Deletion of Fcγ Receptor IIB Renders H-2b Mice Susceptible to Collagen-induced Arthritis

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 (FcγRIIB) 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 FcγRIIB 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 FcγRIIB-deficient, H-2b mice with bovine CII induced CIA at an incidence of 42.2%. The maximal arthritis index of the FcγRIIB-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 FcγRIIB-deficient animals, especially in those mice showing arthritis, but less pronounced than DBA/1 mice. Histological examinations of the arthritic paws from FcγRIIB-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 FcγRIIB, suggesting that FcγRIIB plays a critical role in suppressing the induction of CIA.

[1]  J. Ravetch,et al.  Immunoglobulin G–mediated Inflammatory Responses Develop Normally in Complement-deficient Mice , 1996, The Journal of experimental medicine.

[2]  R. Holmdahl,et al.  B cell‐deficient mice do not develop type II collagen‐induced arthritis (CIA) , 1998, Clinical and experimental immunology.

[3]  C. Werning [Rheumatoid arthritis]. , 1983, Medizinische Monatsschrift fur Pharmazeuten.

[4]  M. Ono,et al.  Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors , 1999, The Journal of experimental medicine.

[5]  R. Holmdahl,et al.  Expression of a transgenic class II Ab gene confers susceptibility to collagen‐induced arthritis , 1994, European journal of immunology.

[6]  M. Ono,et al.  Augmented humoral and anaphylactic responses in FcγRII-deficient mice , 1996, Nature.

[7]  B. Bresnihan,et al.  Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. , 1996, Arthritis and rheumatism.

[8]  M. Feldmann,et al.  Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  M. Nussenzweig,et al.  A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling , 1994, Nature.

[10]  M. Palladino,et al.  Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. Galli,et al.  Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc gammaRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis. , 1997, The Journal of clinical investigation.

[12]  D. Dombrowicz,et al.  Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor α chain gene , 1993, Cell.

[13]  M. Nussenzweig,et al.  A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling , 1994, Nature.

[14]  J. Ravetch,et al.  A dominant role for mast cell Fc receptors in the Arthus reaction. , 1996, Immunity.

[15]  J. Ravetch,et al.  FcR γ chain deletion results in pleiotrophic effector cell defects , 1994, Cell.

[16]  S. Sriram,et al.  Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4 , 1985, The Journal of experimental medicine.

[17]  J. Ravetch Fc receptors: Rubor redux , 1994, Cell.

[18]  L. Klareskog,et al.  Incidence of arthritis and autoreactivity of anti-collagen antibodies after immunization of DBA/1 mice with heterologous and autologous collagen II. , 1985, Clinical and experimental immunology.

[19]  H. Luthra,et al.  Type II collagen-induced arthritis in mice. II. Passive transfer and suppression by intravenous injection of anti-type II collagen antibody or free native type II collagen. , 1984, Arthritis and rheumatism.

[20]  M. Feldmann,et al.  INHIBITORY EFFECT OF TNFα ANTIBODIES ON SYNOVIAL CELL INTERLEUKIN-1 PRODUCTION IN RHEUMATOID ARTHRITIS , 1989, The Lancet.

[21]  関 信男 Type II collagen-induced murine arthritis , 1990 .

[22]  A. DeFranco,et al.  A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcγ Receptors on Macrophages , 1997, The Journal of experimental medicine.

[23]  J. Ravetch,et al.  Cytotoxic antibodies trigger inflammation through Fc receptors. , 1995, Immunity.

[24]  P. Hogarth,et al.  Identification of the mouse IgG3 receptor: implications for antibody effector function at the interface between innate and adaptive immunity. , 1998, Journal of immunology.

[25]  J. Fisher,et al.  Characterization of expression, cytokine regulation, and effector function of the high affinity IgG receptor Fc gamma RI (CD64) expressed on human blood dendritic cells. , 1997, Journal of immunology.

