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International Immunology, Vol. 11, No. 10, 1685-1691, October 1999
© 1999 Japanese Society for Immunology

Genetically determined aberrant down-regulation of Fc{gamma}RIIB1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus

Yi Jiang1, Sachiko Hirose1,2, Reiko Sanokawa-Akakura1, Masaaki Abe1, Xiaoyi Mi1, Na Li1, Yuko Miura1, Jun Shirai1, Danqing Zhang1, Yoshitomo Hamano1 and Toshikazu Shirai1,2

1 Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
2 Core Research for Evolutional Science and Technology, Japan Science and Technology Corp., Kawaguchi, Saitama 332-0012, Japan

Correspondence to: T. Shirai, Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

Systemic lupus erythematosus (SLE) is a multigenic disease associated with IgG hypergammaglobulinemia, IgG anti-nuclear antibodies and immune complex (IC)-type glomerulonephritis. In both human and murine SLE, one susceptibility allele has been mapped to the interval linked to the IgG Fc receptor II (Fc{gamma}RII) gene on chromosome 1. In spontaneous SLE models of NZB and (NZB x NZW) F1 mice, expression of Fc{gamma}RIIB1, which acts as a negative regulator for B cells, was abnormally down-regulated in follicular germinal center B cells from aged mice, compared to findings in non-SLE NZW, while levels in non-germinal center B cells were practically identical. Such strain differences were also evident in young mice upon in vivo stimulation with foreign antigens. In the Fc{gamma}RIIB promoter region, the NZB allele has two deletion sites, including transcription factor-binding sites. Analyses using (NZB x NZW) F1 x NZW backcross mice showed that this NZB allele was significantly linked to hyper-IgG, irrespective of the MHC haplotype, while high levels of IgG antibodies specific for DNA were regulated by a combinatorial effect of the F1-unique MHC haplotype and the NZB Fc{gamma}RIIB allele. Therefore, the Fc{gamma}RIIB promoter polymorphism may possibly predispose to SLE through germinal center B cells abnormally down-regulating Fc{gamma}RIIB1 expression upon autoantigen stimulations and thus escaping negative signals for IgG production.

Keywords: autoimmunity, chromosome 1, disease susceptibility allele, IgG Fc receptors, microsatellite, New Zealand mouse strains, promoter polymorphism

Transmitting editor: K. Okumura


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