Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses.
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.
Xiu
Yan
Y
Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Nakamura
Kazuhiro
K
Abe
Masaaki
M
Li
Na
N
Wen
Xiang Shu
XS
Jiang
Yi
Y
Zhang
Danqing
D
Tsurui
Hiromichi
H
Matsuoka
Shuji
S
Hamano
Yoshitomo
Y
Fujii
Hiroyuki
H
Ono
Masao
M
Takai
Toshiyuki
T
Shimokawa
Toshibumi
T
Ra
Chisei
C
Shirai
Toshikazu
T
Hirose
Sachiko
S
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
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4