[26]  H. Luthra,et al.  Type II collagen-induced arthritis in mice. IV. Variations in immunogenetic regulation provide evidence for multiple arthritogenic epitopes on the collagen molecule. , 1985, Journal of immunology.

[27]  G. Chiocchia,et al.  Therapy against murine collagen‐induced arthritis with T cell receptor Vβ‐specific antibodies , 1991, European journal of immunology.

[28]  M. Dallman,et al.  Immunisation against heterologous type II collagen induces arthritis in mice , 1980, Nature.

[29]  J. Ravetch,et al.  Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. , 1998, Science.

[30]  H. Metzger The Receptor with High Affinity for IgE , 1992, Ciba Foundation symposium.

[31]  A. Kang,et al.  Autoimmunity to type II collagen an experimental model of arthritis , 1977, The Journal of experimental medicine.

[32]  R. Holmdahl,et al.  Germline‐Encoded IgG Antibodies Bind Mouse Cartilage In Vivo: Epitope‐ and Idiotype‐Specific Binding and Inhibition , 1994, Scandinavian journal of immunology.

[33]  S. Galli,et al.  Absence of Fc epsilonRI alpha chain results in upregulation of Fc gammaRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between Fc epsilonRI and Fc gammaRIII for limiting amounts of FcR beta and gamma chains. , 1997, The Journal of clinical investigation.

[34]  J. Ravetch,et al.  Fc receptor genetics and the manipulation of genes in the study of FcR biology , 1998 .

[35]  W. Fridman,et al.  The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. , 1995, Immunity.

[36]  W. Fridman,et al.  Structural Bases of Fcγ Receptor Functions , 1992, Immunological reviews.

[37]  J. David,et al.  Humoral and cellular sensitivity to collagen in type II collagen-induced arthritis in rats. , 1978, The Journal of clinical investigation.

[38]  H. Luthra,et al.  HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: a novel model for human polyarthritis , 1996, The Journal of experimental medicine.

[39]  J. Ravetch,et al.  Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. , 1994, Science.

[40]  H. Luthra,et al.  Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates , 1981, The Journal of experimental medicine.

[41]  W. B. van den Berg,et al.  Role of macrophage-like synovial lining cells in localization and expression of experimental arthritis. , 1995, Scandinavian journal of rheumatology. Supplement.

[42]  T. Takai,et al.  Enhancement of antigen-induced interleukin 4 and IgE production by specific IgG1 in murine lymphocytes. , 1992, Cellular immunology.

[43]  R. Holmdahl,et al.  Chronicity of arthritis induced with homologous type II collagen (CII) in rats is associated with anti-CII B-cell activation. , 1994, Journal of autoimmunity.

[44]  F. Dixon,et al.  Serum transfer of collagen-induced arthritis in mice , 1983, The Journal of experimental medicine.

[45]  R. Schmidt,et al.  Impaired IgG-Dependent Anaphylaxis and Arthus Reaction in FcγRIII (CD16) Deficient Mice , 1996 .

[46]  S. Greenberg,et al.  Tyrosine phosphorylation is required for Fc receptor-mediated phagocytosis in mouse macrophages , 1993, The Journal of experimental medicine.

[47]  P. Tempst,et al.  Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FeγRIIB , 1996, Nature.

[48]  J. V. D. van de Winkel,et al.  Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications. , 1993, Immunology today.

[49]  H. Fujiwara,et al.  Type II collagen-induced murine arthritis. I. Induction and perpetuation of arthritis require synergy between humoral and cell-mediated immunity. , 1988, Journal of immunology.

[50]  R. Holmdahl,et al.  Type II Collagen Autoimmunity in Animals and Provocations Leading to Arthritis , 1990, Immunological reviews.

[51]  A. Houghton,et al.  Fc receptors are required in passive and active immunity to melanoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  J. Ravetch Fc receptors. , 1997, Current opinion in immunology.