Immunopathogenesis of autoimmune bullous dermatoses

自身免疫性大疱性皮肤病的免疫发病机制

基本信息

批准号：
11670847
负责人：
MIYAGAWA Sachiko
金额：
$ 2.3万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670847/
关键词：
pemphiggus vulgaris pemphigus foliaceus desmoglein HLA class II genes bullous pemphigoid デスモグレイン HLA class II遺伝子デスモグレイン3 デスモグレイン1 HLA class II 遺伝子

项目摘要

1.PemphigusPemphigus, 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 … More 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 pemhigoidBullous 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

1.天疱疮天疱疮有寻常型天疱疮（PV）和落叶型天疱疮（PF）两种主要亚型，是一种针对角质形成细胞粘附分子的自身抗体引起的自身免疫性皮肤病，其自身抗原为桥粒芯糖蛋白3（Dsg3）和桥粒芯糖蛋白1。 (Dsg1) 为 PF。最近的研究表明 Dsg1为了确定 MHC II 类可能与 Dsg3 和 Dsg1 自身抗体反应相关，基于 PCR 分析了 HLA-DR 和 -DQ 基因的单倍型和等位基因分布以及分子多态性。 - 85 名日本天疱疮患者（55 名 PV 患者和 30 名 PF 患者）的 RFLP 结果。结果是：（i）所有 PV 患者都携带一种或两种HLA-DRB1^*04和DRB1^*14亚型等位基因，其中HLA-DRB1^*0406/DQA1^*0301/DQB1^*0302、DRB1^*14/DQA1^*0104/DQB1^*05显着增加和与正常对照相比，DRB1^*14/DQA1^*0503/DQB1^*0301 单倍型 PV 患者携带的 HLA-D … More RB1^*04 和 DRB1^*14 等位基因共享疏水性氨基酸残基 Phe^<26>。、Leu^<67> 和 Val^<86>，以及位置 70 处的亲水性氨基酸残基(Gin^<70> 或 Arg^<70>) 和 71 (Arg^<71>) 在 DRB1 β 链上；(ii) HLA-DR 和 -DQ 等位基因分布在 PV 患者中没有根据是否存在而存在差异。抗 Dsg1 与抗 Dsg3 共存的缺失；(iii) HLA-DRB1^*0406 和 DRB1^*14 单倍型在然而，PF 患者仅产生针对 Dsg1 的自身抗体，显示出更多样化的 HLA-DR 和 -DQ 分布，在第 26 位共享疏水性氨基酸残基（Phe^26>、Leu^26> 或 Tyr）。 ^<26>)和67(Leu^<67>、Ile^<67>或Phe^<67>)，以及位置处的亲水性氨基酸残基DRB1 链的 70 (Gln^<70>、Asp^<70> 或 Arg^<70>) 和 71 (Arg^<71>) 这些发现表明，桥粒芯糖蛋白的自身抗体反应可能受到氨基酸残基的调节。 HLA-DRB1 分子肽结合位点的第 26、67、70、71 和 86 位，以及对 Dsg3 的自身免疫反应与 Dsg1.2 相比，HLA-DRB1 链这些位置上的特定氨基酸残基可能更严格地调节。大疱性类天疱疮大疱性类天疱疮 (BP) 是一种自身免疫性大疱性皮肤病，其特征是表皮下水疱和与半桥粒结合的自身抗体HLA-DR 和表皮基底细胞的单倍型和等位基因分布以及分子多态性。 -根据 23 名日本 BP 患者的 PCR-RFLP 结果对 DQ 基因进行了分析，23 名患者中的 18 名 (78%) 携带至少一个 HLA-DRB1^*04 或 DRB1^*1101 等位基因，其中 HLA- 显着增加。 DRB1^*04 (^*0403, ^*0406)/DQA1^*0301/DQB1^*0302 和与对照受试者相比，DRB1^*1101/DQA1^*0505/DQB1^*0302 单倍型以及个体等位基因 DRB1^*1101 和 DQB1^*0302（每次比较校正后的 P<0.05）这些数据与对照受试者不同。公认的 DQB1^*0301 (DQ7) 与白种人中的同一疾病相关，表明不同的 HLA II 类单倍型在遗传上影响不同种族群体对 BP 的易感性，我们的研究结果以及之前关于类天疱疮类自身免疫性大疱性疾病的白种人患者的报告表明，HLA-DRB1 分子可能参与对 BP 抗原的自身免疫反应的调节。较少的