| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Objective. To investigate the role of APRIL and BAFF, new members of the TNF family, in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Results. By exon-specific PCR/SSCP, we identified two novel polymorphisms at codon 67 and 96 in APRIL gene. Both had amino acid substitutions, G67R and N96S, respectively. Only the 67G allele was associated with SLE in 148 Japanese SLE patients with allele frequency 0.662 compared with 0.575 for 146 healthy controls (p=0.0302). The frequency of the individuals who possessed at least one 67G allele in SLE patients (91.9%) was significantly higher than that in normal controls (80.1%) (p=0.0036). We developed ELISA for APRIL and BAFF, and demonstrated that serum levels of APRIL and BAFF were elevated in patients with SLE compared with healthy controls. We also identified a novel polymorphism, P21R, in BR3 gene. P21R is located in the cystein-rich domain of BR3, a specific receptor for BAFF, and could be functionally important. To investigate the reverse-signal through membrane BAFF, we constructed cDNA for membrane BAFF, which was not cleaved by furin convertase, by site-directed mutagenesis.
Conclusion. These results suggest that the 67G allele of APRIL is a contributing factor in the pathogenesis of SLE. The elevated serum levels of APRIL and BAFF may be associated with the pathogenesis of SLE. APRIL and BAFF could be a therapeutic target in the treatment of autoimmune disease.
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