By
From the * Division of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York
10021; and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
The role of complement in immunoglobulin G-triggered inflammation was studied in mice
genetically deficient in complement components C3 and C4. Using the reverse passive Arthus
reaction and experimental models of immune hemolytic anemia and immune thrombocytopenia, we show that these mice have types II and III inflammatory responses that are indistinguishable from those of wild-type animals. Complement-deficient and wild-type animals exhibit comparable levels of erythrophagocytosis and platelet clearance in response to cytotoxic
anti-red blood cell and antiplatelet antibodies. Furthermore, in the reverse passive Arthus reaction, soluble immune complexes induce equivalent levels of hemmorhage, edema, and neutrophillic infiltration in complement-deficient and wild-type animals. In contrast, mice that are
genetically deficient in the expression of Fc receptors exhibit grossly diminished reactions by
both cytotoxic antibodies and soluble immune complexes. These studies provide strong evidence that the activation of cell-based FcR receptors, but not complement, are required for
antibody-triggered murine inflammatory responses.
Self-reactive antibody, either in the form of soluble immune complexes or cellular-bound antibody, produces
injury as a consequence of activation of the inflammatory
response. Type II inflammation, which is characterized by
cytotoxic antibody, is specifically causal in the development
of autoimmune hemolytic anemia (AIHA)1 and immune
thrombocytopenic purpura (ITP). Three discrete pathways are recognized in the pathogenesis of cytotoxic antibody
(1). In one pathway, the direct activation of both the early
and late components of the complement cascade can result
in the formation of the membrane attack complex, producing pores in the cell membrane, and directly lyse the target
cell. This mechanism is presumed to predominate in the
intravascular hemolysis observed in acute hemolytic transfusion reactions after the administration of ABO-incompatible blood (2). Recruitment and activation of cellular effectors may be accomplished by the two other pathways In type III inflammation, the formation and deposition
of soluble immune complexes contributes to a variety of autoimmune syndromes, including arteritis, glomerulonephritis,
and connective tissue disease. The triggering of immune
complex-mediated injury has long been thought to be mediated principally through activation of the classical complement cascade. The formation of immune complexes is
proposed to allow the binding and activation of complement, leading to the formation and release of chemotactic
peptides, with subsequent neutrophil influx, degranulation,
and tissue injury (1). This paradigm is based in part on the
experimental model of cutaneous immune complex injury,
the Arthus reaction (4), which is reported to be attenuated
in animals that have been depleted of complement with cobra venom factor (5, 6).
In this model, antibody binds antigen-forming immune
complexes, resulting in the binding and activation of early
complement components 1, 4, and 2 in the "classical pathway." Activation and cleavage of C3, the central protein of
the cascade, releases C3a, which is a potent chemical mediator of inflammation and exposes a reactive thioester within
the C3b We recently reported a series of experiments on Fc receptor-deficient mice that suggest that Fc receptor activation is required for the inflammatory response in the Arthus
reaction (7) and in models of autoimmune thrombocytopenia and hemolytic anemia (8). These multimeric, cell-surface receptors, which bind the Fc portion of antibodies,
form a critical link between the humoral and cellular immune systems, are expressed by a wide variety of hematopoietic cells, and can bind either monomeric antibody (the high affinity receptor Fc Based on those studies, we proposed a model of immune
complex-mediated inflammation in which the reaction is
initiated by cell-based Fc receptors. Complement was proposed to either act synergistically with FcRs in the initiation phase of the reaction or in the subsequent recruitment
and activation steps. With the development of defined
knockout mice in which the absence of specific complement components is precisely controlled, we have critically examined the role of these molecules in the types II and III
inflammatory responses. In this report, we demonstrate that
mice that are genetically deficient in C3 or C4, as well as
the C5-deficient strain DBA/2, exhibit a reverse passive
Arthus reaction that is indistinguishable from that of wildtype animals. In addition, while Fc Arthus Reagents.
