WT
levels (40.9% survival for IgM-injected RAG1null
mice vs 48.1% survival for WT mice at 48 h, p =
0.62 vs WT). However, survival levels of Cr2null
mice injected with IgM remain significantly below that of WT
littermates (8.3% survival for IgM-injected
Cr2null mice, p = 0.018 vs WT).
Injection of IgM into CD19null mice results in
some recovery of CLP-responsiveness, but not to the level observed for
IgM-injected RAG1null animals (23.5% survival
for IgM-injected CD19null mice, p
= 0.11 vs WT). Therefore, the absence of recovery upon injection of IgM
observed for Cr2null mice and the partial
recovery for CD19null mice suggests that
CD21/CD35 or CD19-deficient mice exhibit impaired survival after CLP
because of defects in complement activation of effector cells, not
because of reduced number of B-1 cells.
TNF- levels in peritoneal lavage of Cr2null and
CD19null mice are decreased compared with WT controls
Previous studies demonstrated that increases in peritoneal TNF-
levels are critical for neutrophil recruitment and bacterial clearance
following CLP (1, 2, 23). Mast cells are an important
source for numerous cytokines, including TNF-. Upon mast cell
activation, TNF- gene segments are readily transcribed; however,
preformed TNF- protein can also be released by mast cell
degranulation (28). As shown in Fig. 2A, a 58% reduction
(p = 0.002) in TNF- levels was observed for
Cr2null mice and a 22% reduction
(p = 0.08) for CD19null
mice compared with WT controls 1 h following CLP. Therefore,
deficiency in CD21/CD35 and CD19 correlates with a reduction in TNF-
levels in peritoneal lavage fluid. Furthermore, because activated mast
cells secrete preformed TNF- in response to CLP (2),
the observed decrease in TNF- levels for knockout mice suggests that
CD21/CD35 and CD19 are involved in mast cell activation.
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Previous studies have demonstrated the importance of influx of
neutrophils in bacterial clearance and host protection in the CLP model
(23). To determine whether the frequency of neutrophils
was reduced in the treated deficient mice, peritoneal lavage was
examined by both flow cytometry (Fig. 2B) and in cytospin
preparations (Fig. 2C) at 3 h post-CLP. These two
independent measures were found to closely agree with one another.
Compared with WT mice, significant reductions are observed for the
percentage of neutrophils in the peritoneal cavity of
CD19null (p = 0.003) and
Cr2null (p = 0.019) mice
3 h following CLP as assessed by flow cytometry (Fig. 2B). For direct examination of cells, peritoneal exudate
cells were concentrated by cytocentrifuge of peritoneal lavage taken at
1 and 3 h post-CLP, and cells were fixed and stained. Comparison
of cytospins prepared from the three groups of mice identified a
relative reduction in neutrophils at both time points in the deficient
animals (Fig. 2C). Mast cells were identified as well and
some are shown in the process of degranulation (see arrows in
upper left panel in Fig. 2C labeled WT,
1 h).
Given the defect in neutrophil influx in Cr2null
and CD19null mice, one would expect a
corresponding increase in number of bacterial CFUs. Serial dilutions of
peritoneal lavage fluid collected 1 h after CLP were plated on
MacConkey agar overnight at 37°C. Colonies were counted and average
colony numbers were 49- and 15-fold higher from the
CD19null and Cr2null
peritoneal lavages, respectively, compared with number of WT
lavage-derived CFUs (Fig. 2B). This indicates that there is
an impairment in bacterial clearance in the
Cr2null and CD19null mice
that is likely responsible for the observed enhanced mortality.
Interestingly, reconstitution of CD19null mice
with IgM before CLP treatment did not lead to a reduction in CFUs
compared with vehicle-injected CD19null mice
(data not shown).
Expression of CD21/CD35 and CD19 on peritoneal mast cells by flow cytometry
The observation that both Cr2null and
CD19null mice exhibit defects in neutrophil
recruitment and bacterial clearance corresponding to a decrease in
peritoneal TNF- levels following CLP suggests a role for the
receptors in mast cell activation. This hypothesis prompted an
examination of whether peritoneal mast cells express CD21/CD35 and/or
CD19 on their surface. Peritoneal lavage cells from untreated WT,
Cr2null, and CD19null mice
were analyzed by flow cytometry for expression of the coreceptor. The
analysis revealed significant levels of both CD19 (Fig. 3A) and CD21/CD35 (Fig. 3B) on the surface of c-Kit-positive PMCs. Mean fluorescence
intensities (MFI) of CD19 and CD21/CD35 staining are significantly
above levels determined for receptor-deficient animals (20-fold greater
MFI anti-CD19 Abs (Fig. 3C), p = 0.001,
and 2-fold greater MFI for the less intense staining 7G6-FITC Ab (Fig. 3D), p = 0.014). Flow cytometry experiments
were also performed using directly conjugated anti-CD19 Abs while
gating on propidium iodide-negative cells with similar results (data
not shown). Expression of CD21/CD35 and CD19 on PMCs is heterogeneous,
with some c-Kit-positive cells expressing low levels and a proportion
expressing high levels. These results demonstrate that CD21/CD35 and
CD19 are both expressed on the surface of murine peritoneal mast
cells.
