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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3855-3863
Mast Cells Induce Autoantibody-Mediated Vasculitis Syndrome Through
Tumor Necrosis Factor Production Upon Triggering Fc Receptors
By
Norihiko Watanabe,
Bunshiro Akikusa,
Seung Yong Park,
Hiroshi Ohno,
Liliane Fossati,
Gianluca Vecchietti,
J. Engelbert Gessner,
Reinhold E. Schmidt,
J. Sjef Verbeek,
Bernhard Ryffel,
Itsuo Iwamoto,
Shozo Izui, and
Takashi Saito
From the Department of Molecular Genetics, Graduate School of
Medicine, the Second Department of Pathology, School of Medicine, and
the Second Department of Internal Medicine, Chiba University, Chiba,
Japan; the Department of Pathology, Centre Medical Universitaire,
University of Geneva, Geneva, Switzerland; the Department of Clinical
Immunology, Hannover Medical School, Hannover, Germany; the Department
of Human and Clinical Genetics, Leiden University Medical Center,
Leiden, The Netherlands; and the Department of Immunology, University
of Cape Town, Groote Schuur Hospital, Observatory, South Africa.
 |
ABSTRACT |
The generation of autoantibodies and deposition of immune complexes
(ICs) in tissue play a primary role in autoimmune diseases. However,
the IC-triggered response consists of complex mechanisms that make it
difficult to identify the pathogenesis and develop specific therapy. We
clarified here a sequential mechanism for the induction of
hypersensitivity angiitis by analyzing the responsible Fc receptor
(FcR), effector cells, and mediators in an animal model using
FcR-deficient mice. In this model, rheumatoid factor-mediated skin
vasculitis was induced in wild-type mice, whereas FcR -deficient mice
did not develop the vasculitis. Adoptive transfer of various FcR+ cells into FcR-deficient mice showed that mast
cells but not macrophages derived from wild-type mice triggered skin
vasculitis. Mast cells derived from either FcRIII-deficient or tumor
necrosis factor (TNF)-deficient mice did not possess the inducibility
of skin vasculitis. These results indicate that triggering of vascular inflammation was induced by mast cells through IC binding on FcRIII. TNF produced by such activated mast cells was mainly responsible for
the pathogenesis of autoantibody-mediated vasculitis. These findings
illustrate the clinical significance of mast cells, Fc receptors,
and TNF in IC-induced vasculitis syndrome.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
VASCULITIS IS A clinicopathologic process
characterized by inflammation and necrosis of blood vessels that leads
to vessel occlusion and ischemia of tissues. Vasculitis may occur as a
primary process or as a component of other underlying diseases. The
pathogenesis of vasculitis involves a variety of mechanisms acting in
concert to bring about necrotizing inflammation of vessel walls.
Although most types of vasculitis are associated with immunologic abnormalities, the primary immunopathogenic events for initiating the
vascular inflammation are still unknown.
In some human vasculitis syndromes, elevated levels of circulating
immune complexes (ICs) and deposits of complement and Ig in vasculitic
lesions are frequently observed, implying that ICs might play a primary
role in their pathogenesis. These syndromes include
Henoch-Schönlein purpura, essential cryoglobulinemia, hepatitis
B-associated polyarteritis nodosa (PAN), and vasculitis associated with
collagen diseases and are collectively called hypersensitivity
angiitis. Although these syndromes have long been suspected of being
mediated mainly by complement activation, just how the pathogenic IC
formation initiates the process of inflammation is still not fully understood.
IgG Fc receptors (FcRs) are expressed primarily on immune effector
cells and link cellular and humoral immunity and trigger inflammatory
activities of effector cells. There are 3 classes of FcR: FcRI
(CD64), FcRII (CD32), and FcRIII (CD16). Whereas FcRI is a
high-affinity receptor, FcRII and FcRIII are low-affinity receptors, which bind only polymeric IgG or IC. Whereas FcRII is a
single-chain receptor, both FcRI and FcRIII require the association of chains (FcR) with a ligand-binding  chain for surface expression and signal transduction. FcR is also associated with high-affinity IgE receptor (Fc RI). Indeed, FcR-deficient mice lack the functional expressions of FcRI, FcRIII, and
FcRI.1,2 Recent analyses of various FcR-deficient mice
have shown that FcR plays crucial roles in IC-triggered
inflammation.1-6 FcR-deficient mice were unable to
induce IgG-mediated phagocytosis by macrophages and IgE-mediated
anaphylaxis by mast cells.1 More importantly, it was shown
that Arthus reaction induced by specific ICs was severely reduced in
both FcR- and FcRIII-deficient mice.4,5 FcR-deficient
mice also exhibited reduced experimental hemolytic anemia and
thrombocytopenia,3 Ab-dependent antitumor
immunity,7 and anti-glomerular basement membrane (GBM)
Ab-induced or genetically occurring glomerulonephritis.2,8
These results of experimental inflammatory type II and III responses
suggest the possibility that a wide range of inflammatory diseases and
related autoimmune diseases may be initiated by FcR-dependent
mechanisms. Therefore, we analyzed the contribution of FcR to the
pathogenesis of vasculitis as a model of human hypersensitivity
angiitis by using FcR-deficient mice2 and then analyzed
the sequential mechanisms, including identification of the responsible
effector cells, receptors, and mediators using various gene-knockout mice.
