Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses

Yan Xiu, Kazuhiro Nakamura, Masaaki Abe, Na Li, Xiang Shu Wen, Yi Jiang, Danqing Zhang, Hiromichi Tsurui, Shuji Matsuoka, Yoshitomo Hamano, Hiroyuki Fujii, Masao Ono, Toshiyuki Takai, Toshibumi Shimokawa, Chisei Ra, Toshikazu Shirai, Sachiko Hirose

Research output: Contribution to journalArticlepeer-review

101 Citations (Scopus)

Abstract

FcγRIIB1 molecules serve as negative feedback regulator for B cell Ag receptor-elicited activation of B cells; thus, any impaired FcγRIIB1 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 FcγRIIB1 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 FcγRIIB1 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.

Original languageEnglish
Pages (from-to)4340-4346
Number of pages7
JournalJournal of Immunology
Volume169
Issue number8
DOIs
Publication statusPublished - 2002 Oct 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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