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, E and F). Abs to Gr-1 were used
to identify granulocyte lineages, and anti-B220 Abs to identify
peritoneal B cells. Not surprisingly, B cells express very high levels
of CD19 and also express CD21/CD35. However, Gr-1-positive cells
express significantly less CD19 and CD21/CD35 compared with both
c-Kit-positive PMCs and B220-positive cells. Thus, the levels of CD19
and CD21/CD35 immunoreactivity on PMCs does not appear to represent
background fluorescence. Colocalization of CD21/CD35 and CD19 on the surface of c-Kit-positive peritoneal mast cells
On B lymphocytes, CD21/CD35 and CD19 form a coreceptor signaling
complex with CD19 serving as the primary signaling molecule and
CD21/CD35 binding to C3-bound Ag (14). To directly examine
colocalization of receptors on PMCs, peritoneal lavage preparations
from WT, Cr2null, and
CD19null untreated mice were stained as described
above, isolated by flow cytometric cell sorting, and analyzed by
confocal microscopy. As expected, all cells in the field of view
express c-Kit receptors as evidenced by PE staining (Fig. 4.). The punctate staining of the c-Kit
receptor in some samples may be a result of receptor aggregation during
the sorting procedure. Importantly, c-Kit staining, while abundant on
the cell surface, does not distinctly colocalize with these CD19 and
CD21/CD35 molecules on the surface. Significantly, CD19 and CD21/CD35
colocalize on WT peritoneal mast cells (see upper left panel
where staining is turquoise/white). Analysis of 50 separate cells
identifies 68.55 ± 3.06% of the visualized FITC (CD21/CD35) and
CyC (CD19) staining areas are colocalized (visualized as
turquoise/white). In contrast, only 14.4 ± 3.06% of the CyC
(CD19) fluorochrome is not colocalized with FITC (CD21), and 16.7
± 3.03% of FITC stain is not colocalized with CyC. Thus, CD21/CD35
and CD19 are both expressed by PMCs and the majority of the receptors
appear to colocalize on the cell surface.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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levels in peritoneal lavage, which occurs rapidly following CLP, is
impaired in both CD19null and
Cr2null animals compared with WT littermates.
PMCs are thought to represent a major source of early TNF- release
and secretion of this cytokine is crucial for adequate neutrophil
recruitment to the peritoneal cavity. Correspondingly,
Cr2null and CD19null mice
demonstrate a significantly decreased frequency of neutrophils among
peritoneal exudate cells harvested 3 h following CLP compared with
WT controls. Consistent with reduced TNF- and neutrophil influx was
the finding of increased numbers of enteric bacteria in lavage fluid of
the deficient mice.
A response to acute septic peritonitis induced by the CLP procedure
likely involves a multistep process with different cellular and
molecular components. Because IgM and early complement proteins are
required for protection (3, 9), it is proposed that, upon
release of bacteria, natural IgM binds to the bacterial cell surface
resulting in activation of the classical complement cascade. This
initiation phase is followed by an effector phase where, in addition to
complement lysis of bacteria, PMCs are activated to secrete mediators,
including TNF-, which function to recruit neutrophils to the site of
infection. The observation that injection of IgM into
CD19null mice before CLP improves survival
highlights the balance between the two phases of the CLP response. CD19
is likely involved in the mast cell response to CLP because restoration
of survival is not complete (Fig. 1B), and significant
numbers of colony forming enteric bacteria remain even upon injection
of IgM (data not shown).
Importantly, CD21/CD35 and CD19 expression is detected on PMCs by both
flow cytometry and confocal analysis, suggesting a direct role for
these receptors in triggering PMC activation. CD19 functions as a
coreceptor on B cells, which lowers the threshold of Ag required to
activate B cells 10- to 100- fold (14). Coligation of both
the B cell receptor and CD19 amplifies early signals such as tyrosine
phosphorylation and intracellular Ca2+ increases.
