title: Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses.
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.
authors.affiliation: Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Xiang Shu
authors.initials: XS
authors.lastname: Wen
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Danqing
authors.initials: D
authors.lastname: Zhang
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tsurui
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Hamano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujii
authors.forename: Masao
authors.initials: M
authors.lastname: Ono
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.forename: Toshibumi
authors.initials: T
authors.lastname: Shimokawa
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Shirai
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000483:Alleles; D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D011110:Polymorphism, Genetic / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4