Abstract:
Thrombotic thrombocytopenic purpura (TTP) is an extremely rare and fatal thrombotic disorder characterized by impaired enzyme activity of von Willebrand factor cleaving protease, also known as ADAMTS13. Immune-mediated TTP (iTTP) is an acquired form of TTP caused by the production of auto-antibodies against ADAMTS13. The pathophysiology of autoimmune disorders is multifactorial, with several human leukocyte antigen (HLA) alleles identified as a genetic risk factor for autoimmune diseases known as susceptible HLA. In the early 2010s, three distinct European groups revealed that DRB1*11 is one of the most susceptible alleles in acquiring iTTP among Caucasians based on HLA typing data. Several in silico predictions for allele-restricted ADAMTS13 epitopes against T cells are made in this context, followed by an in vitro validation employing mass spectrometry using eluted peptides and T-cell assays. However, similar analyses in a genetically distinct Japanese population have not yet been conducted. We used next-generation sequencing to perform HLA typing for 52 Japanese patients with iTTP from 19 institutes. Our detailed analysis revealed that the specific allele DRB1*08:03 was identified as a genetic risk factor for iTTP in Japanese patients, but there were no statistically significant differences in the allele frequency of DRB1*11 between iTTP and healthy controls.
摘要:
血栓性血小板减少性紫癜(TTP)是一种极其罕见和致命的血栓性疾病,其特征是vonWillebrand因子裂解蛋白酶的酶活性受损,也称为ADAMTS13。免疫介导的TTP(iTTP)是由产生抗ADAMTS13的自身抗体引起的TTP的获得性形式。自身免疫性疾病的病理生理学是多因素的,几个人类白细胞抗原(HLA)等位基因被鉴定为自身免疫性疾病的遗传风险因素,称为易感HLA。在2010年代早期,根据HLA分型数据,三个不同的欧洲群体显示,DRB1*11是高加索人获得iTTP的最易感等位基因之一.在这种情况下,对针对T细胞的等位基因限制性ADAMTS13表位进行了一些计算机预测,然后使用质谱分析使用洗脱的肽和T细胞测定进行体外验证。然而,尚未对遗传上不同的日本人群进行类似的分析。我们使用下一代测序对来自19个研究所的52名日本iTTP患者进行HLA分型。我们的详细分析显示,特定等位基因DRB1*08:03被确定为日本患者iTTP的遗传风险因素,但iTTP与健康对照组的DRB1*11等位基因频率差异无统计学意义。