Polyclonal rabbit IgG and polyclonal rabbit
anti-OVA IgG were from Cappel Laboratories (Cochranville,
PA), and were resuspended according to manufacturer's instructions. Any precipitate was removed by microfuging at 12,000 g
for 5 min. Phosphate-buffered formalin was purchased from VWR
Scientific (Bridgeport, NJ); chicken egg OVA, Evan's blue, and all
chemical reagents were from Sigma Immunochemicals (St. Louis,
MO). All solutions for injection were diluted in 0.9% NaCl and sterile filtered through a 0.2 µm syringe filter. MPO assay was performed as described previously (11). Avertin was a kind gift from
Elizabeth Lacy (Memorial Sloan Kettering Cancer Center, New
York). All surgical supplies were purchased from Baxter Healthcare Corp. (Valencia, CA).
Antierythrocyte and Platelet Antibodies.
The IgG fraction of rabbit
Knockout Mice.
Mice with genetically deleted complement
components 3 and 4, as well as mice with a deleted Arthus Reaction.
Mice were anesthetized with 0.3-0.5 ml i.p.
of Avertin and their backs were shaved. 30 µg of control rabbit
IgG or rabbit anti-OVA in a volume of 7.5 µl were injected intradermally with a 30-G needle, followed by OVAlbumin at 20 mg/kg i.v., prepared in a solution of 2 mg/ml. Mice were killed
at the indicated time points using CO2 asphyxiation, and the dorsal skins were harvested by careful dissection.
Quantitation of Edema.
Edema was quantified by two methods. In the first, 1% Evan's blue was added to the intravenous injectate, mice were killed at a 2-h time point, and the size of the
extravasated blue spot was measured directly. In the second
method, the area of extravasation or control site was removed using a surgical punch biopsy, and the weight was determined.
Each tissue section was weighed directly, and specific edema was
quantified by subtracting the weight of the control area from that
injected with anti-OVA IgG. Error margins for all indices were
calculated as ± SD.
Quantitation of Hemorrhage.
Mice were killed at 8 h, and the
dorsal skin was harvested. The amount of hemorrhage was assessed by either (a) measurement of the purpuric spot, or (b) direct microscopy of formalin-fixed sections. In this latter method,
a scale of 0 to 4+ was used.
Quantitation of Neutrophil Infiltration.
Mice were killed at 8 h,
and the injected areas of skin were removed by punch biopsy.
Neutrophil content was assessed by the quantitation of myeloperoxidase, as described previously (11), or by direct microscopic assessment of formalin-fixed, hematoxylin and eosin-stained specimens.
The amount of infiltration was quantitated on a scale of 0 to 4+.
Experimental Immune Hemolytic Anemia.
Mice were injected with
200 µg i.p. of rabbit Experimental Immune Thrombocytopenia.
2-4-mo-old mice were
injected with 20 µg i.v. of purified mouse mAb 6A6. 20 µl of
blood obtained from the retroorbital plexus was diluted in buffer
containing ammonium oxalate (Unopette Kits; Becton Dickinson). Platelets were counted using a hematocytometer under a
phase-contrast microscope.
Reverse Passive Arthus Reactions, A Type III Inflammatory
Response, Develop Normally in Complement-Deficient Mice
The Arthus reaction can be divided into three distinct
cellular responses: edema, which is maximal at ~2-4 h, and
hemorrhage and neutrophil infiltration, which peak in intensity at 8 h (15). Therefore, the Arthus reaction was evaluated at both 2 and 8 h, and was scored for edema, hemorrhage, and neutrophil infiltration.
