Fas gene polymorphism affecting Fas expression levels and autoimmune disease

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  • AKAKURA REIKO
    Department of Pathology (II), Juntendo University School of Medicine
  • SHU WEN XIANG
    Department of Pathology (II), Juntendo University School of Medicine
  • ABE MASAAKI
    Department of Pathology (II), Juntendo University School of Medicine
  • KYO EKI
    Department of Pathology (II), Juntendo University School of Medicine
  • HIROSE SACHIKO
    Department of Pathology (II), Juntendo University School of Medicine

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  • Fas遺伝子多型によるFas発現制御と自己免疫疾患
  • Fas イデンシ タケイ ニ ヨル Fas ハツゲン セイギョ ト ジコ メンエキ シッカン

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Abstract

Objective : Based on studies using MRL/lpr mice, deleterious mutation of Fas gene associated with deletion of Fas-mediated apoptosis is associated with autoimmune disease with autoantibody production. We previously found that autoantibody.producing BI cells in SLE-prone (NZB×NZW) F1 mice have a low capacity to express Fas antigen on the cell surface and are resistant to Fas.mediated apoptosis. Although (NZB×NZW) F1 mice have no Fas gene mutation, it is plausible to speculate that Fas gene polymorphism affecting Fas expression levels may be involved in (NZB×NZW) F1 disease. In the present study, we focused on this issue and examined Fas gene polymorphisms in New Zealand mice. Methods and Results : 1) There were nine SNPs (single nucleotide polymorphisms) in the 5' flanking region of Fas gene including the reported promoter region between NZB and NZW strains. 2) Both T and B cells in NZB mice expressed lower Fas levels and were more resistant to Fasmediated apoptosis compared with those in NZW mice. 3) Taking advantage of the NZW-interval congenic mouse strains containing the NZB-type Fas gene polymorphism, the Fas expression level seemed to be controlled by the polymorphic region of Fas gene.4) NZB-type Fas gene polymorphism is significantly associated with B1 cell frequencies and IgG anti-DNA antibody production in (NZB×NZW) F1×NZW　backcross　progeny. Conclusions : These results suggest that the NZB-type Fas gene polymorphism functions as one of the SLE-susceptibility genes in (NZB×NZW) Fl mice.

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