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RI/III and C5aR in the Reverse Arthus Reaction1
*
Department of Clinical Immunology,
Institute of Medical Microbiology, and
Department of Functional Anatomy, Medical School Hannover, Hannover, Germany; and
Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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-/- mice, manifestation of disease is almost
exclusively determined by FcR on effector cells, arguing for a minor
role of complement. In contrast, data obtained with
C5aR-/- mice suggested that, dependent on the tissue
site, complement is more important than FcR. In this paper, we
demonstrate that, in response to IgG immune complex formation,
FcRI/III- and C5aR-mediated pathways are both necessary and only
together are they sufficient to trigger the full expression of
inflammation in skin and lung. Moreover, both effector systems are not
entirely independent, suggesting an interaction between FcR and
C5aR. Therefore, FcR-mediated responses can be integrated through
C5aR activation, which may explain why these two receptor pathways have
previously been considered to dominate each
other. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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It has long been accepted that IC-mediated activation of complement via the classical pathway represents the initial trigger of the Arthus response. The ensuing inflammation is mediated by a group of proinflammatory molecules, the lytic membrane attack complex C5b-9 and the anaphylatoxins C3a and C5a. C5a leads to increased vascular permeability and promotes migration and activation of leukocytes (6). It’s not only a potent chemotactic agent for PMN, mast cells, and monocytes, it also enhances adhesion of PMN to endothelial cells and induces mediator release from leukocytes (7, 8). Studies with C5aR-deficient mice demonstrate a strongly reduced Arthus reaction in skin, lung, and peritoneum (9). A similar degree of attenuation occurs after blocking C5a-C5aR interaction with a specific C5aR antagonist (C5aRA), indicating that the complement effect in IC inflammation is predominantly mediated by C5aR (10).
During the last few years, studies using mice deficient in Fc receptors
for IgG (FcR) have revealed a critical role of FcR, especially
FcRIII, in the pathogenesis of IC diseases (11, 12, 13). It
has been proposed that the initiation of the inflammatory cascade
depends almost entirely on mast cell FcR-triggered activation
leading to secondary reactions such as local complement production
(14, 15). Supporting this concept, mice lacking FcR
(deficient in both FcRI and FcRIII), but not C3-, C4-, and
C5-deficient mice, show an impaired Arthus reaction (16).
However, not all results are in agreement with that redefinition.
First, complement-sufficient and complement-depleted
FcRIII-deficient mice show that IC-mediated cutaneous Arthus
reaction is induced via a complement-dependent and a
FcRIII-dependent pathway (17). Second, it is unclear
why C5-deficient mice show no impaired cutaneous inflammation, whereas
a marked reduction has been described for other organs, including lung
and peritoneum (16, 18, 19). Third, the contribution of
complement and/or FcR may differ with the genetic background. This
has been demonstrated for PMN recruitment in an IC peritonitis model,
which is more strongly affected by complement-depletion in BALB/c mice
compared with C57BL/6 mice (20).
In the present study, we examined the responses to IC activation by
combining several FcR deficiencies with dysfunction of complement,
specifically at the level of the C5aR. We secured comparability of the
different mouse strains by using wild-type (WT) and FcRIII- and
FcR-deficient mice all on the same genetic background. To study the
Arthus reaction comprehensively, we simultaneously assessed the
immunopathology in distinct organs, i.e., skin and lung, of the same
animal, employing several parameters for each. By using this strategy,
we identified dependent and independent contributions of both
FcRI/III- and C5aR-triggered pathways, which gives an explanation of
why these two effector systems previously have been considered to
dominate each other.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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FcRIII-deficient mice were generated as decribed
(17). They were bred for eight generations onto C57BL/6
mice under pathogen-free conditions in the animal facility of Hannover
Medical School. The homozygous FcRIII-/-
mice were selected and WT FcRIII+/+ C57BL/6
littermates were used for all comparisons. C57BL/6 mice homozygous for
FcR-/- were obtained from Taconic
(Germantown, NY). All these mice were male and were used at 8–12 wk of
age. Experiments were conducted in accordance with the regulations of
the local authorities.