2 h after the intravenous injection
of antigen and Evan's blue, the skins of wild-type, C3
Representative skin sections
demonstrating the purpuric lesions induced by immune
complexes at 8 h after intravenous injection of antigen are
shown in Fig. 2 A. The C3
Fig. 3 A shows representative histological sections from an 8-h Arthus reaction in wild-type (left), C3
Type II Inflammatory Responses, Experimental
AIHA and Thrombocytopenia Develop Normally in
Complement-deficient Mice
Complement-deficient mice were challenged passively
with anti-MRBC and antiplatelet antibodies to determine
whether the pathogenic effects of cytotoxic antibodies are dependent on an intact complement cascade. C3
Similar results were obtained in a second model of type
II hypersensitivity, experimentally induced immune thrombocytopenia (Fig. 6). The capacity of C3-deficient mice to
develop thrombocytopenia after intravenous injection with
a mouse monoclonal IgG1 antiplatelet antibody 6A6 (12)
was nearly identical to wild-type littermates, while the
Fc
While the manifestations of inflammation have been recognized for nearly two millenia, the specific interactions
that trigger and propagate this complex physiological response are still poorly understood. The inflammatory response has been categorized into four mechanistic types,
with IgG responses subdivided into fixed (type II) and soluble immune complex (type III)-triggered inflammation. Inflammatory responses to immune complexes, as modeled
by the Arthus reaction, have been attributed to the presence of antibody, neutrophils, and complement components. Depletion of antibodies or neutrophils results in the
ablation of the Arthus reaction; depletion of complement
components leads to more varied effects. Although the aggregate results of these experiments have led to the development of the widely accepted paradigm of immunological injury, in which complement is an essential component,
this model has failed to account for the disparate results that
have been obtained with complement depletion in different species.
We recently reported the result of studies of the Arthus
reaction in Fc receptor-deficient mice, which unexpectedly demonstrated the near absence of immune complex-
mediated inflammation in these mice. In contrast, complement depletion with cobra venom factor had little detectable
effect. Although these studies established the key role of Fc
receptors in initiating the inflammatory response to immune complexes while suggesting a secondary role for
complement, the precise contribution of each of these
components to the intact reaction was more difficult to assess, given the uncertainties inherent in the methods used
to deplete complement components. Using the currently
accepted paradigm of immunological injury, it would be
expected that mice lacking complement components C3, C4, or C5 would exhibit diminished responsiveness to immune complexes. The use of genetically defined mutant
mice that completely lack these components is uniquely
suited to definitively resolve this issue. We have shown that
these mice exhibit the three classical parameters of immunological injury, edema, hemorrhage and neutrophil infiltration in a manner that is indistinguishable from that of wild-type controls. In contrast, mice that lack Fc receptors
exhibit grossly diminished reactions, as measured by these
parameters.
Previous studies have shown that complement depletion
by a variety of methods, including treatment with cobra
venom factor (5, 6), preformed immune complexes, zymosan (16), and soluble recombinant CR1 (17, 18), had led to
responses that were far from consistent, with substantially
different conclusions regarding the importance of complement derived from the use of different species in different
models of immunological injury. Thus, complement depletion using cobra venom factor was shown to dramatically
reduce neutrophil accumulation and proteinuria in experimental acute nephrotoxic nephritis in rats and rabbits, and
similarly reduced the cutaneous Arthus reaction in rats.
However, in rabbits and guinea pigs, neutrophil accumulation was observed in cutaneous Arthus reactions despite
treatment with cobra venom factor, suggesting "either that
levels of C3 in the extravascular spaces were not sufficiently
depleted or that in Arthus reactions in skin a second mechanism of neutrophil accumulation was found" (19).
