| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
1.Pemphigus
Pemphigus, which has two major subtypes pemphigus vulgaris (PV) and pemphigus foliaceus (PF), is an autoimmune skin disease caused by autoantibodies against keratinocyte adhesion molecules. The autoantigens are determined to be desmoglein 3 (Dsg3) for PV and desmoglein 1 (Dsg1) for PF.Recent studies suggest that Dsg1 may also participate in the autoimmune responses of PV patients. To determine possible MHC class II associations with autoantibody responses to Dsg3 and Dsg1, haplotype and allele distributions, along with molecular polymorphisms, of HLA-DR and -DQ genes were analyzed based on the PCR-RFLP results in 85 Japanese patients with pemphigus (55 patients with PV and 30 patients with PF).
The results were : (i) all PV patients carried one or two alleles of HLA-DRB1^*04 and DRB1^*14 subtypes, with significant increases of HLA-DRB1^*0406/DQA1^*0301/DQB1^*0302, DRB1^*14/DQA1^*0104/DQB1^*05 and DRB1^*14/DQA1^*0503/DQB1^*0301 haplotypes compared to normal controls. The HLA-D
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RB1^*04 and DRB1^*14 alleles carried by PV patients shared hydrophobic amino acid residues Phe^<26>, Leu^<67> and Val^<86>, as well as hydrophilic amino acid residues at positions 70 (Gin^<70> or Arg^<70>) and 71 (Arg^<71>) on the DRB1 beta chain ; (ii) HLA-DR and -DQ allele distributions did not differ among PV patients according to the presence or absence of anti-Dsg1 co-existing with anti-Dsg3 ; (iii) the HLA-DRB1^*0406 and DRB1^*14 haplotypes were also significantly increased among PF patients. However, the PF patients, all producing autoantibodies to only Dsg1, showed more diverse HLA-DR and -DQ distributions, sharing hydrophobic amino acid residues at positions 26 (Phe^<26>, Leu^<26>, or Tyr^<26>) and 67 (Leu^<67>, Ile^<67>, or Phe^<67>), as well as hydrophilic amino acid residues at positions 70 (Gln^<70>, Asp^<70> or Arg^<70>) and 71 (Arg^<71>), of the DRB1 chain. These findings suggest that autoantibody responses to desmogleins might be regulated by amino acid residues at positions 26, 67, 70, 71 and 86 at peptide binding sites of HLA-DRB1 molecules, and that autoimmune responses to Dsg3 might more strictly be regulated by specific amino acid residues at these positions of the HLA-DRB1 chain than those to Dsg1.
2.Bullous pemhigoid
Bullous pemphigoid (BP), an autoimmune bullous skin disease, is characterized by subepidermal blisters and autoantibodies that bind to hemidesmosomes of epidermal basal cells. Haplotype and allele distributions, along with molecular polymorphisms, of HLA-DR and -DQ genes were analyzed based on the PCR-RFLP results in 23 Japanese BP patients. Eighteen of 23 patients (78%) carried at least one allele of HLA-DRB1^*04 or DRB1^*1101, with significant increases of HLA-DRB1^*04 (^*0403, ^*0406)/DQA1^*0301/DQB1^*0302 and DRB1^*1101/DQA1^*0505/DQB1^*0302 haplotypes as well as individual alleles DRB1^*1101 and DQB1^*0302 (corrected P<0.05, for each comparison), when compared to control subjects. These data differ from the accepted DQB1^*0301 (DQ7) association with the same disease among Caucasians, indicating that different HLA class II haplotypes genetically influence susceptibility to BP among different ethnic groups. Our findings, together with previous reports on Caucasian patients with the pemphigoid group of autoimmune bullous diseases, suggest that HLA-DRB1 molecules might participate in the regulation of autoimmune responses to BP antigens. Less
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