The Journal of Experimental Medicine
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*Joint Disorders
*Rheumatoid Arthritis
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© The Rockefeller University Press, 0022-1007/1999/1/187/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 1, January 4, 1999 187-194

Articles

Deletion of Fc{gamma} Receptor IIB Renders H-2b Mice Susceptible to Collagen-induced Arthritis

Takae Yuasa*,{ddagger}, Satoshi Kubo*, Tadashi Yoshino§, Azusa Ujike*,{ddagger}, Kimio Matsumura*, Masao Ono*,{ddagger}, Jeffrey V. Ravetch||, and Toshiyuki Takai*,{ddagger}

From the * Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; the {ddagger} 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

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

Key Words: collagen-induced arthritis • autoimmunity • Fc receptor • gene targeting • macrophage

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

Abbreviations used: BCR, B cell receptor; CII, collagen type II; CIA, collagen-induced arthritis; Fc{gamma}RI, Fc{gamma}RIIB, and Fc{gamma}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.


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