Immunopathogenesis of autoimmune bullous dermatoses

自身免疫性大疱性皮肤病的免疫发病机制

• 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

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（pemphigus）是一种由抗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，主要有寻常型天疱疮（pemphigus vulgaris，PV）和落叶型天疱疮（pemphigus foliaceus，PF）两种亚型。PV的自身抗原为桥粒芯糖蛋白3（Dsg 3），PF的自身抗原为桥粒芯糖蛋白1（Dsg 1）。为了确定MHC II类分子与Dsg 3和Dsg 1自身抗体应答之间可能的关联，基于85名日本天疱疮患者的PCR-RFLP结果，分析了HLA-DR和-DQ基因的单倍型和等位基因分布以及沿着的分子多态性（55例PV患者和30例PF患者）。结果是：（i）所有PV患者携带HLA-DRB 1 ^*04和DRB 1 ^*14亚型的一个或两个等位基因，其中HLA-DRB 1 ^*0406/DQA 1 ^*0301/DQB 1 ^*0302显著增加，与正常对照相比，DRB 1 ^*14/DQA 1 ^*0104/DQB 1 ^*05和DRB 1 ^*14/DQA 1 ^*0503/DQB 1 ^*0301单倍型。HLA-D ...更多信息 PV患者携带的RB 1 ^*04和DRB 1 ^*14等位基因共享疏水性氨基酸残基Phe^<26>、Leu^<67>和瓦尔^<86>，以及DRB 1 β链上第70位（Gln ^<70>或Arg^<70>）和第71位（Arg^<71>）的亲水性氨基酸残基;（ii）根据抗Dsg 1与抗Dsg 3共存的存在或不存在，PV患者中HLA-DR和-DQ等位基因分布没有差异;（iii）PF患者中HLA-DRB 1 ^*0406和DRB 1 ^*14单倍型也显著增加。然而，所有产生仅针对Dsgl的自身抗体的PF患者显示出更多样化的HLA-DR和-DQ分布，在DRBl链的位置26（Phe^<26>、Leu^<26>或Tyr^<26>）和67（Leu^<67>、Ile^<67>或Phe^<67>）处共享疏水性氨基酸残基，以及在位置70（Gln^<70>、Asp^<70>或Arg^<70>）和71（Arg^<71>）处共享亲水性氨基酸残基。这些发现表明，对桥粒芯糖蛋白的自身抗体应答可能受HLA-DRB 1分子肽结合位点26、67、70、71和86位氨基酸残基的调节，并且对Dsg 3的自身抗体应答可能比对Dsg 1的自身抗体应答更严格地受HLA-DRB 1链这些位置的特定氨基酸残基的调节。一种自身免疫性大疱性皮肤病，其特征在于表皮下水疱和与表皮基底细胞的半桥粒结合的自身抗体。根据23例日本BP患者的PCR-RFLP结果，分析了HLA-DR和-DQ基因的单倍型和等位基因分布以及沿着的分子多态性。23例患者中有18例（78%）携带至少一种HLA-DRB 1 ^*04或DRB 1 ^*1101等位基因，HLA-DRB 1 ^*04显著增加（^*0403，DRB 1 ^*1101/DQA 1 ^* 0505/DQB 1 ^*0302单倍型以及单个等位基因DRB 1 ^* 1101和DQB 1 ^*0302（每次比较，校正P&lt;0.05）。这些数据与公认的DQB 1 ^*0301（DQ 7）与白种人中相同疾病的相关性不同，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，加上以前的报告与类天疱疮组的自身免疫性大疱性疾病的白人患者，表明HLA-DRB 1分子可能参与调节BP抗原的自身免疫反应。少

项目成果

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Miyakawa S、Amagai M、Iida T 等人：“寻常型天疱疮中抗桥粒芯糖蛋白 1 抗体的晚期发展：与疾病进展的相关性。”Br J Dermatol。

Miyagawa S, et al: "Late development of anti-desmoglein 1 antibodies in pemphigus vulgaris : correlation with disease progression."Bt J Dermatol. 141・12. 1084-1087 (1999)

Miyakawa S 等人：“寻常型天疱疮中抗桥粒芯糖蛋白 1 抗体的晚期发展：与疾病进展的相关性”。Bt J Dermatol 141·12 (1999)。

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宫川幸子：“当今的治疗指南：天疱疮、类天疱疮、疱疹样皮炎”Igaku Shoin 2 (1999)。

Miyagawa S, et al: "HLA-DRB1 polymorphisms and autoimmune responses to desmogleins in Japanese patients with pemphigus."Tissue Antigens. 54・10. 333-340 (1999)

Miyakawa S 等人：“日本天疱疮患者的 HLA-DRB1 多态性和对桥粒芯蛋白的自身免疫反应”。组织抗原 54・10 (1999)。