Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences.
Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University.
Rheumatology (Oxford). 2021 Jan 5;60(1):445-450. doi: 10.1093/rheumatology/keaa269.
While the aetiology of idiopathic multicentric Castleman disease (iMCD) remains unclear, the involvement of autoinflammatory mechanisms has been suggested. Herein we report a Japanese patient with iMCD with a novel heterozygous Ile729Met mutation in exon 10 of the Mediterranean fever (MEFV) gene.
We performed genetic analysis via targeted next-generation sequencing analysis and Sanger sequencing and conducted molecular dynamics simulations to investigate the hydrophobic interactions around the 729th amino acid in human pyrin.
In February 2011, a 59-year-old man was diagnosed with IgG4-related disease at our department based on the findings of cervical and hilar lymphadenopathies, typical lung lesions and cervical lymph node biopsy. The patient was followed up without treatment, as he was asymptomatic. However, he had been experiencing prolonged fatigue and fever with high levels of CRP since June 2017. Axillary lymph node biopsy findings led to the diagnosis of iMCD. He was successfully treated with an IL-6 inhibitor and has been in remission for 12 months. Genetic analyses for hereditary autoinflammatory disease-related genes were performed, revealing a novel heterozygous Ile729Met mutation in exon 10 of the MEFV gene. We identified that this novel mutation significantly altered the local interaction of the human pyrin B30.2 domain by molecular dynamics simulation analysis and experimentally had the potential for inflammasome activation with increased inflammatory cytokines.
The abnormal function of pyrin due to a mutation in the MEFV gene in this patient may have contributed to the development of MCD by inducing IL-6 production via inflammasome signalling.
特发性多中心 Castleman 病（iMCD）的病因仍不清楚，有人提出自身炎症机制的参与。本文报道了一例日本 iMCD 患者，其 Mediterranean 热（MEFV）基因第 10 外显子存在新型杂合 Ile729Met 突变。
我们通过靶向下一代测序分析和 Sanger 测序进行遗传分析，并进行分子动力学模拟，以研究人类 pyrin 第 729 位氨基酸周围的疏水性相互作用。
2011 年 2 月，一名 59 岁男性因颈淋巴结和肺门淋巴结肿大、典型肺部病变和颈淋巴结活检，在我院被诊断为 IgG4 相关疾病。由于患者无症状，因此未进行治疗，仅进行随访。然而，自 2017 年 6 月以来，他一直有持续疲劳和发热，伴有 CRP 水平升高。腋窝淋巴结活检结果导致 iMCD 的诊断。他成功接受了白细胞介素 6 抑制剂治疗，目前缓解期已持续 12 个月。遗传性自身炎症性疾病相关基因的遗传分析显示 MEFV 基因第 10 外显子存在新型杂合 Ile729Met 突变。我们通过分子动力学模拟分析确定，这种新型突变显著改变了人类 pyrin B30.2 结构域的局部相互作用，并且实验表明其具有通过炎性小体信号诱导 IL-6 产生而激活炎性小体的潜力。
由于该患者 MEFV 基因的突变导致 pyrin 功能异常，可能通过炎性小体信号诱导 IL-6 产生，从而导致 MCD 的发生。