In type II inflammatory responses, exemplified by AIHA
and ITP, a number of pathogenic mechanisms may contribute individually or collectively to cytotoxicity, including spontaneous agglutination and splenic sequestration,
complement-mediated lysis and C3b and Fc In human ITP, the efficacy of an anti-Fc The relative importance of Fc receptor-mediated immunological injury may exhibit species variation, as has been
observed for the complement-mediated pathway. However, the existence of this pathway as a distinct entity seems
certain, such that it is major pathway in initiating and propagating immunological injury. The availability of genetically determined mutations in specific components of the
complement and Fc receptor pathways will further clarify the specific roles that each of these systems play in the
complex interactions of both innate and acquired immunity, and may offer a new focus for the treatment of immunological diseases.
engagement of C3bR and/or Fc
Rs. Ligand cross-linking of these
Fc
Rs on effector cells in vitro, including NK cells, neutrophils, basophils, eosinophils, and monocyte-derived cells,
initiates the activation of a wide array of effector functions, including phagocytosis, antibody-dependent cellular cytotoxin
(ADCC), and the release of inflammatory mediators that can
ultimately lead to cellular destruction and the amplification of the inflammatory response (3). Either or both of these latter two mechanisms have been presumed responsible for the
extravascular hemolysis seen in warm AIHA and ITP.
chain, leading to covalent attachment to the antibody-antigen complex. This linkage not only stabilizes
formation of the C5 convertase, but provides a ligand for
complement receptors CR1, CR2, and CR3. CR1 and
CR3 are important in inflammation because they facilitate
uptake of antigen and activation of leukocytes. Formation
of C5 convertase is an important step both in the release of
the chemotactic peptide C5a and in the assembly of the
membrane attack complex, i.e., C5-C9.
RI) or immune complexes (the low
affinity receptors Fc
RII and Fc
RIII; 9). In our experiments, mice with a genetic deficiency in the
subunit of
the Fc receptor complex, which therefore fail to express
functional Fc
RI and Fc
RIII, as well as the high affinity
receptor for IgE, Fc
RI (10), unexpectedly exhibited a
grossly diminished Arthus reaction, as well as dramatically reduced levels of IgG-mediated erythrophagocytosis and
platelet clearance. These mice had levels of complement
and complement receptor equivalent to wild-type animals
and normal responses to "alternative" complement pathway activation (7). The presence of an intact complement
cascade alone was therefore insufficient in triggering and
propagating the Arthus reaction and type II inflammation,
indicating an additional requirement for Fc receptor engagement.
R-deficient mice are
resistant to antierythrocyte and antiplatelet antibodies, C3deficient and wild-type mice develop comparable degrees
of anemia and thrombocytopenia. These studies establish
the independence of these reactions on an intact complement cascade, as well as the primacy of Fc receptors in triggering antibody-mediated inflammation.
-mouse RBC
-(MRBC) sera (Cappel) was obtained by protein A/G affinity chromatography (Pierce Chemical Co., Rockford, IL). The IgM fraction was obtained by mannan-binding
protein affinity chromatography (Pierce). Mouse monoclonal
6A6, an IgG1 antiplatelet antibody (12), was a kind gift from Dr.
R. Good (University of South Florida College of Medicine,
Tampa, FL), and was purified from ammonium sulphate-precipitated concentrated tissue culture supernatants, followed by protein A/G affinity chromatography. The purity of all antibody
preparations was confirmed by PAGE.
subunit,
were obtained using the method of homologous recombination,
as previously described (10, 13). DBA/2 mice were purchased
from Jackson Immuno Research Laboratories, Inc. (West Grove,
PA). Mice were used at 8-12 wk of age, and were age and sex
matched for each experiment. Wild-type controls were obtained
by breeding the littermates of knockout animals.
-MRBC IgG. Hematocrits were determined
with heparinized microhematocrit capillary tubes (Becton Dickinson & Co., Mountain View, CA) and a hematocentrifuge (Baxter) using 200 µl of blood obtained from the retroorbital plexus.
Hematoxylin and eosin-stained, formalin-fixed sections were
prepared from 2-mo-old mice that were killed 2 d after injection with 200 µg i.p. of rabbit
-MRBC IgG. Magnification is at 400.