Reverse passive Arthus reaction in skin and lung
Mice were anesthetized with ketamine and xylazine and shaved at
their basolateral sides. Rabbit IgG anti-OVA Ab (30 µg; Sigma,
Munich, Germany) was injected intradermally at multiple sites. In
addition, the trachea was cannulated and 150 µg Ab was applied.
Immediately thereafter, 200 µl of 0.25% Evans blue together with 20
mg/kg of OVA Ag were given i.v. Where indicated, mice were injected
twice with 4.25 µg purified cobra venom factor (CVF) (Naja
naja, Calbiochem-Novabiochem, Bad Soden, Germany) i.p. at 24 and
16 h before the Arthus reaction to deplete complement. Serum
complement levels were determined as described (21). In
additional experiments, mice received C5aRA 
pIIIA8 to inhibit
C5aR-triggered activation (10). Hereby, 200 µl
antagonist was given at a concentration of 7.3 x
10-6 M before application of anti-OVA IgG,
and then 100 µl antagonist was given at 60 and 120 min after IC
challenge. Mice were killed 4 h after initiation of the Arthus
reaction and were assayed for infiltration of PMN, hemorrhage, and
plasma exudation in skin, lavaged lung tissue, and bronchoalveolar
lavage (BAL) fluid.
BAL and quantitation of hemorrhage and PMN accumulation in bronchoalveolar space
Pulmonary vasculature was gently flushed with PBS with a catheter positioned in the root pulmonary artery. Lungs were lavaged with PBS (1 ml, five times at 4°C) after cannulation of the trachea. The volume of collected BAL fluid was measured in each sample and total cell count was assessed with a hemocytometer (Neubauer Zählkammer, Gehrden, Germany). The amount of erythrocytes represented the degree of hemorrhage. For quantitation of PMN accumulation, differential cell counts were performed on cytospins (10 min at 55 x g) stained with May-Grünwald/Giemsa using 300 µl of BAL fluids.
Myeloperoxidase (MPO) assay in skin and lung
Skin punches of the injection sites 1 cm in diameter, lavaged lung tissues, and BAL fluids were assessed for PMN accumulation by MPO activity as described (22). Briefly, homogenized tissue was suspended in 50 mM potassium phosphate buffer (pH 6.0, 0.5% hexadecyltrimethylammoniumbromide). Cells were broken by three cycles of freezing and thawing and subsequent sonication. The supernatant was mixed with 0.167 mg/ml o-dianisidine dihydrochloride (Sigma) and 0.0005% hydrogen peroxide. The amount of MPO was calculated by assessing the change in absorbance at 450 nm. A serial dilution of MPO from human PMN (Calbiochem-Novabiochem) served as standard. Samples were run in duplicate.
Measurement of plasma exudation in skin and lung
Evans blue dye binds avidly to albumin and serves as a marker of extravasation of plasma proteins into skin and lung. This technology compares favorably with the methodology involving radiolabeled albumin (23). One-centimeter skin punches were harvested, placed in 1 ml of formamide, sonicated for 10 min, and incubated at 37°C for 16 h. The concentration of dye in appropriate dilutions of skin eluate, BAL fluid, and serum was measured spectrophotometrically at 620 nm. Serum samples were also measured at 405 nm to account for hemolysis. Extinction at 405 nm was multiplied with factor 0.014 and deducted from the extinction at 620 nm. This factor corrects for extinction caused by murine hemoglobin at 620 nm. Plasma exudation was quantitated by multiplying the ratio of extinction in BAL fluid or skin punches to extinction in plasma by the dilutions of the specimens.
