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.
[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. DOI:10.1093/intimm/11.10.1685 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genes that predispose to SLE are closely related to key events in pathogenesis of this disease. As much of the pathology can be attributed to high affinity autoantibodies and/or their immune complexes, some of the genes may exert effects in the process of emergence, escape from tolerance mechanisms, activation, clonal expansion, differentiation, class switching and affinity maturation of self-reactive B cells. A number of growth and differentiation factors and signaling molecules, including positive and negative regulators, are involved in this process. Genetic variations associated with functional deficits in some of such molecules can be involved in the susceptibility for SLE. As is the case with SLE, hereditary factors play significant roles in the pathogenesis of B cell chronic lymphocytic leukemia (B-CLL). Patients with B-CLL or their family members frequently have immunological abnormalities, including those associated with SLE. It is suggested that certain genetically determined regulatory abnormalities of B cells may be a crossroad between B-CLL and SLE. A thorough understanding of the genetic pathways in B cell abnormalities leading to either SLE or B-CLL is expected to shed light on their association. New Zealand mouse strains are pertinent laboratory models for these studies. Chromosomal locations of several major genetic loci for abnormal proliferation, differentiation and maturation of B cells and relevant candidate genes, located in close proximity to these intervals and potentially related to the SLE pathogenesis, have been identified in these mice. Further studies make for a wider knowledge and understanding of the pathogenesis of SLE and related B-cell malignancy.
International Reviews Of Immunology 02/2000; 19(4-5):389-421. DOI:10.3109/08830180009055505 · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: FcgammaRIIB1 molecules serve as negative feedback regulator for B cell Ag receptor-elicited activation of B cells; thus, any impaired FcgammaRIIB1 function may possibly be related to aberrant B cell activation. We earlier found deletion polymorphism in the Fcgr2b promoter region among mouse strains in which systemic autoimmune disease-prone NZB, BXSB, MRL, and autoimmune diabetes-prone nonobese diabetic, but not NZW, BALB/c, and C57BL/6 mice have two identical deletion sites, consisting of 13 and 3 nucleotides. In this study, we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcgammaRIIB1 expression levels in germinal center B cells and up-regulates IgG Ab responses. We did luciferase reporter assays to determine whether NZB-type deletion polymorphism affects transcriptional regulation of Fcgr2b gene. Although NZW- and BALB/c-derived segments from position -302 to +585 of Fcgr2b upstream region produced significant levels of luciferase activities, only a limited activity was detected in the NZB-derived sequence. EMSA and Southwestern analysis revealed that defect in transcription activity in the NZB-derived segment is likely due to absence of transactivation by AP-4, which binds to the polymorphic 13 nucleotide deletion site. Our data imply that because of the deficient AP-4 binding, the NZB-type Fcgr2b allele polymorphism results in up-regulation of IgG Ab responses through down-regulation of FcgammaRIIB1 expression levels in germinal center B cells, and that such polymorphism may possibly form the basis of autoimmune susceptibility in combination with other background contributing genes.
The Journal of Immunology 11/2002; 169(8):4340-6. DOI:10.4049/jimmunol.169.8.4340 · 4.92 Impact Factor
B Odemis, M Y Akpınar, E Oztas, U B Kuzu, G Aydog, E Kayacetin
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