/
,
C4
/
, FcR
/
, and DBA/2 mice were harvested and
edema was quantified by the direct measurement of the size
of the extravasated blue dye, as well as by weighing standardized skin punches. As seen in Fig. 1 (center), the edema
in C3 knockout mice is indistinguishable from that of wildtype animals (left). C4-mice and DBA/2 mice demonstrated the same response as C3
/
animals (data not
shown). In contrast, FcR chain-deficient mice have no detectable edema (Fig. 1, right). These results are quantified in
Fig. 1 B, showing the similarity of edema in wild-type and complement-deficient strains, as compared to the dramatic
reduction observed in FcR
/
mice.
Fig. 1.
Quantitation of
edema in the reverse passive Arthus
reaction. (A) Macroscopic visualization for +/+ (left), complement-deficient (middle), and FcRdeficient (right) mice. 30 mg of
control rabbit IgG (upper left spot)
or rabbit anti-OVA IgG was injected intradermally, followed immediately by 2 mg/kg i.v. OVA.
Dormal skins were harvested after
2 h, using 1% Evan's blue in the
intravenous injectate. (B) Quantitation of edema at 8 h. Microscopic
sections were graded for the extent of edema on a scale of 0-4+;
n >12 for each genotype, and error bars represent ± SD.
[View Larger Versions of these Images (46 + 7K GIF file)]
/
(center) and C4
/
and
DBA/2 strains (data not shown) were indistinguishable
from wild-type controls (left) for this parameter; FcR-deficient mice are protected from the hemorrhagic response
(right). Microscopic quantitation of hemorrhage for all
strains is shown in Fig. 2 B, and is in agreement with the
macroscopic results.
Fig. 2.
Quantitation of 8-h
hemorrhage in the reverse passive Arthus reaction. (A) 30 mg
of rabbit IgG (upper left spot) or
rabbit anti-OVA IgG was injected intradermally, followed by
2 mg/kg i.v. OVA. Dorsal skins
were harvested after 8 h. (B) Aggregated results based on the direct microscopic grading of
hemorrhage on a scale of 0-4+.
Results are ± SD; n >12 in each
group.
[View Larger Versions of these Images (40 + 7K GIF file)]
/
(center), and FcR
/
(right)
mice. Once again, a vigorous neutrophil infiltration is observed in the C3 knockout animals and wild-type controls, with FcR-deficient mice exhibiting a near absence of infiltrating cells. C4-deficient mice and DBA/2 mice (not shown)
were able to recruit neutrophils, as were wild-type or C3deficient mice. Quantitation by microscopy (Fig. 3 B) or
MPO activity (data not shown) reveals that only FcR-deficient mice have a reduction in this parameter.
Fig. 3.
Quantitation of 8-h
neutrophil infiltration in the reverse passive Arthus reaction. (A)
30 mg of rabbit IgG (upper left spot) or rabbit anti-OVA IgG was injected intradermally, followed by 2 mg/kg i.v. OVA. Dorsal skins
were harvested after 8 h. (B) Aggregated results based on the direct
microscopic grading of neutrophil infiltration on a scale of 0-4+.
Results are ± SD; n >12 in each group.
[View Larger Versions of these Images (7 + 52K GIF file)]
/
mice and
their wild-type littermates were injected with 200 µg of a
polyclonal rabbit anti-MRBC IgG fraction. As shown in
Fig. 4, wild-type and C3-deficient animals became anemic,
reaching similar nadir average hematocrits on day 4 after injection (26.5 ± 4 and 29 ± 6%, respectively). In contrast,
Fc
R-deficient mice were protected with nadir hematocrits of 39.75 ± 2.5%. The resistance of Fc
R-deficient
mice is explained at least in part by a loss of erythrophagocytosis by hepatic Kuppfer cells. Fig. 5 reveals that hepatic
erythrophagocytosis is comparable in wild-type and C3deficient mice, but is absent in Fc
R-deficient mice. The
susceptibility of C3-deficient mice was shown to be isotype
dependent. As expected, they are protected from hemolytic
anemia when the antibodies are of the IgM isotype. After
injection of 100 µg of an IgM fraction of a polyclonal rabbit anti-MRBC sera, wild-type mice developed mean nadir hematocrits of 32%, while C3
/
mice only reached
mean nadirs of 40% (data not shown).