Histologic and immunohistochemistry studies
To process lung tissues for histological examination after lavage, they were fixated in 4% buffered paraformaldehyde, embedded in paraffin, and stained with hematoxylin and eosin according to conventional procedures. In additional experiments, lavaged lung tissues were prepared for immunohistochemistry. The alkaline phosphatase antialkaline phosphatase (APAAP) technique was used to phenotype neutrophils (Gr1; Dianova, Hamburg, Germany). Cryostat sections were incubated with the primary Abs for 30 min at 21°C. After washing with TBS-Tween (0.05% Tween 20; Serva, Heidelberg, Germany), incubations were done with the bridging Ab Z0494 and the rat-APAAP Ab complex D0488 for 30 min. To increase the staining intensity, the last two steps were repeated once. Fast blue (Sigma) served as substrate for alkaline phosphatase. Positive and negative controls produced the expected results.
Statistical analysis
Statistical analysis was performed using the SPSS v. 8.0
statistical package (SPSS, Chicago, IL). To analyze differences of mean
values between groups, a two-sided unpaired Student‘s t
test was used; p < 0.05 was considered significant and
p < 0.001 was considered highly significant.
Independent contribution of FcR and C5aR was assessed by two-way,
two-factorial ANOVA (univariate general linear model procedure).
Function or dysfunction of either receptor was coded in a binary
variable (factor). Between-subject effects indicated independent
contribution of a factor.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Reverse passive Arthus reactions in the skin were performed to
dissect the relative contribution of FcRI, FcRIII, and complement
during cutaneous, IC-triggered inflammation. C57BL/6 mice deficient in
the ligand-binding 
-chain of FcRIII
(FcRIII-/-) or deficient in the FcR-chain
critical for signaling of both FcRIII and FcRI
(FcR-/-) were compared with WT C57BL/6 mice.
Inflammatory responses were quantitated by measurement of MPO in
homogenized tissue as a marker of PMN infiltration and by assessment of
Evans blue in tissue extracted by formamide, indicating the degree of
microvascular permeability. In WT mice, a strong accumulation of PMN
with a concomitant increase of plasma exudation was observed within
4 h after IC challenge (Fig. 1
,
A and B). In FcRIII-/-
mice, recruitment of PMN was markedly decreased and comparable to that
seen in FcR-/- mice (Fig. 1A).
Cutaneous plasma exudation differed in that the attenuation observed in
FcRIII-/- was further reduced to background
levels in FcR-/- mice (Fig. 1B).
These data identify FcRIII as the dominant FcR in PMN influx and
suggest that both FcRI and FcRIII can trigger enhanced vascular
permeability.
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R in cutaneous Arthus reaction. This was based on
the observation that complement depletion with CVF completely abrogated
the inflammatory response, as defined by Evans blue extravasation, only
in FcRIII-/- mice and not in control mice
(17). The FcRIII-/- mice and
their normal littermates used in that study had a mixed genetic
background of C57BL/6 and 129 strains. Interestingly, although rather
ineffective in mixed C57BL/6 and 129 strains, the treatment with CVF
resulted in a significant attenuation of inflammation in WT mice of
C57BL/6 strain. By using two i.p. injections of 4.25 µg CVF 24 and
16 h before IC challenge, a strong reduction of PMN influx and a
complete suppression of plasma exudation were observed (Fig. 1
, A and B). This finding illustrates that
variations in the genetic background of C57BL/6 and 129 mice are of
strong influence of the inflammatory response to the Arthus reaction.
