Two distinct regions of the mouse beta Fc gamma R gene control its transcription.
ABSTRACT The low-affinity receptors for the Fc portion of IgG (Fc gamma RII and Fc gamma RIII) are born by most of the immunocompetent cells and mediate a wide spectrum of biological activities. Macrophages, mast cells and lymphocytes express the type II Fc gamma R whereas the type III Fc gamma R is expressed on macrophages, mast cells and NK cells. In mice, the beta Fc gamma R gene codes for Fc gamma RII and the alpha Fc gamma R gene codes for the ligand-binding Fc gamma RIII alpha-chain. We have previously demonstrated that the methylation of the 5' region of these genes control their expression. In the present paper, we investigate the role of two unmethylated regions of the beta gene, the promoter and the third intron, in the control of its transcription. We show, by using two cell lines representative of B and mast cells, that different promoter fragments determine, in these two cell types, the transcription of the beta Fc gamma R gene. The third intron of the beta Fc gamma R gene contains sequences, which, introduced upstream to homologous or heterologous promoter, inhibit the transcriptional activity of these promoter. Thus, in B cells and in mast cells, the transcription of the beta Fc gamma R gene is controlled by two distinct regions of the gene.
- SourceAvailable from: Toshikazu Shirai[Show abstract] [Hide abstract]
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 (FcgammaRII) gene on chromosome 1. In spontaneous SLE models of NZB and (NZB x NZW) F(1) mice, expression of FcgammaRIIB1, 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 FcgammaRIIB promoter region, the NZB allele has two deletion sites, including transcription factor-binding sites. Analyses using (NZB x NZW) F(1) 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 F(1)-unique MHC haplotype and the NZB FcgammaRIIB allele. Therefore, the FcgammaRIIB promoter polymorphism may possibly predispose to SLE through germinal center B cells abnormally down-regulating FcgammaRIIB1 expression upon autoantigen stimulations and thus escaping negative signals for IgG production.International Immunology 11/1999; 11(10):1685-91. · 3.14 Impact Factor
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ABSTRACT: Systemic lupus erythematosus (SLE) is a systemic antibody-mediated autoimmune disease that develops under the control of multiple susceptibility genes. Genetic studies in murine and human SLE have identified several chromosomal intervals that contain candidate susceptibility genes. However, the ultimate identification of the genes and their roles in disease process need much further investigation. Spontaneous murine SLE models provide useful tools in this respect. In this chapter, we show this line of investigation, particularly focusing on the roles of major histocompatibility complex (MHC) class II and immunoglobulin G Fc receptors (FcgammaRs). The existence of high-affinity autoantibodies is evidence that autoimmunity in SLE is antigen-driven. Thereby, MHC class II haplotypes have been implicated in SLE susceptibility; however, because of the linkage disequilibrium that exists among the class I, II and III genes within the MHC complex, it has been difficult to discriminate the relative contributions of individual loci. On the other hand, the extent of antibody synthesis upon antigen stimulation and associated inflammatory cascades are controlled in several ways by the balance of stimulatory and inhibitory signaling molecules on immune cells. Stimulatory/inhibitory FcgammaRs mediate one such mechanism, and there are reports indicating the association between polymorphic FcgammaRs and SLE. However, as stimulatory and inhibitory FcgammaRs cluster on the telomeric chromosome 1, the absolute contribution of individual genes has been difficult to dissect. In studies of genetic dissection using interval-congenic and intragenic recombinant mouse strains of SLE models, we show evidence and discuss how and to what extent MHC class II molecules and stimulatory/inhibitory FcgammaRs are involved in SLE susceptibility.Springer Seminars in Immunopathology 11/2006; 28(2):163-74. · 4.17 Impact Factor
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ABSTRACT: FcgammaRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcgammaRIIB is also involved in the complex regulation of defence against infection. A loss-of-function polymorphism in FcgammaRIIB protects against severe malaria, the investigation of which is beginning to clarify the evolutionary pressures that drive ethnic variation in autoimmunity. Our increased understanding of the function of FcgammaRIIB also has potentially far-reaching therapeutic implications, being involved in the mechanism of action of intravenous immunoglobulin, controlling the efficacy of monoclonal antibody therapy and providing a direct therapeutic target.Nature Reviews Immunology 05/2010; 10(5):328-43. · 32.25 Impact Factor