When tyrosine phosphorylated, CD19 provides a binding site for the
guanine nucleotide exchange factor Vav (29). The guanine
nucelotide excgange factor activity of Vav results in activation of the
small GTPases Ras, Rac, and Rho. Some of these GTPases are involved in
exocytosis and membrane ruffling, cellular processes that may be
important for mast cell degranulation (30, 31). It is
conceivable that expression of CD21/CD35 on mast cells is important for
innate immune responses and that inclusion of CD19 results in a more
potent signal. Given that PMCs respond very rapidly to peritoneal
bacteria by secreting mediators such as TNF-, putative signals
provided by CD19 may be of biological importance.
However, in B cells, the coreceptor complex acts in concert with the B cell receptor, and signals very little if at all on its own (29). In the context of acute septic peritonitis, CD21/CD35 and CD19 may therefore cooperate with another receptor(s) to induce rapid degranulation. There are several candidates for such a second receptor. For example, byproducts generated by complement cascade initiation such as the C5a anaphylatoxin may be responsible for contributing to mast cell activation in the CLP model. Indeed, mice deficient in C5a receptors are unable to clear intrapulmonary-instilled Pseudomonas aeruginosa infections (32), and C5a has been previously implicated in mast cell activation (33). However, Prodeus et al. (3) found that, whereas C5-deficient mice have reduced survival following CLP, neutrophil recruitment was unimpaired. The enhanced mortality observed in the C5null mice is therefore likely due to the absence of a functional membrane attack complex, rather than failed mast cell activation.
Interestingly, mice deficient in CD11b/CD18 (CR3 receptor) have increased mortality following CLP (10). However, the reduced numbers of mast cells in the peritoneal cavity of CR3null mice may account for the observed susceptibility to CLP. Recently, Malaviya et al. (34) have identified a receptor which binds to the FimH subunit on E. coli. This glycosylphosphatidylinositol-anchored receptor, CD48, is expressed on the surface of mast cells. One hypothesis is that innate immune recognition receptors such as CD48 efficiently trigger mast cell degranulation when combined with complement-mediated stimulation of a CD21/CD35/CD19 coreceptor. This would not only amplify responses to acute peritoneal infections, but would also impose a requirement of at least two separate signals to adequately trigger mast cells. This might be important for ensuring that the potent inflammatory effects of mast cells are only activated in appropriate contexts.
Taken together, these results demonstrate another link between the complement system and mast cell responses. These findings may be relevant for understanding how innate immunity enhances responses to acute infections. Future experiments will determine how CD21/CD35 and CD19 influence mast cell activation, perhaps in coordination with other receptors, in a variety of mast cell-mediated responses both in vivo and in vitro.
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Acknowledgments |
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Footnotes |
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2 J.L.G. and D.Y.O. contributed equally to this paper.
3 Current address: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
4 Address correspondence and reprint requests to Dr. Michael C. Carroll, Department of Pathology, Center for Blood Research, Harvard Medical School, Boston, MA 02115.
5 Abbreviations used in this paper: PMC, peritoneal mast cell; CLP, cecal ligation and puncture; WT, wild type; MFI, mean fluorescence intensity; CyC, CyChrome.
Received for publication August 3, 2000. Accepted for publication September 11, 2000.
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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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J. A. Boyce, E. A. Mellor, B. Perkins, Y.-C. Lim, and F. W. Luscinskas Human mast cell progenitors use alpha 4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions Blood, April 15, 2002; 99(8): 2890 - 2896. [Abstract] [Full Text] [PDF]
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Y. Kaburagi, M. Hasegawa, T. Nagaoka, Y. Shimada, Y. Hamaguchi, K. Komura, E. Saito, K. Yanaba, K. Takehara, T. Kadono, et al. The Cutaneous Reverse Arthus Reaction Requires Intercellular Adhesion Molecule 1 and L-Selectin Expression J. Immunol., March 15, 2002; 168(6): 2970 - 2978. [Abstract] [Full Text] [PDF]
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 I. Celik, C. Stover, M. Botto, S. Thiel, S. Tzima, D. Kunkel, M. Walport, W. Lorenz, and W. Schwaeble Role of the Classical Pathway of Complement Activation in Experimentally Induced Polymicrobial Peritonitis Infect. Immun., December 1, 2001; 69(12): 7304 - 7309. [Abstract] [Full Text] [PDF]
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