In support, the hemolytic activity is significantly lower in C57BL/6
mice compared with that in 129 mice (17), which may
indicate that strain-specific differences in complement activity can
contribute to the observed heterogeneity. The importance of complement
was further confirmed with the specific C5aRA pIIIA8
(10). In WT mice, MPO activity and plasma exudation
decreased by more than 60 and 80%, respectively, after C5aRA treatment
(Fig. 1, A and B). This indicates a critical role
for C5a, as recently suggested in C5aR-/- mice
(9). A complete suppression for both parameters was
similarly observed in FcRIII-/- mice and in
FcR-/- mice after inhibition of
C5aR-triggered activation by C5aRA (Fig. 1, A and
B). Taken together, these results demonstrate that FcR
and C5aR are codominant receptor pathways in the initiation of the
inflammatory cascade in skin of C57BL/6 mice. Arthus reaction in the lung
It is still unclear whether the pathogenesis of the inflammatory
response in IC diseases follows a general pattern (13) or
if tissue-specific differences exist (9). Thus, the
immunopathological cascade was induced not only in the skin, but also
simultaneously in the lung in the same animals, allowing for an
assessment of organ-specific differences under exactly the same
experimental conditions. In WT mice, the profound pulmonary IC
inflammatory response with enhanced PMN infiltration, plasma exudation,
and hemorrhage into the bronchoalveolar space was markedly suppressed,
although not completely abolished, by application of either CVF or
C5aRA (Fig. 2A, C,
and D). Interestingly, interstitial PMN influx, as defined
by MPO activity in lavaged lung tissue, was substantially attenuated
after C5aRA treatment, whereas systemic complememt depletion by CVF
resulted in increased MPO activity (Fig. 2B). This finding
is in accordance with the recognized ability of CVF to induce
accumulation of PMN, especially in the lung (25).
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RI and FcRIII to the
pathophysiology in the lung was further evaluated. In both
FcRIII-/- and
FcR-/- mice, alveolar PMN infiltration as
well as interstitial PMN accumulation in lavaged lung tissue was
substantially decreased (Fig. 3,
A and B). The reduction in hemorrhage seen in
FcRIII-/- mice was further attenuated in
FcR-/- mice (Fig. 3C). This
result shows that both FcRI and FcRIII contribute significantly
to this parameter. Unexpectedly, plasma exudation in the lung was
largely independent of FcRI and FcRIII (Fig. 3D),
which is different than what has been observed in the skin (Fig. 1B). This finding was confirmed by histological studies
demonstrating marked perivascular edemas in WT mice (Fig. 4A) which were also evident in
FcRIII-/- mice (Fig. 4B) and
FcR-/- mice (Fig. 4C). The
residual proportion of hemorrhage and plasma exudation seen in
FcRIII-deficient mice was completely abrogated after C5aRA treatment
(Fig. 3, C and D). In contrast, interstitial MPO
activity of FcRIII-/- mice and
FcR-/- mice was not affected, and alveolar
PMN influx was totally absent after inhibition of C5aR (Fig. 3, A and B). As shown by immunohistochemistry,
Gr1-positive PMN in C5aRA-treated FcR-/-
mice retarded in the pulmonary vasculature, apparently unable to
migrate along a chemotactic gradient into the alveolar space (Fig. 4D).
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|
R
and C5aR are codominant receptors in the initiation of the Arthus
response in both skin and lung and further suggest that the sequelae of
IC-triggered inflammation are not necessarily the endpoints of the same
reaction. Tissue site-specific differences exist with respect to plasma
exudation, which is almost entirely dependent on C5aR in the lung and
on both C5aR and FcR in the skin. FcRIII is the dominant FcR
for cutaneous and alveolar PMN influx. Interestingly, FcRI is of
additional importance for plasma exudation in the skin and hemorrhage
in the lung. These observations, combined with the recent report that
FcRI contributes significantly to enhanced PMN infiltration in
IC-induced peritonitis (20), indicate that effector cells
expressing FcRI are involved in IC-triggered inflammation. In the
lung, the alveolar macrophage expressing FcRI, FcRII, and
FcRIII is the most prominent cell type in the alveoli and is known
to promote IC injury through the production of cytokines (TNF-,
platelet-activating factor, etc.), chemokines (macrophage-inflammatory
protein-2, cytokine-induced neutrophil chemoattractant-1, etc.), and
vasoactive substances (reviewed in Ref. 26). In the skin,
resident mast cells, epidermal Langerhans cells (both of which express
FcRIII), and macrophages are the most likely involved cell types
(15, 27). These mast cells have already been demonstrated
to contribute significantly to IC-induced injury in skin (15, 28). However, because FcRIII, but not FcRI, is expressed
on mast cells, it appears that skin macrophages are of additional
importance.
