Department of Microbiology, Capital Medical University School of Basic Medical Sciences, Beijing, China.
Department of Neurosurgery, Capital Medical University Sanbo Brain Hospital, Beijing, China.
Ann Clin Transl Neurol. 2021 Mar;8(3):558-570. doi: 10.1002/acn3.51289. Epub 2021 Jan 19.
Rasmussen's encephalitis (RE) is a rare and severe progressive epileptic syndrome with unknown etiology. Infection by viruses such as human cytomegalovirus (HCMV) has been hypothesized to be a potential trigger for RE. Interferon-induced transmembrane protein-3 (IFITM3) single-nucleotide polymorphism (SNP) rs12252 is associated with the severity of viral infection disease. This study aimed to address the possibility that HCMV infection and IFITM3 rs12252 might be associated with RE disease progression.
The expression of HCMV and IFITM3 was detected with immunohistochemical staining, in situ hybridization and immunofluorescence double staining. The genotype of IFITM3 rs12252 was detected using the Sanger sequencing method. A genetic association analysis was carried out for this SNP and HCMV antigen expression. The relationship between this SNP and the clinical characteristics of these patients was further analyzed. In in vitro study, HCMV replication in SH-SY5Y cells with overexpressed IFITM3 variant was detected by immunofluorescence and real-time RT-PCR.
Elevated expression of HCMV and IFITM3 was observed in the brain tissue of RE patients. Moreover, the IFITM3 polymorphism rs12252-C was found to associate with HCMV high detection and rapid disease progression in RE patients with the IFITM3 rs12252-CC genotype. In vitro study showed the overexpressed IFITM3 variant was associated with HCMV high infection level.
These results suggest that the IFITM3 rs12252-C is associated with the disease progression of RE patients via facilitating persistent HCMV infection in brain tissue and provides new insight into understanding the pathogenesis of RE.
拉森氏脑炎（RE）是一种罕见且严重的进行性癫痫综合征，其病因不明。病毒感染，如人类巨细胞病毒（HCMV），被认为是 RE 的潜在触发因素。干扰素诱导跨膜蛋白 3（IFITM3）单核苷酸多态性（SNP）rs12252 与病毒感染疾病的严重程度相关。本研究旨在探讨 HCMV 感染和 IFITM3 rs12252 是否与 RE 疾病进展相关。
采用免疫组织化学染色、原位杂交和免疫荧光双染检测 HCMV 和 IFITM3 的表达。采用 Sanger 测序法检测 IFITM3 rs12252 的基因型。对该 SNP 与 HCMV 抗原表达进行遗传关联分析。进一步分析该 SNP 与患者临床特征的关系。在体外研究中，通过免疫荧光和实时 RT-PCR 检测过表达 IFITM3 变异体的 SH-SY5Y 细胞中的 HCMV 复制。
在 RE 患者的脑组织中观察到 HCMV 和 IFITM3 的表达升高。此外，IFITM3 多态性 rs12252-C 与 RE 患者的 HCMV 高检出率和快速疾病进展相关，IFITM3 rs12252-CC 基因型患者的 HCMV 高检出率和快速疾病进展。体外研究表明，过表达的 IFITM3 变异体与 HCMV 高感染水平相关。
这些结果表明，IFITM3 rs12252-C 通过促进脑组织中持续性 HCMV 感染与 RE 患者的疾病进展相关，为理解 RE 的发病机制提供了新的见解。