Fig. 4.
Experimental murine immune hemolytic anemia
induced by rabbit polyclonal
anti-MRBC IgG. Daily hematocrits of wild-type (filled squares
and dotted line), homozygous chain-deficient (filled squares),
and homozygous C3-deficient
mice (open squares). Mean hematocrits obtained from five mice in
each group are presented.
[View Larger Version of this Image (10K GIF file)]
Fig. 5.
Histological appearance of the liver in wild-type (+/+), homozygous -chain-deficient (
/
) and homozygous C3-deficient mice
(C3
/
) injected with rabbit
-MRBC IgG.
[View Larger Version of this Image (179K GIF file)]
R-deficient mice were resistant. C3-deficient and wildtype mice decreased their platelet count to ~5 and 1% of
baseline levels within 4 h after injection, while Fc
R-deficient mice maintained platelet counts of >90% of baseline
levels.
Fig. 6.
Experimental immune murine thrombocytopenia
induced by mAb 6A6. Platelet
counts (× 103/µl) of wild-type
(filled squares and dotted line), homozygous chain-deficient (filled
squares), and homozygous C3deficient mice (open squares). Mean
data from groups of four mice
are shown.
[View Larger Version of this Image (12K GIF file)]
R receptor-
mediated removal of opsonized targets by reticuloendothelial cells of the spleen and liver. The predominant mechanism is likely to be dependent on the specific autoantibody
and target cell. In murine experimental immune hemolytic
anemia, pathogenic mAb derived from NZB mice have
been found to mediate pathogenesis through either complement-dependent (20) and -independent pathways (21).
In the C4-deficient guinea pig, the reduced but persistent clearance of erythrocytes sensitized with rabbit anti-RBC
IgG was interpreted as evidence that IgG receptor interactions, although quantitatively less important, may be required in addition to complement receptor interactions for
effective phagocytosis (22). Our data using a polyclonal
rabbit IgG fraction show that in a murine system capable of
activating both complement-dependent and -independent
pathways, loss of Fc
R, but not complement interactions, prevents anemia. This difference is readily appreciated histologically, as mediated by Fc
R-dependent Kuppfer cell
erythrophagocytosis. While our previous data could not
exclude the possibility that Fc
R receptor erythrophagocytosis was synergistically activated by C3b interactions (8),
the lack of protection in C3-deficient mice argues that
Fc
R receptor engagement is necessary and sufficient for
hepatic Kuppfer cell erythrophagocytosis of rabbit IgG opsonized MRBCs.
R antibody, Fc
fragments, anti-human RBC (anti-D), and intravenous
gammaglobulin together suggest that Fc
R interactions are
critical to the clearance of platelets (23). However these
reagents may also potentially interact with complement
components and thus provide therapeutic benefit through
complement depletion. Our previous data with Fc
R receptor-deficient mice, combined with the lack of protection in C3-deficient mice, argues strongly that Fc
R interactions, and not complement receptors, are pivotal in the
clearance of opsonized platelets.
Address correspondence to Jeffrey V. Ravetch at his present address, The Rockefeller University, 1230 York Avenue, New York, NY 10021.
Received for publication 28 May 1996
These studies were supported by grants from the National Institutes of Health to M.C. Carroll and J.V. Ravetch, from the American Arthritis Foundation (to M.C. Carroll) by the DeWitt Wallace Foundation (to J.V. Ravetch) and by the Memorial Sloan-Kettering Cancer Center Clinical Scholars Program (to R. Clynes, National Cancer Institute grant CA-09512).1. | Roitt, I., J. Brostoff, and D. Male. 1993. In Immunology, 3rd ed. Mosby, Inc., London. 20.1-20.2. |
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