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MATERIALS AND METHODS |
Mouse.
C57BL/6 and Balb/c mice were purchased from the Shizuoka Laboratory
Animal Corp (Hamamatsu, Japan). The establishment and characteristics
of FcR-, FcRIII-, and tumor necrosis factor (TNF)
 -deficient mice have been described
previously.2,4,9,10 FcR / mice were
established with C57BL/6 background by the use of C57BL/6 ES cell line,
and FcRIII- and TNF-deficient mice derived from ES cells with
129-origin were backcrossed several generations with C57BL/6 mice. For
the present experiments, these knockout mice were crossed again with
BALB/c mice to obtain Igha allotype background to be
recognized by 6-19 monoclonal antibody (MoAb).11 The
offsprings were intercrossed to obtain FcR+/ and
FcR/ mice. The FcR alleles were analyzed with tail
DNA by polymerase chain reaction (PCR) using pairs of primers: the pair
of 5'-GGAATTCGCTGCCTTTCGGACCTGGAT-3' (exon 3-specific) and 5'-GCCAACGCTATGTCCTGATAG-3' (neor-specific) for
the targeted allele, and the other pair of the former one (exon
3-specific) and 5'-GAAAATCGATGCTGTCCT GTTTTTGTA-3' (exon
4-specific) for the wild-type allele. All mice were bred and maintained
in our own animal facility under SPF conditions and used for
experiments at 10 to 15 weeks of age.
Antibodies.
Hybridoma cells producing 6-19 MoAb were established from MRL-lpr/lpr
mice11; their characteristics have been extensively analyzed.12-14 Hybridomas producing anti-CD4 (GK-1.5) and
anti-CD8 (53-6.7) MoAbs were obtained from ATCC (Rockville,
MD) and MoAbs were obtained from ascites and purified over
protein A-beads column. Biotinylated IgE (anti-dinitrophenol [DNP]
IgE; Sigma, St Louis, MO), anti-c-Kit MoAb (ACK4; kindly provided by
Dr Shin-ichi Nishikawa, Department of Molecular Genetics, Kyoto
University Graduate School of Medicine, Kyoto, Japan),
anti-FcRII/III (2.4G2), fluorescein isothiocyanate (FITC)
anti-Mac-1 MoAb, phycoerythrin (PE) anti-Gr-1 MoAb, and anti-rat IgG
(PharMingen, San Diego, CA) were used for cytometric analysis. Anti-TNP
MoAb (PharMingen) was used for stimulation of mast cells and
macrophages through FcR as immobilized IgG1.
Cell preparation.
For mast cell preparation, bone marrow cells from wild-type and
knockout mice were cultured by 10% fetal calf serum (FCS) supplemented
with 15% WEHI-3 conditioned medium as a source of interleukin-3
(IL-3). Nonadherent cells were harvested and resuspended in the same
medium weekly. After 4 weeks of culture, greater than 90% of the cells
were c-kit+. These bone marrow-derived mast cells were
harvested and resuspended in phosphate-buffered saline (PBS) at a
density 1 × 106 per 30 µL or 1 × 107 per 300 µL for subcutaneous (SC) and intravenous
(IV) injections, respectively. The mast cells were
immediately injected into FcR/ mice with or without
6-19 inoculation 7 days before. For macrophage preparation, 3 mL of
thioglycolate medium (DIFCO, Detroit, MI) was injected
intraperitoneally (IP) into FcR+/ littermates. Seven days after injection, the peritoneal cavity was washed with PBS
and the fluid was collected. To obtain activated macrophages, 20 µg
of lipopolysaccharide (LPS; serotype 0127:B8; Sigma) was injected 2 days before cell harvest. Adherent cells in 2.5 mmol/L EDTA/PBS were
harvested and resuspended in PBS at the same densities as for the SC
and IV injections described above. Approximately 90% to 95% of the
recovered cells were Mac-1+.
