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Immunogenetic analysis of the pathogenesis of the seronegative autoimmune disease

血清阴性自身免疫病发病机制的免疫遗传学分析

基本信息

批准号：
10670763
负责人：
SHINOMIYA Noriaki
金额：
$ 2.05万
依托单位：
Toho University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670763/
关键词：
childhood-onset MG AChR antibody seronegative autoimmune diseases DQB1^*0604 HLA-DQB chain AChR sensitized CD4+ T cell TH1-like phenotype TH1細胞小児期発症重症筋無力症重症筋無力症潜在性全身型 HLA-ClassIIアリルタイプ CDR3領域のアミノ酸配列 TCRVα TCRVβレパトリー TH1 TH0

项目摘要

Myasthenia gravis (MG) is a disease characterized by an autoimmune reaction against the acetylcholine receptor (AChR) at the neuromuscular junction. As the childhood-onset MG patients had negative or low titer of the serum AChR antibody, it was useful for the elucidation in the pathogenesis of the seronegative autoimmune diseases to analysis the cause of the childhood-onset myasthenia gravis. We have examined the frequencies of HLA-DRB, DQA and DQB alleles by PCR/SSO method and TCR Vα/β repertories from autologous AChR sensitized T cell line using RT-PCR in the childhood-onset MG patients with the general (G) type. The childhood-onset MG patients with G type were strongly associated with DRB1^*1302 / DQA1^*0102 / DQB1^*0604 allelic haplotype (pc<10^<-20>, R.R.=53.4). In the clinical course of these patients, the cellular immune responses have played the important role for the recurrence or the exacerbation. DQB1^*0604, which was found to be strongly associated with G type MG with childhood-onset, has a hydrophobic residue (valine, V) at position 57 of the DQB1 chain. This amino acid polymorphism of the DQB chain may be associated with insulin dependent diabetes mellitus, which is thought T cell-mediated immunity as the pathogenesis of the development. This data suggest that T cell-mediated immunity may be associated with development of G type MG with the childhood-onset. Therefore, the polymorphic residues in the HLA-DQB chain may contribute to susceptibility to clinically unique latent general (LG) type or G type MG.Furthermore, AChR sensitized CD4+ T cell line from G type MG patient expressed strongly TCRVα1, 2 or 3, and TCRVβ 6.1 or 8 clone. These T cell lines had activated TH1-like phenotype by IL-2 and IFN-γ production. In conclusion, childhood-onset MG patients with LG+G type may differ in the pathogenic mechanisms from those with other types of MG with adult-onset in which the autoantibodies are thought to be pathogenic.

重症肌无力(MG)是一种以神经肌肉连接部位抗乙酰胆碱受体(AChR)的自身免疫反应为特征的疾病。由于儿童期起病MG患者血清AChR抗体滴度为阴性或低滴度，因此分析儿童期起病重症肌无力的病因有助于阐明血清阴性自身免疫性疾病的发病机制。采用聚合酶链式反应/单链构象多态性分析方法检测儿童起病(G)型重症肌无力(MG)患者的HLADRB、DQA和DQB等位基因频率，并用RT-PCR法检测AChR致敏T细胞株的TCRVα/β表型。儿童起病的G型MG患者与DRB1^*1302/DQA1^*0102/DQB1^*0604等位基因单倍型(PC&lt；10^&lt；-20&gt；，R.R.=53.4)密切相关。在这些患者的临床病程中，细胞免疫反应在复发或恶化中发挥了重要作用。DQB1^*0604在DQB1链的第57位有一个疏水残基(valine，V)，与儿童发病的G型MG有很强的相关性。DQB链的这种氨基酸多态性可能与胰岛素依赖型糖尿病有关，后者被认为是T细胞免疫介导的发病机制。提示T细胞免疫可能与儿童发病的G型MG有关。因此，HLADQB链上的多态残基可能与临床独特的隐匿型MG或G型MG的易感性有关。此外，G型MG患者经AChR致敏的T细胞株强烈表达TCRVα1、2或3，以及TCRVβ6.1或8克隆。这些T细胞株通过产生IL-2和干扰素-γ来激活Th1样表型。总之，儿童起病的LG+G型MG患者的发病机制可能与其他类型的成人起病的MG患者不同，在成人发病的MG患者中，自身抗体被认为是致病的。