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Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus¹

Qingshun Lin^*,, Yan Xiu^*, Yi Jiang, Hiromichi Tsurui^*, Kazuhiro Nakamura^*, Sanki Kodera^*, Mareki Ohtsuji^*, Naomi Ohtsuji^*, Wakana Shiroiwa^*,, Kazuyuki Tsukamoto^*, Hirofumi Amano, Eri Amano, Katsuyuki Kinoshita, Katsuko Sudo^¶, Hiroyuki Nishimura^||, Shozo Izui^#, Toshikazu Shirai^* and Sachiko Hirose^2,*

^* Department of Pathology, Department of Obstetrics and Gynecology, and Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan; Central Laboratory of First Clinical College, China Medical University, Shenyang, China; ^¶ Animal Research Center, Tokyo Medical University, Tokyo, Japan; ^|| Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan; and ^# Department of Pathology and Immunology, Centre Médical Universitaire, Geneva, Switzerland

Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (FcRs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of FcRs is probably involved in pathogenesis. However, how and to what extent each FcR contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory FcRs are intact, inhibitory FcRIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory FcRs, we established two gene-manipulated BXSB strains: one deficient in stimulatory FcRs (BXSB.^–/–) and the other carrying wild-type Fcgr2b (BXSB.IIB^B6/B6). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.^–/– had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIB^B6/B6, which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.^–/– were activated, as in wild-type BXSB, but not in BXSB.IIB^B6/B6. Our results strongly suggest that both types of FcRs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory FcRs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired FcRIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.

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The JI 2006 177: 1373-1374. [Full Text]