Induction of skin vasculitis and glomerulonephritis.
Pristane-treated mice were injected with a mixture of anti-CD4 MoAb
(GK1.5) and anti-CD8 MoAb (53-6.7; 500 µg of each MoAb) 1 day before
and 1 day after the hybridoma injection. Hybridoma cells instead of
6-19 MoAb were inoculated because both skin vasculitis and
glomerulonephritis can be induced only after the implantation of
hybridoma cells. Mice were inoculated IP with 107 6-19 hybridoma cells and killed when moribund (generally 7 to 12 days after
the implantation of hybridomas). The macroscopic appearance of skin
lesions was carefully noted. The ear skin and kidneys were subjected to
histological analysis. Positive vasculitis was evaluated by macroscopic
observation of skin purpura of the ear and the extravasation of
erythrocytes by histological analysis. Leukocyte invasion in the ear
lesion was always associated with positive vasculitis, in conjunction
with extravasation of erythrocytes.
Histological analysis.
Blocks of ear skin and kidneys were obtained at autopsy and sections
were stained with hematoxylin-eosin (HE) and periodic-acid Schiff (PAS)
for histopathological examination. Sections were also studied for
deposition of IgG3 by direct staining with FITC-conjugated antimouse
IgG3 Ab (PharMingen). For staining of mast cells in the skin, ears from
wild-type and TNF/ mice were fixed in formalin, and
sections were stained with naphthol AS-D chloroacetate, N,N'-dimethylformaide, and hexazotized new fuchsin, pH 6.3.
Serum titration of Ab and blood urea nitrogen (BUN).
Blood was collected from mice at death for IgG3 and BUN determinations.
After removal of fibrin clot at 37°C, sera were placed in conical
tubes at 4°C for 3 days to precipitate cryoglobulin. The
supernatant was used for BUN determination, whereas the precipitates were used for the measurement of the serum 6-19 MoAb level. The precipitates were washed and resolubilized in 4 mol/L urea in the same
volume as the original sera. The solubilized samples were subjected to
enzyme-linked immunosorbent assay (ELISA) using plates coated with
sheep antimouse Ig Ab. After washing, horseradish peroxidase
(HRP)-conjugated sheep antimouse IgG3 (Serotec, Oxford, UK) was added. Then, after incubation with o-Phenylenediamine as a substrate (Wako, Osaka, Japan), the samples were read
spectrophotometrically with an ELISA plate reader. J606, the IgG3 class
myeloma protein, was used to generate a reference standard curve.
Flow cytometric analysis.
Mast cells were stained with nonlabeled antibody or with biotinylated
IgE for 60 minutes on ice, followed by PE anti-rat IgG or PE
streptavidine for 40 minutes. Mast cells were also stained with
directly labeled antibodies for 60 minutes. After washing, cells were analyzed on a FACScan (Becton Dickinson, Mountain View, CA) using CELL Quest software (Becton Dickinson).
Degranulation assay of mast cells.
Mast cells were incubated with or without 10 µg/mL of anti-DNP mouse
IgE for 2 hours at 37°C. The cells were then challenged with 15 ng/mL of DNP-bovine serum albumin (DNP-BSA; Sigma) for 30 minutes.
Nonsensitized mast cells stimulated with 200 ng/mL of A23187 (Wako)
were used for positive control. The supernatants were collected for
measurement of -hexosaminidase. The cell pellets were lysed with
0.5% Triton X in tyrode buffer (130 mmol/L NaCl, 5 mmol/L KCl, 1.4 mmol/L CaCl2, 1 mmol/L MgCl2, 5.6 mmol/L
glucose, 10 mmol/L HEPES, and 0.1% BSA, pH 7.4). Supernatants and cell lysates were incubated with substrate (1.3 mg/mL p-nitrophenyl-N-acetyl -D-glucosamine [Sigma] in 0.1 mol/L sodium citrate, pH 4.5) for 2 hours at 37°C. The reaction was stopped by 0.2 mol/L glycine and
the enzyme reactivity was evaluated by measuring optical density at 405 nm. The percentage of specific -hexosaminidase release was
calculated as follows: percentage re- lease = 100 × supernatant activity/(supernatant activity + cell lysate activity).
Measurement of TNF.
Mast cells and macrophages were stimulated with 50 µg/mL immobilized
mouse IgG1 or 12 µg/mL immobilized 2.4G2 for 30 minutes. Culture
supernatants were collected and TNF levels in supernatant were
measured using an ELISA kit (Endogen, Woburn, MA) according to the
manufacturer's protocol.
| |
RESULTS |
We have previously shown that a fraction of murine IgG3 anti-IgG2a
rheumatoid factor (RF) MoAbs with cryoglobulin activity, typically
represented by 6-19 MoAb derived from lupus-prone MRL/MpJ-lpr/lpr (MRL-lpr) mice, induces skin vasculitis in association with IC formation and glomerulonephritis resembling wire-loop glomerular lesions in normal mice.11,12 We used this animal model of
hypersensitivity angiitis associated with cryoglobulinemia to analyze
the molecular basis of the induction of skin vasculitis.
FcR-deficient mice did not develop skin vasculitis.
To determine whether FcR is involved in the induction of skin
vasculitis and glomerulonephritis in vivo, we injected 6-19 hybridoma
cells into FcR+/ and FcR/ mice and analyzed
the development of inflammatory responses. A protocol of injecting purified 6-19 MoAb cannot be used because of its cryoprecipitability. Seven to 12 days after the IP injection of 6-19 hybridoma,
FcR+/ mice developed vascular purpura on the skin of ears,
tails, and footpads. In contrast, none of the FcR/
mice injected with 6-19 hybridoma developed the characteristic purpura
(Table 1 and
Fig 1A). Histological examination confirmed
these results (Fig 2). 6-19-treated
FcR+/ mice exhibited leukocytoclastic vasculitis in the skin,
characterized by infiltration of polymorphonuclear leukocytes (PMNs)
and extravasation of erythrocytes (Fig 2B). In contrast, treated
FcR/ mice did not show any indication of inflammatory
responses (Fig 2C), remaining the same as untreated normal mice (Fig
2A). Serum levels of IgG3 (Table 1) and the presence of intracapillary
PAS-positive materials, likely ICs with cryoglobulins, in the skin were
comparable in FcR+/ and FcR/ mice. Indeed,
immunofluorescence staining of sections of affected skin by anti-IgG3
MoAb demonstrated that IgG3 deposits corresponding to the PAS-positive
material in the vascular lumens were present in both groups of mice
(Fig 3A and B, see page
3858
). These
results indicate that skin vasculitis is completely inhibited in
FcR/ mice despite the fact that the depositions of ICs
containing IgG
3
were similar to those in wild-type mice.
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| Fig 1.
Macroscopic appearance of skin vasculitis. (A)
6-19-treated FcR+/ mice developed purpura in the ear, tail,
and footpads (upper mouse), whereas 6-19-treated FcR/ mice
failed to develop vascular purpura (lower mouse). (B) 6-19-treated
FcR/ mice were SC inoculated with 1 × 106 BMMC
in the left ear and with PBS in the right ear as a control. After 1 to
2 days, vascular purpura appeared in the restricted site of the BMMC
injection (arrow).
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| Fig 2.
Representative histological appearance of 6-19-induced
skin lesions. The sections of the ear from untreated normal mice (A)
and 6-19-treated FcR+/ (B), FcR/ (C), and
TNF / (D) mice were prepared 12 days after IP injection of
6-19 hybridoma cells. Tissues sections were stained with HE (original
magnification × 100). FcR+/ mice developed leukocytoclastic
vasculitis characterized by the infiltration of PMNs and the
extravasation of erythrocytes (B). FcR/ and TNF/ mice
did not develop leukocytoclastic vascular lesions (C and D). Note that
in (D), darkly stained cells were melanocytes due to 129 background and
that small numbers of PMNs had infiltrated the skin of TNF/
mice.
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| Fig 3.
Deposition of IgG3 RF on the vessel wall of ear skin. Ear
sections from 6-19-treated FcR+/ (A) and FcR/ (B)
mice and nontreated FcR+/mice (C) were stained with
FITC-anti-IgG3 Ab (original magnification × 200).
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Differential effects of FcR on induction of vasculitis and
glomerulonephritis.
In contrast to the results with skin vasculitis, both FcR+/
and FcR/ mice developed typical glomerulonephritis by
6-19 treatment: exudation of PMNs, disseminated plugging of glomerular capillaries by voluminous PAS-positive hyaline thrombi, an increase in
glomerular cellularity (Fig 4B and C), and
electron-dense subendothelial deposits resembling wire-loop lesions
(data not shown), as previously described15 (Fig 4A). All
mice became sick and showed muscle weakness and low mobility from 7 to
12 days after the 6-19 injection, and they finally died. The serum
levels of BUN from FcR+/ and FcR/ mice were
equally elevated at the moribund stage (Table 1). These results
indicate that, unlike skin vasculitis, deposition of 6-19 cryoglobulin
induces glomerulonephritis in an FcR-independent manner. This is
compatible with earlier reports that 6-19 MoAb possesses different
pathogenic potential for vasculitis and
glomerulonephritis.11,13,14 Because there was no difference
in the induction of this type of nephritis between FcR+/
and/ mice, we focused on the analysis of vasculitis to
try to identify the effector cells and effector mediators involved in
this disease.
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| Fig 4.
Representative histological appearance of 6-19-induced
glomerular lesions. The sections of the ear from untreated normal mice
(A) and 6-19-treated FcR+/ (B), FcR/ (C), and
TNF/ (D) mice were prepared 12 days after the IP injection
of 6-19 hybridoma cells. Tissues sections were stained with HE
(original magnification × 400). 6-19-treated FcR+/ mice
developed glomerulonephritis with global proliferative and exudative
changes (B). FcR/ and TNF/ mice developed similar
glomerular lesions (C and D).
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Mast cells as the responsible effector cells of vasculitis.
To determine the pathogenic effector cells that trigger vasculitis, we
devised a cell transfer system in which various FcR+ cells
from wild-type mice were transferred SC or IV into 6-19-injected FcR/ mice that had the depositions of IC but did not
develop vasculitis. As shown in Table 2,
the IV transfer of 1 × 107 bone
marrow-derived mast cells (BMMC) induced typical skin vasculitis, whereas the injection of peritoneal macrophages did not. To assess the
possibility that the capability of macrophages to induce the disease
was dependent on the stage of activation, LPS-activated macrophages
were also IV injected. However, these cells failed to trigger
vasculitis (Table 2). To exclude the possibility that the macrophages
might be trapped in tissues and/or could not migrate into the ear, we
performed a similar experiment by SC injection of these
FcR+ cells into the ear (1 × 106 cells
per site). The results were the same; only mast cells induced skin
vasculitis in 6-19-injected FcR/ mice (Table 2). In
this case, vascular purpura developed on the restricted site, where mast cells were transferred 1 to 4 days (2 days in most cases) after
the SC injection of BMMC, and the rest of the skin remained intact (Fig
1B). These results indicate that, among FcR-expressing cells, mast
cells possess the specific ability to induce FcR-mediated skin
vasculitis. To confirm the phenotype and function of the mast cells
that were used for the transfer experiment, we characterized the BMMC
by the staining of cell surface molecules and degranulation assay
(Fig 5A and B). BMMC cultured
in vitro for 4 weeks became almost a homogeneous population that
coexpressed c-Kit and FcRII/III and did not express Mac-1 and Gr-1.
BMMC from wild-type mice but not from FcR/ mice
expressed FcRI (Fig 5A). These BMMC from wild-type mice released
-hexosaminidase, a granule-associated enzyme of the murine mast
cells, in response to cross-linking of FcRI, whereas BMMC from
FcR/ mice showed no such release. FcR/ BMMC released -hexosaminidase upon stimulation
with Ca2+ ionophore, indicating that these cells contained
the enzyme but failed to release it (Fig 5B). These data indicate that
the BMMC used in the analysis represented functional mast cells.
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| Fig 5.
Characterization of the BMMC and macrophages used for
transfer experiment. (A) Surface expression of Fc R, c-Kit,
FcRII/III, Mac-1, and Gr-1 on BMMC. BMMC from FcR +/+,
FcR/, and TNF/ mice were stained with biotinylated
IgE plus avidin-PE, anti-c-Kit, 2.4G2, anti-Mac-1 MoAb, and
anti-Gr-1 MoAb. The dotted line indicates control staining. (B)
-hexosaminidase assay of BMMC. BMMC from FcR +/+,
FcR/, and TNF/ mice were stimulated by FcRI
cross-linking by biotin-IgE and avidin or by
Ca2+-ionophore for 30 minutes. -hexosaminidase
activity in the supernatants and the lysate of the cell pellets was
quantified by spectrophotometric analysis as described in Materials and
Methods. Total -hexosaminidase content (supernatant activity plus
lysate activity) was similar in these cells (data not shown). (C)
FcR-induced release of TNF. Macrophages and BMMC from FcR
+/+, FcR/, and TNF/ mice were stimulated with
or without 50 µg/mL immobilized IgG1 or 12 µg/mL immobilized 2.4G2
for 30 minutes. TNF released into the media was measured by ELISA.
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FcRIII as the receptor responsible for induction of vasculitis.
BMMC developed in the presence of IL-3 are thought to represent the in
vitro equivalent of mucosal mast cells16 and coexpress FcRII, FcRIII, and FcRI.17 To examine
the specific contribution of the Fc receptors for the recognition of
ICs and induction of vasculitis, BMMC from FcR+/,
FcR/, and FcRIII/ mice that express
FcRII/FcRIII/FcRI, FcRII, and FcRII/FcRI,
respectively, were transferred into 6-19-injected
FcR/ mice. FcRIII/ mice lacking the
chain of FcRIII have been shown to be deficient in IgG-mediated
mast cell degranulation, to be resistant to IgG-dependent passive
cutaneous anaphylaxis, and to exhibit an impaired Arthus reaction.4 Transfer of BMMC from either
FcR/ mice or FcRIII/ mice could not
induce skin vasculitis in 6-19-injected FcR/, but
those from FcR+/ mice caused vasculitis
(Table 3). IV transfer of BMMC from
FcR/ and FcRIII/ mice, similar to
that shown in Table 3 for SC transfer, failed to induce skin vasculitis (data not shown). This result clearly demonstrates that FcRIII, but
not other FcRs on mast cells, is responsible for the initiation of
vascular inflammation. This was confirmed by the finding that the
injection of 6-19 cells failed to induce skin vasculitis in FcRIII/ mice (data not shown).
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Table 3.
FcRIII on Mast Cells and TNF Released From Mast
Cells Are Responsible for the Pathogenesis of Skin Vasculitis
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TNF as the primary mediator for induction of vasculitis.
Aggregation of FcR or FcR on mast cells leads to the rapid
release of various mediators, including histamine, proteoglycans, and
proteases from cytoplasmic granules, and to the induction of the
synthesis and secretion of other mediators such as leukotrienes, prostaglandins, and platelet-activating factor (PAF) as well as a
variety of cytokines, including TNF. Among these, leukotrienes, PAF,
and TNF are possible candidates for mediators of leukocytoclastic angiitis, because they strongly induce PMN recruitment and the destruction of vessel walls. Among them, TNF turned out to be a crucial
mediator, based on our finding that TNF-deficient mice10 failed to develop skin vasculitis in this system
despite the fact that some PMNs were observed in the ear section (Fig 2D). On the other hand, these mice still developed glomerulonephritis similar to wild-type and FcR/ mice (Fig 4D and
Table 4). Staining of ear skin from
wild-type and TNF/ mice with naphthol AS-D chloroacetate esterase exhibited similar distribution and number of
mast cells in the tissue (Fig 6, see page
3858
). These results suggest that TNF is important for the effector
phase of mast cells, but not for maturation or migration. To further
establish the critical role of TNF in the induction of vasculitis,
particularly in relationship with mast cells, BMMC from
TNF-deficient mice were transferred subcutaneously into
6
-
19
-injected FcR/ mice. We found that the transfer
of BMMC from TNF/ mice also failed to induce skin
vasculitis in
6
-
19
-treated FcR/ mice (Table 3). BMMC
from TNF/ mice show a similar surface phenotype (FcR+c-Kit+FcRII/III+Mac-
1
 Gr-
1
)
to wild-type BMMC and also function similarly in terms of the release
of -hexosaminidase in response to FcR cross-linking (Fig 5A and
B). Furthermore, we found that BMMC release a higher level of TNF than
macrophages in the early phase of stimulation through FcR (Fig 5C).
These data suggest that TNF released from mast cells upon stimulation
via FcRIII is the main mediator responsible for the pathogenesis of
skin vasculitis.
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| Fig 6.
Esterase staining of skin of the ear. Ear skin
tissues from wild-type and TNF/ mice were fixed in formalin
and sections were stained with naphthol AS-D chloroacetate,
N,N'-dimethylformamide, and hexazotized new fuchsin, pH 6.3. Arrowheads indicate esterase-positive cells. Estimated numbers of mast
cells were 16.4 ± 1.4/field and 18.1 ± 3.2/field, respectively.
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| |
DISCUSSION |
When organ damage becomes clinically evident, various bystander cells
and effector molecules present in the tissues make it difficult to
understand the pathogenesis. However, in the present study, we
succeeded in unraveling this complex pathogenesis by identifying the
effector cells, receptors, and mediators responsible for the induction
of skin vasculitis by the use of various knockout mice. To the best of
our knowledge, this is the first analysis of such sequential mechanisms
of the cells, receptors, and mediators responsible for the pathogenesis
of a particular disease. We developed a transfer system in which
various FcR+ cells from several knockout mice, such as
FcR-, FcRIII-, and TNF-deficient mice, were transferred into 6-19 MoAb-treated FcR-deficient mice to identify the responsible cells
and molecules. This system was fundamentally based on the observation
that there were similar levels of IC deposition on the vessels of
FcR+/ and FcR/ mice, although only the
former developed vasculitis.
