Genetically determined aberrant down-regulation of FcγRIIB1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus

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Abstract
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 (FcγRII) gene on chromosome 1. In spontaneous SLE models of NZB and (NZB × NZW) F1 mice, expression of FcγRIIB1, 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 FcγRIIB promoter region, the NZB allele has two deletion sites, including transcription factor-binding sites. Analyses using (NZB × NZW) F1 × 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 FcγRIIB allele. Therefore, the FcγRIIB promoter polymorphism may possibly predispose to SLE through germinal center B cells abnormally down-regulating FcγRIIB1 expression upon autoantigen stimulations and thus escaping negative signals for IgG production.