Poma Anello Marcello, Hammerstad Sarah Salehi, Genoni Angelo, Basolo Alessio, Dahl-Jorgensen Knut, Toniolo Antonio
Department of Surgical, Medical, Molecular Pathology and Clinical Area, University of Pisa, 56126 Pisa, Italy.
Department of Pediatric Medicine, Oslo University Hospital, 0450 Oslo, Norway.
Microorganisms. 2021 Apr 19;9(4):876. doi: 10.3390/microorganisms9040876.
Hashimoto's thyroiditis and Graves' disease are autoimmune thyroid disorders (AITD) of unknown origin. Enterovirus (EV) infection of thyroid cells has been implicated as a possible initiator of cell damage and of organ-specific autoimmunity. We asked whether persistent infection of human epithelial cells with EV strains obtained from thyroid tissue of AITD patients could be associated with transcriptional changes capable of fostering immunopathology.
EV isolates obtained from thyroid tissue of AITD cases were used to infect the AV3 epithelial cell line. AV3 cells incubated with a virus-free medium from thyroid tissue of subjects without evidence of thyroid autoimmunity were used as uninfected controls. