By
From the * Department of Experimental Immunology, Institute of Development, Aging and Cancer,
Tohoku University, Sendai 980-8575, Japan; the Core Research for Evolutional Science and
Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan;
the § Second Department of Pathology, Okayama University Medical School, Okayama 700-8558, Japan; and the
Laboratory of Molecular Genetics and Immunology, The Rockefeller University,
New York 10021
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Autoimmune diseases, like rheumatoid arthritis, result from a dysregulation of the immune response culminating in hyperactivation of effector cells leading to immune-mediated injury. To
maintain an appropriate immune response and prevent the emergence of autoimmune disease,
activation signals must be regulated by inhibitory pathways. Biochemical and genetic studies
indicate that the type IIB low-affinity receptor for immunoglobulin (Ig)G (FcRIIB) inhibits
cellular activation triggered through antibody or immune complexes and may be an important
component in preventing the emergence of autoimmunity. To investigate the role of Fc
RIIB
in the development of type II collagen (CII)-induced arthritis (CIA), a model for rheumatoid arthritis in humans, we have examined its contribution in determining the susceptibility to CIA
in the nonpermissive H-2b haplotype. H-2b mice immunized with bovine CII do not develop
appreciable disease. In contrast, immunization of the Fc
RIIB-deficient, H-2b mice with bovine CII induced CIA at an incidence of 42.2%. The maximal arthritis index of the Fc
RIIB-deficient mice developing CIA (6.9 ± 3.6) was comparable to that of DBA/1 mice (8.6 ± 1.9), an H-2q strain susceptible for CIA induction. IgG1, IgG2a, and IgG2b antibody responses
against CII were elevated in the Fc
RIIB-deficient animals, especially in those mice showing
arthritis, but less pronounced than DBA/1 mice. Histological examinations of the arthritic paws from Fc
RIIB-deficient mice revealed that cartilage was destroyed and bone was focally
eroded in association with marked lymphocyte and monocyte/macrophage infiltration, very
similar to the pathologic findings observed in DBA/1 mice. These results indicate that a nonpermissive H-2b haplotype can be rendered permissive to CIA induction through deletion of
Fc
RIIB, suggesting that Fc
RIIB plays a critical role in suppressing the induction of CIA.
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The Fc receptors (FcRs) for Igs constitute a family of
hematopoietic cell surface molecules that include receptors which can either stimulate or inhibit cellular responses upon binding of antibody-antigen complexes (for
reviews, see references 1). Triggering the activation receptors, FcRI and III or Fc
RI elicits a variety of effector
functions, including phagocytosis (7), antibody-dependent cell-mediated cytotoxicity (10), and the release of
inflammatory mediators (for reviews, see references 1 and
2). Analysis of FcR-deficient mice has revealed the central
roles these receptors play in the mechanism of initiating type I, II, and III hypersensitivity reactions. In vivo,
the binding of antibody-antigen complexes to their cognate FcRs is both necessary and sufficient to trigger anaphylaxis (11, 12, 14), autoimmune hemolytic anemia
and thrombocytopenia (13), the Arthus reaction (17),
and autoimmune glomerulonephritis (20). In addition, the
interaction of cytotoxic antitumor antibodies with FcRs is a necessary prerequisite for mediating the in vivo activity of these molecules (21).
These activation responses are modulated by the type IIB
FcR for IgG (FcRIIB),1 the most widely expressed FcR.
Fc
RIIB suppresses B cell, mast cell, and macrophage activation triggered by cross-linking B cell receptor (BCR) or
FcRs (22). Disruption of Fc
RIIB by gene targeting resulted in mice with elevated Ig levels in response to both
thymus-dependent and thymus-independent antigens, enhanced passive cutaneous anaphylaxis reaction (26), and
enhanced immune complex (IC)-mediated alveolitis (25).
These studies indicate that Fc
RIIB physiologically acts as
a negative regulator of IC-triggered activation (26) and may function in vivo to suppress autoimmunity by regulating both B cell responses and effector cell activation.
Collagen-induced arthritis (CIA), a model for rheumatoid arthritis (RA) in humans, is a chronic inflammatory arthropathy that can be induced in susceptible rodents by immunization with native type II collagen (CII [27-31]). The histopathology of this arthritis is characterized by a proliferative synovitis that erodes the adjacent cartilage, ultimately producing articular injury and ankylosis. Detailed investigations of the immune responses to CII have been undertaken to determine the precise sequence of events leading to CIA. The development of arthritis is thought to be associated with the synergistic effect of high levels of cell-mediated and humoral immunity to CII (27, 29, 30). CIA and RA are clearly associated with the MHC region (32), and in mice only H-2q and H-2r haplotypes are susceptible to CIA (33, 34). The responsible gene in the H-2q haplotype has been isolated and codes for the Aq class II molecule (35), which binds peptides derived from CII, thus leading to T cell activation which is of crucial importance for development of arthritis in this model (36, 37). In addition, a strong B cell response is activated in CIA, producing IgG directed towards CII-specific structures (28, 38). There is evidence that these antibodies are directly pathogenic, as shown by transfer experiments (39, 40), as well as synergizing with activated T cells to promote the development of arthritis (41, 42). B cell-deficient mice on a susceptible background do not develop CIA, indicating that B cells play a crucial role for development of CIA (43).
In this study, we demonstrate that FcRIIB-deficient
(Fc
RIIB
/
) mice on a nonpermissive background (H-2b)
become susceptible to CIA induction upon immunization
with CII. The histopathological characteristics of the arthritic paws were similar to those observed in CIA-susceptible DBA/1 mice (H-2q). Fc
RIIB
/
animals show augmented anti-CII IgG production, as well as elevated release
of proinflammatory mediators by macrophages stimulated with IgG ICs, suggesting a mechanism for CIA induction
in a nonpermissive background. These results suggest that
Fc
RIIB normally suppresses the emergence of autoimmune disease, and its modulation could be a factor in determining susceptibility and disease severity in the pathogenesis of RA.
![]() |
Materials and Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals.
FcInduction of Arthritis.
Bovine CII was obtained from Collagen Gijutsu-kenshukai (Tokyo, Japan) and dissolved at a concentration of 4 mg/ml in 0.02 M Tris/0.15 M NaCl (pH 8.0) at 4°C. Mice were immunized at the tail base with 200 µg of CII emulsified in CFA containing Mycobacterium tuberculosis strain H37Rv (Wako Pure Chemical Industries Ltd.) and boosted at the same location with 200 µg CII plus IFA (Wako Pure Chemical Industries Ltd.) 21 and 42 d later. The mice were observed for the development of arthritis starting from day 16 after immunization and bled periodically for anti-CII antibody determination. The clinical severity of arthritis was quantified according to the following scoring system: 0, no change; 1, swelling in one joint (digitus, wrist, or ankle); 2, swelling in more than one joint or mild inflammation of paws; 3, severe swelling of the entire paw and/or ankylosis. Each paw was graded, so that each mouse could achieve a maximum score of 12. At the end of the experiment, joints were prepared for histopathology. Joints were examined for erosions, pannus formation, and synovium infiltrates.Assay for Detection of Serum Anti-CII Antibodies.
Serum antibody titers were measured by modification of an ELISA assay described previously (44). In brief, a 96-well microplate (Falcon; Becton Dickinson Labware) was coated with 50 µl/well of a 20 µg/ml solution of CII in PBS at 4°C overnight, washed three times with PBS containing 0.05% Tween 20 and 0.1% BSA, and then blocked with 250 µl/well of PBS containing 0.2% BSA at 4°C overnight. The diluted serum (1:400-20,000) was added at 50 µl/well and allowed to react at 4°C overnight. The wells were washed three times with PBS containing 0.05% Tween 20, incubated with 50 µl of a 1:200 dilution of goat anti-mouse IgG1, IgG2a, IgG2b, or IgM coupled to horseradish peroxidase (Sigma Chemical Co.) at 4°C for 2 h, washed three times with PBS containing 0.05% Tween 20, and developed at room temperature for 30 min with 0.1 ml of TrueBlue Peroxidase Substrate (Kirkegaard & Perry Labs). The OD450 was read using a microplate reader (Biolumin 960; Molecular Dynamics).Cytokine Production.
Mice were injected intraperitoneally with 1 ml of 5% thioglycollate, and peritoneal exudate cells were harvested 4 d later. The cells were suspended in DMEM supplemented with 10% heat-inactivated FCS, to a concentration of 106 cells/ml. The cells were plated in 24-well culture plates (Sumilon; Sumitomo Bakelite Co., Tokyo, Japan) at 1 ml/well and incubated for 1 h at 37°C in 95% air, 5% CO2. Nonadherent cells were removed by rinsing the monolayers with PBS, and the purified macrophages were subjected to the determination of IL-1Proliferation of Lymph Node Cells.
For cell proliferation assays, male mice were immunized with 500 µg CII emulsified in CFA intradermally in both hind footpads, the neck, and at the base of the tail. Inguinal, popliteal, and axillary lymph nodes from the immunized mice were obtained 10 d after immunization. The tissue was minced through sterile wire mesh, resulting in single cell suspensions. Cells (5 × 105/well) from immunized mice were cultured in 96-well, flat-bottomed microplates (Falcon; Becton Dickinson Labware) in the absence or presence of 5, 50, or 100 µg/ml of CII at 37°C in 5% CO2 for 4 d. During the final 18 h of culture, cells were pulsed with 0.5 µCi of [3H]TdR. Cells were harvested on glass fiber filters by using an automated sample harvester (Packard Japan). The incorporated radioactivity was measured with a scintillation spectrometer (Aloka Co. Ltd.). The results of the [3H]TdR incorporation assay were expressed as the mean cpm ± SD of triplicate determinations from each of the three lymph node cell preparations derived from different mice.Histological Study.
The mice were killed with an overdose of diethyl ether. Their arthritic paws were removed and fixed in 10% neutral buffered formalin. The tissues were decalcified in a 5% EDTA-2Na solution. The joints were then embedded in paraffin. The specimens were cut into 6-µm sections and stained with hematoxylin and eosin.Statistical Analysis.
Statistical differences between groups for onset of arthritis, the arthritic index, the mean maximum arthritis score, serum levels of antibodies, and T cell proliferation were calculated using Student's t test; differences in the frequency of arthritis were calculated using Fisher's test. P < 0.05 was considered significant. ![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Immunization of DBA/1 mice (H-2q) with CII
results in typical and progressive polyarthritis in parallel
with the production of high levels of anticollagen antibody,
as described (27). Neither arthritis nor high levels of antibody are induced in BALB/c (H-2d), C3H/He (H-2k), or
C57BL/6 (H-2b) mice (27, 42). Many lines of evidence indicate that CIA susceptibility is restricted to only two H-2
alleles, H-2q and H-2r (33, 34). Although the FcRIIB
/
mice were generated on H-2b background (25), a haplotype not susceptible to CIA induction, we set out to determine if deletion of this inhibitory receptor would convert a
nonsusceptible strain of mice into a susceptible one. Fc
RIIB-deficient male mice were immunized with CII/
CFA and then boosted with CII/IFA, and monitored for
the occurrence of arthritis in comparison to age and sex-matched H-2b wild-type or DBA/1 mice. Three separate
experiments were conducted with similar results as summarized in Table I. Fig. 1 shows the time course and severity
of CIA in one such experiment. Fc
RIIB-deficient mice
develop arthritis with a time course and severity comparable to DBA/1 mice when immunized with CII. Although
the incidence of arthritis in Fc
RIIB-deficient mice was
lower than DBA/1 (42.2 vs. 95.2%), it was dramatically enhanced compared with wild-type H-2b mice (42.2 vs.
7.0%). In those mice that developed arthritis, the mean onset of disease for Fc
RIIB
/
mice was comparable to that
in DBA/1 controls (35.3 vs. 33.2). Similarly, the mean
maximal arthritic index of the mutant animals (6.9 ± 3.6)
was also comparable to DBA/1 controls (8.6 ± 1.9).
|
|
Histopathological features of the CIA induced in FcRIIB
/
mice were examined (Fig. 2). The joints of nonarthritic
wild-type mice appeared histologically normal, with no significant inflammatory cell infiltration or cartilage-bone destruction (Fig. 2 D). In contrast, the arthritic lesions of the
Fc
RIIB
/
mice showed massive lymphocytic and monocyte/macrophage infiltration associated with cartilage-bone
destruction (Fig. 2 E) similar to that observed in DBA/1 immunized animals (Fig. 2 F). Thus, the results obtained by
histopathologic examination of Fc
RIIB
/
mice immunized with CII verified a destructive arthritis, which is qualitatively similar to the arthritis induced in DBA/1 mice.
|
Antibodies specific for CII play a major role in the
pathogenesis of CIA (28, 38). We determined the collagen-specific IgG1, IgG2a, IgG2b, and IgM antibody production in the sera of FcRIIB
/
and DBA/1 immunized
mice. Data derived from sera taken periodically during the
experiment are presented in Fig. 3. The mean of all mice of
different groups is presented regardless of whether or not
the mice had developed arthritis (Fig. 3, A-D). As described previously, Fc
RIIB
/
mice have higher antibody
levels in response to both thymic-dependent and -independent antigens. As expected, Fc
RIIB
/
mice had higher
anti-CII antibody titers than those of wild-type mice for all
isotypes tested. However, these responses to CII were
lower than those observed in DBA/1 mice. The augmented anti-CII IgG responses in arthritic Fc
RIIB
/
mice were more pronounced compared with those of nonarthritic wild-type mice (Fig. 3, E-G). Therefore, this
enhanced antibody response to CII in the Fc
RIIB
/
mice could contribute to the emergence of CIA in this
nonpermissive strain.
|
Since CIA is dependent on dysregulation of both humoral and cell-mediated responses, we determined whether the absence of FcRIIB altered the phenotype of the cell-mediated immune response to CII.
Therefore, we compared the specific proliferative responses and cytokine production of CII-primed lymph node cells
derived from Fc
RIIB
/
, wild-type H-2b, and DBA/1
mice. As shown in Fig. 4, antigenic stimulation with CII
induced higher levels of proliferation in DBA/1 animals and similar lower levels of specific proliferation in Fc
RIIB
/
and wild-type animals. Similar results were obtained when
IFN-
production was used as a measure of specific T
cell stimulation. These results indicate that disruption of
Fc
RIIB does not appreciably modify the antigen-specific
T cell response in nonpermissive animals and is not likely
to account for the susceptibility of these animals to CIA.
|
At later stages of
autoimmune arthritis, local synthesis of cytokines such as
IL-1, TNF, and other inflammatory mediators is likely to
be responsible for the progression from inflammation to a
destructive arthritis. Supporting this notion are studies showing that anti-TNF antibodies or an IL-1 receptor antagonist reduce cytokine production by synovium cells
from RA patients (45; for a review, see reference 31), and
ameliorated arthritis in DBA/1 mice (46, 47). In several
phases of joint inflammation, macrophages secrete chemoattractants for polymorphonuclear cells and monocytes
(IL-6, IL-1, GM-CSF, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1) and upregulate integrins and vascular adhesion molecules through their
production of IL-1 and TNF-
(31). Deletion of Fc
RIIB
decreases the threshold of IC necessary to trigger mast cell
and macrophage activation in vitro and in vivo (25) and
could contribute to the development of CIA in nonsusceptible H-2 backgrounds by either lowering threshold response or increasing the total cytokine response. To determine if macrophages derived from Fc
RIIB
/
animals
showed enhanced release of inflammatory mediators upon stimulation, we determined the levels of IL-1
produced
upon stimulation with IgG-opsonized SRBCs. As shown
in Fig. 5, thioglycollate-elicited peritoneal macrophages
from Fc
RIIB
/
mice released quantitatively more IL-1
than those from wild-type controls and at levels comparable to macrophages derived from DBA/1 mice. Thus, the
absence of Fc
RIIB makes macrophages more sensitive to
stimulation with IgG ICs, and results in a higher level of secretion of a proinflammatory mediator.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Autoimmune disease results from the dysregulation of
the normal immune response, resulting in the loss of tolerance to self-antigens, augmented T and B cell responses,
and inappropriate activation of effector cell pathways. Disruption of the ability to generate T or B cell responses
blocks the development of autoimmunity and autoimmune
disease, while disruption of effector cell pathways attenuates disease development. However, identification of the genetic components that modulate these central pathways
which could confer susceptibility to the development of
disease has been stymied by the complex multigenic nature
of these disorders. It has been known for some time that
the MHC haplotype is one such susceptibility factor in
both human and animal systems. In the murine model of
RA, CIA, H-2 haplotype determines the susceptibility of
an animal to the development of disease. In this study, we demonstrate that the inhibitory FcR for IgG, FcRIIB, is
another susceptibility gene, functioning to suppress the development of CIA in nonsusceptible hosts. Deletion of Fc
RIIB converts a nonsusceptible H-2b animal to one susceptible to the development of CIA. The mechanism by
which deletion of Fc
RIIB results in susceptibility to CIA involves augmentation of both antibody and effector cell
responses, supporting a threshold model for autoimmune
disease.
Association of arthritis with high levels of autoantibodies has highlighted the importance of the anticollagen antibody responses in inducing arthritis. Antiserum or purified IgG antibody to CII can transfer arthritis to the susceptible DBA/1 mice (39). This passively transferred arthritis exhibits the histopathologic characteristics of the early lesions of disease induced through immunization of susceptible hosts. The resulting disease is transient and less severe than the disease induced in immunized DBA/1 mice, suggesting that anti-CII antibodies alone are not sufficient to give rise to the full range of lesions that characterize CIA. In contrast, a typical arthritis could be induced by adoptive transfer of anti-CII antibody from arthritic DBA/1 mice together with T cells from DBA-1 mice presensitized with heat-denatured collagen (42). These results indicate the crucial importance of the synergy between humoral and cell-mediated immunities in the pathogenesis of typical arthritis (42).
A strong B cell response is activated in CIA, producing
IgG directed towards CII-specific structures. There is evidence that these antibodies are pathogenic, as exemplified
by transfer experiments, and promote T cell-mediated arthritis development. In contrast, levels of anti-CII autoantibodies in serum do not correlate with CIA development, as
high levels can be detected in nondiseased mice. Thus, the
role of B cells in both the priming and effector phases of
the disease is unclear. Svensson et al. (43) reported that the
B cell-deficient mice of the CIA-susceptible strains B10.Q
and B10.RIII (H-2r) are resistant to CIA induction, although the anti-CII T cell reactivity does not differ between B cell-deficient and B cell-sufficient mice, thus indicating a crucial role for B cells in the induction of
arthritis. In the present report, we show that the anti-CII IgG antibody response is enhanced in FcRIIB
/
mice,
especially in those mice exhibiting arthritis (Fig. 2), suggesting that the relatively high anti-CII IgG level could be one of the pathogenic factors, although unlikely by itself to explain the induction of disease in the H-2b background.
RA is an autoimmune disease in which macrophages are
believed to play a central role (48, 49). We found that macrophages from FcRIIB
/
mice were hyperresponsive to
stimulation with IgG ICs, leading to augmented release of a
proinflammatory mediator, IL-1
(Fig. 5), that is able to
upregulate integrins and vascular adhesion molecules. At
later stages of autoimmune arthritis, local synthesis of cytokines is probably responsible for progression of inflammation to a destructive arthritis (46, 47). Thus, the heightened sensitivity of macrophages to ICs is likely another pathogenic factor making Fc
RIIB
/
mice more susceptible to
CIA than control mice.
The present study thus suggests that the development of
autoimmune disease represents the dysregulation of both
humoral and effector pathways. The contribution of each
component may be below a critical threshold to result in
the development of disease, as has been suggested by the
genetic studies in the NZB/NZW F1 autoimmune glomerulonephritis model (20). FcRIIB is a pleiotropic receptor,
functioning to downregulate both B cell and effector cell
responses. The finding that deletion of Fc
RIIB converts nonsusceptible H-2b mice into susceptible animals for CIA
suggests that a similar role may be found in other autoimmune disease models and in human susceptibility to autoimmune disease. Therefore, strategies that result in the
upregulation of this receptor and its signaling would represent potential new therapeutic approaches to the treatment of autoimmune diseases.
![]() |
Footnotes |
---|
Address correspondence to Toshiyuki Takai, Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Sendai 980-8575, Japan. Phone: 81-22-717-8501; Fax: 81-22-717-8505; E-mail: tostakai{at}idac.tohoku.ac.jp
Received for publication 8 October 1998 and in revised form 26 October 1998.
We are grateful to Drs. M. Sasano (Santen Pharmaceuticals Co.) and H. Ohmori (Okayama University) for helpful discussions, and to N. Takagi for secretarial support.
This work is supported by research grants from the Ministry of Education, Science, Sports and Culture of Japan, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST) (to T. Takai), and by grants from the National Institutes of Health and the Juvenile Diabetes Foundation (to J.V. Ravetch).
Abbreviations used in this paper
BCR, B cell receptor;
CII, collagen type II;
CIA, collagen-induced arthritis;
FcRI, Fc
RIIB, and Fc
RIII, type I
high-affinity Fc receptor for IgG, type IIB, and type III low-affinity receptors for IgG, respectively ;
IC, immune complex;
RA, rheumatoid arthritis.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1. | Ravetch, J.V., and J.-P. Kinet. 1991. Fc receptors. Annu. Rev. Immunol. 9: 457-492 [Medline]. |
2. | Metzger, H.. 1992. The receptor with high affinity for IgE. Immunol. Rev. 125: 37-48 [Medline]. |
3. |
Fridman, W.H.,
C. Bonnerot,
M. Daëron,
S. Amigorena,
J.L. Teillaud, and
C. Sautes.
1992.
Structural bases of Fc![]() |
4. | van de Winkel, J.G.J., and P.J.A. Capel. 1993. Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications. Immunol. Today. 14: 215-221 [Medline]. |
5. | Ravetch, J.V.. 1994. Fc receptors: rubor redux. Cell. 78: 553-560 [Medline]. |
6. | Takai, T., and J.V. Ravetch. 1999. Fc receptor genetics and the manipulation of genes in the study of FcR biology. In Immunoglobulin Receptors and Their Physiological and Pathological Roles in Immunity. J.G.J. van de Winkel and P.M. Hogarth, editors. Kluwer Academic Publishers Group, Netherlands. In press. |
7. | Greenberg, S., P. Chang, and S.C. Silverstein. 1993. Tyrosine phosphorylation is required for Fc receptor-mediated phagocytosis in mouse macrophages. J. Exp. Med. 177: 529-534 [Abstract]. |
8. |
Crowley, M.T.,
P.S. Costello,
C.J. Fitzer-Attas,
M. Turner,
F. Meng,
C. Lowell,
V.L.J. Tybulewicz, and
A.L. DeFranco.
1997.
A critical role for Syk in signal transduction and phagocytosis mediated by Fc![]() |
9. |
Gavin, A.L.,
N. Bames,
H.M. Dijstelbloem, and
P.M. Hogarth.
1998.
Identification of the mouse IgG3 receptor: implications for antibody effector function at the interface between innate and adaptive immunity.
J. Immunol.
160:
20-23
|
10. | Fanger, N.A., D. Voigtlaender, C. Liu, S. Swink, K. Wardwell, J. Fisher, R.F. Graziano, L.C. Pfefferkorn, and P.M. Guyre. 1997. Characterization of expression, cytokine regulation, and effector function of the high affinity IgG receptor Fc gamma RI (CD64) expressed on human blood dendritic cells. J. Immunol. 158: 3090-3098 [Abstract]. |
11. |
Hazenbos, W.L.W.,
J.E. Gessner,
F.M.A. Hofhuis,
H. Kuipers,
D. Meyer,
I.A.F.M. Heijnen,
R.E. Schmidt,
M. Sandor,
P.J.A. Capel,
M. Däeron, et al
.
1996.
Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc![]() |
12. |
Takai, T.,
M. Li,
D. Sylvestre,
R. Clynes, and
J.V. Ravetch.
1994.
FcR ![]() |
13. | Clynes, R., and J.V. Ravetch. 1995. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity. 3: 21-26 [Medline]. |
14. |
Dombrowicz, D.,
V. Flamand,
K.K. Brigman,
B.H. Koller, and
J.-P. Kinet.
1993.
Abolition of anaphylaxis by targeted
disruption of the high affinity immunoglobulin E receptor ![]() |
15. |
Miyajima, I.,
D. Dombrowicz,
T.R. Martin,
J.V. Ravetch,
J.P. Kinet, and
S.J. Galli.
1997.
Systemic anaphylaxis in the
mouse can be mediated largely through IgG1 and Fc![]() |
16. |
Dombrowicz, D.,
V. Flamand,
I. Miyajima,
J.V. Ravetch,
S.J. Galli, and
J.-P. Kinet.
1997.
Absence of Fc![]() ![]() ![]() ![]() ![]() ![]() ![]() |
17. | Sylvestre, D.L., and J.V. Ravetch. 1994. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science. 265: 1095-1098 [Medline]. |
18. | Sylvestre, D.L., and J.V. Ravetch. 1996. A dominant role for mast cell Fc receptors in the Arthus reaction. Immunity. 5: 387-390 [Medline]. |
19. |
Sylvestre, D.,
R. Clynes,
M. Ma,
H. Warren,
M.C. Carroll, and
J.V. Ravetch.
1996.
Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice.
J. Exp. Med.
184:
2385-2392
|
20. |
Clynes, R.,
C. Dumitru, and
J.V. Ravetch.
1998.
Uncoupling of immune complex formation and kidney damage in
autoimmune glomerulonephritis.
Science.
279:
1052-1054
|
21. |
Clynes, R.,
Y. Takechi,
Y. Moroi,
A. Houghton, and
J.V. Ravetch.
1998.
Fc receptors are required in passive and active immunity to melanoma.
Proc. Natl. Acad. Sci. USA.
95:
652-656
|
22. |
Daëron, M.,
S. Latour,
O. Malbec,
E. Espinosa,
P. Pina,
S. Pasmans, and
W.H. Fridman.
1995.
The same tyrosine-based
inhibition motif, in the intracytoplasmic domain of Fc![]() |
23. |
Muta, T.,
T. Kurosaki,
Z. Misulovin,
M. Sanchez,
M.C. Nussenzweig, and
J.V. Ravetch.
1994.
A 13-amino-acid motif in the cytoplasmic domain of Fc![]() |
24. |
Ono, M.,
S. Bolland,
P. Tempst, and
J.V. Ravetch.
1996.
Role of the inositol phosphatase SHIP in negative regulation
of the immune system by the receptor Fc![]() |
25. |
Clynes, R.,
J.S. Maizes,
R. Guinamard,
M. Ono,
T. Takai, and
J.V. Ravetch.
1999.
Modulation of immune complex-
induced inflammation in vivo by the coordinate expression
of activation and inhibitory Fc receptors.
J. Exp. Med.
189:
179-185
|
26. |
Takai, T.,
M. Ono,
M. Hikida,
H. Ohmori, and
J.V. Ravetch.
1996.
Augmented humoral and anaphylactic responses in Fc![]() |
27. | Courtenay, J.S., M.J. Dallman, A.D. Dayan, A. Marten, and B. Mosedale. 1980. Immunization against heterologous type II collagen induces arthritis in mice. Nature. 283: 666-668 [Medline]. |
28. | Holmdahl, R., L. Jansson, D. Gullberg, K. Rubin, P.O. Forsberg, and L. Klareskog. 1985. Incidence of arthritis and autoreactivity of anti-collagen antibodies after immunization of DBA/1 mice with heterologous and autologous collagen II. Clin. Exp. Immunol. 62: 639-646 [Medline]. |
29. | Trentham, D.E., A.S. Townes, and A.H. Kang. 1977. Autoimmunity to type II collagen: an experimental model of arthritis. J. Exp. Med. 146: 857-868 [Abstract]. |
30. | Trentham, D.E., A.S. Townes, A.H. Kang, and J.R. David. 1978. Humoral and cellular sensitivity to collagen in type II collagen-induced arthritis in rats. J. Clin. Invest. 61: 89-96 [Medline]. |
31. | Feldmann, M., F.M. Brennan, and R.N. Maini. 1996. Rheumatoid arthritis. Cell. 85: 307-310 [Medline]. |
32. | Nabozny, G.H., J.M. Baisch, S. Cheng, D. Cosgrove, M.M. Griffiths, H.S. Luthra, and C.S. David. 1996. HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: a novel model for human polyarthritis. J. Exp. Med. 183: 27-37 [Abstract]. |
33. | Wooley, P.H., H.S. Luthra, J.M. Stuart, and S.C. David. 1981. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I-region) linkage and antibody correlates. J. Exp. Med. 154: 688-700 [Abstract]. |
34. |
Wooley, P.H.,
H.S. Luthra,
M.M. Griffiths,
J.M. Stuart,
A. Huse, and
C.S. David.
1985.
Type II collagen-induced arthritis in mice. IV. Variations in immunogenetic regulation
provide evidence for multiple arthritogenic epitopes on the
collagen molecule.
J. Immunol.
135:
2443-2451
|
35. | Brunsberg, U., K. Gustafson, L. Jansson, E. Michaëlsson, L. Ährlund-Richter, S. Pettersson, R. Mattsson, and R. Holmdahl. 1994. Expression of transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. Eur. J. Immunol. 24: 1698-1702 [Medline]. |
36. | Ranges, G.E., S. Sriram, and S.M. Cooper. 1985. Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J. Exp. Med. 162: 1105-1110 [Abstract]. |
37. |
Chiocchia, G.,
M.C. Boissier, and
C. Fournier.
1991.
Therapy against murine collagen-induced arthritis with T cell receptor V![]() |
38. | Mo, J., A. Scheynius, and R. Holmdahl. 1994. Antibody recognition of mouse cartilage in vivo; epitope- and idiotype-specific binding and inhibition. Scand. J. Immunol. 39: 122-130 [Medline]. |
39. | Stuart, J.M., and F.J. Dixon. 1983. Serum transfers of collagen-induced arthritis in mice. J. Exp. Med. 158: 378-392 [Abstract]. |
40. | Holmdahl, R., M. Andersson, T.J. Goldshmidt, K. Gustafsson, L. Jansson, and J.A. Mo. 1990. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol. Rev. 118: 193-232 [Medline]. |
41. | Holmdahl, R., C. Vingsbo, V. Malmström, L. Jansson, and M. Holmdahl. 1994. Chronicity of arthritis induced with homologous type II collagen (CII) in rats is dependent on anti-CII B-cell activation. J. Autoimmun. 7: 739-752 [Medline]. |
42. |
Seki, N.,
Y. Sudo,
T. Yoshioka,
S. Sugihara,
T. Fujitsu,
S. Sakuma,
T. Ogawa,
T. Hamaoka,
H. Senoh, and
H. Fujiwara.
1988.
Type II collagen-induced murine arthritis. Induction and perpetuation of arthritis require synergy between
humoral and cell-mediated immunity.
J. Immunol.
140:
1477-1484
|
43. | Svensson, L., J. Jirholt, R. Holmdahl, and L. Jansson. 1998. B cell-deficient mice do not develop type II collagen-induced arthritis (CIA). Clin. Exp. Immunol. 111: 521-526 [Medline]. |
44. | Ohmori, H., N. Hase, M. Hikida, T. Takai, and N. Endo. 1992. Enhancement of antigen-induced interleukin 4 and IgE production by specific IgG1 in murine lymphocytes. Cell. Immunol. 145: 299-310 [Medline]. |
45. |
Brennan, F.M.,
D. Chantry,
A. Jackson,
R. Maini, and
M. Feldmann.
1989.
Inhibitory effect of TNF![]() |
46. |
Thorbecke, G.J.,
R. Shah,
C.H. Leu,
A.P. Kuruvilla,
A.M. Hardison, and
M.A. Palladino.
1992.
Involvement of endogenous tumour necrosis factor ![]() ![]() |
47. | Williams, R.O., L.J. Mason, M. Feldmann, and R.N. Maini. 1994. Synergy between anti-CD4 and anti-TNF in the amelioration of established collagen-induced arthritis. Proc. Natl. Acad. Sci. USA. 91: 2762-2766 [Abstract]. |
48. | Mulherin, D., O. Fitzgerald, and B. Bresnihan. 1996. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum. 39: 115-124 [Medline]. |
49. | van Lent, P.L., A.E. Holthuysen, L. van den Bresselaar, N. van Rooijen, L.B. van de Putte, and W.B. van den Berg. 1995. Role of macrophage-like synovial lining cells in localization and expression of experimental arthritis. Scand. J. Rheumatol. 24(Suppl. 101):83-89. |