Because 6-19 MoAb-induced vasculitis was induced neither in
B-cell-depleted mice that had markedly reduced serum levels of IgG2a12 nor by a chimeric 6-19 MoAb whose  chain was
replaced by  light chain,12 the formation of IC of host
IgG2a and IgG3 anti-IgG2a RF must be crucial for the induction of the
disease. The fact that non-IgG3 RFs13 were unable to induce
vasculitis despite their reactivity to IgG2a further suggests that the
pathogenicity of ICs arises from a self-associating property of IgG3.
Although such ICs were precipitated at a similar level on the vessels
of FcR/ mice, as shown by histochemical staining for
IgG3, the deposition of these auto-ICs per se could not lead to the
development of vasculitis. Apparently, complement activation is not
essential in the pathogenesis of skin vasculitis.15
Instead, the triggering of the disease is mediated by recognition of IC
by FcR+ cells, which activates these cells and induces the
secretion of several inflammatory mediators that recruit PMNs and
induce damage to blood vessels.
It was surprising to find that the cells responsible for triggering
skin vasculitis are mast cells. Mast cells have been known to be the
main effector cells in IgE- and IgG-mediated type I hypersensitivity.
However, considering the recent report by Sylvestre and
Ravetch5 that mast cells trigger Arthus reaction, it could easily be supposed that mast cells also play a critical role in type
III hypersensitivity diseases. Indeed, our observation that vasculitis
in FcR/ mice was induced as soon as 1 to 3 days after
IV transfer of mast cells suggests that mast cells recognize IC on the
vessel walls and trigger vasculitis within a short period. This
suggests an additional function of mast cells, ie, they not only reside
in the cutaneous or mucosal surface sensitized by antigen-specific IgE,
but also survey ICs and direct their clearance. Although the
inducibility of vasculitis was not detected in macrophages in our
system, the possibility that small populations of macrophages or other
types of FcR+ cells also possess the capacity to induce
vasculitis cannot be ruled out. However, because a subcutaneous cell
transfer system was used, we could exclude the possibility that the
inability of macrophages to induce vasculitis was due to the failure to migrate into the tissues.
We determined that FcRIII on mast cells and TNF from mast cells are
the responsible receptor and mediator, respectively, for triggering
this type of vasculitis. Because FcRIII apparently lacks a
significant affinity to the complexes of the IgG3
isotype,18 an efficient interaction of host IgG2a present
in the IgG3 cryoglobulin complexes with FcRIII may be responsible
for the activation of mast cells. This idea is consistent with the fact
that non-IgG3 anti-IgG2a RF lacking cryoglobulin activity or IgG3
cryoglobulins lacking anti-IgG2a RF activity fail to induce skin
vasculitis.13,14 TNF can be released rapidly from
preformed granules of mast cells, and then its transcripts are induced
at a later stage of activation.19 TNF production by mast
cells was induced upon stimulation through FcR, particularly
FcRIII.20 Furthermore, several studies have demonstrated
that TNF is an important mediator of mast cell-dependent leukocyte
recruitment both in response to IgE and antigen21 or
ICs22 and also is strongly involved in the damaging of
vessel walls.23 These previous results are consistent with
our present observation that TNF released from mast cells upon
cross-linking of FcRIII with ICs plays an essential role in the
induction of vasculitis. In fact, the BMMC from FcR+/+ mice used in
our transfer experiments released TNF in response to FcR
cross-linking within a short period. BMMC release more TNF than
macrophages do, probably due to the immediate degranulation of
preformed TNF within the granules in mast cells, which macrophages
do not possess. Such degranulation may induce a rapid increase of
TNF concentration in local areas and induce the expression of
adhesion molecules in endothelial cells and leukocytes. Over a longer
time course (>6 hours), TNF released from FcR+/+ macrophages
reached to the similar or even higher level of that of BMMC in vitro
(data not shown). However, such late secretion of TNF from
macrophages appears to be less effective in inducing vasculitis.