One might assume that FcR and complement represent a redundant
system, leading to less attenuation by dysfunction of one pathway with
the remaining pathway partly substituting the response. However, as
shown in this study, the sum of attenuations caused by FcR deletion
and C5aR blockade is far above 100% in all parameters analyzed.
Therefore, both pathways may in part act independently, but also have
to act in a cascade of events with one pathway dependent on triggering
by the other as first suggested by Sylvestre and Ravetch
(14). Action independent from the other pathway can be
derived from the inflammatory response present with one pathway
functional and the other dysfunctional. This has been formally assessed
by ANOVA (p values for between-subject effects of
the factors FcR and C5aR, respectively: alveolar PMN infiltration,
0.007, 0.002; pulmonary interstitial PMN infiltration, 0.026, 0.307;
alveolar hemorrhage, 0.003, 0.058; pulmonary plasma exudation, 0.196,
0.002; cutaneaous PMN infiltration, 0.007, 0.002; and cutaneous plasma
exudation, 0.017, 0.15). This demonstrates that the FcR and C5aR
pathways contribute significantly to the inflammatory response, with
the exceptions of C5aR in interstitial PMN influx and FcR in
pulmonary plasma exudation. On the other hand, the sum of the
independent contributions obtained by adding the mean values of single
groups does not reach the full strength of the inflammatory response as
seen in WT mice. This fact suggests a dependent interaction between
FcR and C5aR which may explain the controversy about their relative
roles (9, 13).
In summary, we have used FcRIII- and FcR-deficient mice in
combination with a specific antagonist against C5aR to distinguish
between FcRI-, FcRIII-, and C5aR-mediated effects. This approach
enabled us to demonstrate that the initiation of the inflammatory
cascade in IC disease is mainly determined through the action of
FcRIII and C5aR pathways. Furthermore, the comparison between
FcRIII-/- and
FcR-/- mice shows that FcRI plays an
additional role. The earlier observations of
C5aR-/- mice (9) suggested a
strict tissue-site dependency of C5aR. We observed minor differences
for both FcR and C5aR, with the exception that vascular permeability
was more prominently mediated by C5aR in lung and by FcR in skin. In
addition, our findings not only support the current idea that FcRIII
is a dominant receptor in acute inflammation (17) but also
extend this concept by integrating the interplay between FcRI,
FcRIII, and C5aR with dependent and independent actions. Finally,
the data strengthen the view that both FcR and C5aR have to be
considered as potential targets in immunotherapy of IC disease in
humans.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. J. Engelbert Gessner, Abteilung für Klinische Immunologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany. E-mail address:
3 Abbreviations used in this paper: IC, immune complex; BAL, bronchoalveolar lavage; C5aRA, C5aR antagonist; MPO, myeloperoxidase; PMN, polymorphonuclear leukocytes; WT, wild type; CVF, cobra venom factor.
Received for publication August 9, 1999. Accepted for publication October 26, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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RIII (CD16) deficient mice. Immunity 5:181.[Medline]
RIII (CD16) deficient mice show IgG-isotype dependent protection to experimental autoimmune hemolytic anemia. Blood 92:3997.RII/III modulate the antigen-presenting capacity of murine dendritic epidermal Langerhans cells for IgG-complexed antigens. J. Immunol. 155:1725.[Abstract]
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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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). Treatments with CVF and
C5aRA are indicated (IC + CVF, 
; and IC + C5aRA, 
). Mice
receiving only Ag or Ab served as controls (Ag, 
; and Ab, dotted
bars). Ag control group and Ab control group each comprised five WT
mice per group, and IC treatment groups comprised eight to twelve mice
per group (except for IC + C5aRA, which had five to six mice per
group). Data are expressed as mean ± SEM. Differences for both
parameters were significant or highly significant for the IC treatment
groups of WT mice compared with Fc