There are several possibilities for the selective inducibility of
inflammation by mast cells in vivo, such as differences in the release
of inhibitory molecules, diversion by FcRI or FcRII, different
requirements of cofactors, and so on. Among them, TNF released from
mast cells appears to be the most upstream key mediator for the
initiation of skin vasculitis. TNF promotes the recruitment of
inflammatory leukocytes into tissues, which release lysosomal enzymes,
oxygen radicals, and arachidonic acid metabolites. These mediators
directly damage the endothelium and result in the generation of other
toxic mediators, such as eicosanoids, and the production of
inflammatory cytokines (IL-1, TNF, etc) from infiltrating
lymphocytes. These factors are chemotactic for leukocytes, thereby
promoting further migration of leukocytes and the perpetuation of this
process. It was noted that small numbers of PMNs aggregated at the ear
of 6-19-treated TNF-deficient mice, although vasculitis did not
develop. In contrast, infiltrating cells were not observed at all in
FcR/ mice. This difference may suggest the possibility
that some other mediators TNF are also involved cooperatively with TNF
to induce vasculitis.
Unlike the case of vasculitis, 6-19 MoAb-induced glomerulonephritis was
not inhibited in FcR/ mice. It has been shown that, whereas vasculitis requires IC with cryoglobulin, glomerulonephritis was induced by the deposition of cryoglobulin alone, independently of
IC formation.12 We also observed that the anti-GBM Ab
inducible glomerulonephritis was not induced at all in
FcR/ mice.2 FcR-dependent development of
glomerulonephritis has also been demonstrated in (NZBxNZW)F1
mice.8 Thus, in terms of the requirement of FcR for the
induction of diseases, it is indeed essential for the induction of skin
vasculitis as well as the glomerulonephritis inducible by anti-GBM Ab
and also for that in BWF1 mice, whereas 6-19-induced
glomerulonephritis is induced independently of FcR and IC formation.
In contrast, preliminary results showed that FcR/ mice
backcrossed with MRL/lpr mice developed lethal glomerulonephritis (GN) as severe as conventional MRL/lpr mice. Considering
that MRL/lpr mice spontaneously generate extremely large amounts of IgG3 cryoglobulins,24,25 these results suggest that
lupus-like nephritis in MRL/lpr mice might be more dependent on the
production of IgG3 cryoglobulins, unlike the BWF1 mice. Thus, this
illustrates the heterogeneity of the induction mechanisms of GN in
different murine models of systemic lupus erythematosus.
GN in BWF1 mice and anti-GBM Ab-induced glomerulonephritis may be
triggered by the recognition of IC and the release of specific
mediators by specific FcR+ cells such as mast cells for
vasculitis and mesangial cells for glomerulonephritis. The distinct
mechanism of 6-19 MoAb-induced glomerulonephritis still has to be determined.
The position of FcRIII as the gateway to the immune cascade leading
to skin vasculitis makes it a potentially attractive candidate as a
target for directed immunotherapy. Instead of the corticosteroids often
used as the first line of treatment for hypersensitivity angiitis, a
functional FcR blocker that can inhibit the function of and/or
signaling through FcRs and then impede mast cell activation should
be developed as a pathogenesis-specific treatment. For example, soluble
FcR,26 anti-FcR antibodies, or FcR binding
peptides could be used. Furthermore, considering the fact that TNF
production upon degranulation of mast cells induces vasculitis, the
administration of antiallergic drug (degranulation inhibitor) or
anti-TNF Ab may also function as a potent treatment for the vasculitis
syndrome. The frequency of IgG3 anti-IgG2a cryoglobulins in human
cryoglobulinemia has not been precisely analyzed. It may not be very
frequent, because Gorevic et al27 reported that 22% of the
cryoglobulins from their 40 cryoglobulinemia patients were found to be
monoclonal IgG, whereas 62% were mixed, containing 2 or more Ig
classes. In these cases, all of the sera tested showed RF activity and
93% of the patients presented cutaneous involvement (purpura).
Accordingly, a certain proportion of human hypersensitivity angiitis
cases might be induced by mechanisms similar to those described here,
suggesting the possible application of the treatment discussed above
for the diseases.
| |
ACKNOWLEDGMENT |
The authors are grateful to M. Sakuma and R. Shiina for preparing
MoAbs, Dr K. Arase for experimental help, and H. Yamaguchi for
secretarial assistance.
| |
FOOTNOTES |
Submitted December 22, 1998; accepted July 21, 1999.
Supported by Grants-in-Aids for Scientific Research from the Ministry
of Education, Science and Culture and from the Ministry of Welfare, a
grant from the Swiss National Foundation for Scientific Research, and a
grant from the Deutsche Forschungsgemeinschaft DFG Ge 892/5-1 and SFB 244.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Takashi Saito, PhD, Department of Molecular
Genetics, Chiba University Graduate School of Medicine, 1-8-1 Inohana,
Chuo-ku, Chiba 260-8670, Japan; e-mail: saito{at}med.m.chiba-u.ac.jp.
| |
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ABSTRACT
INTRODUCTION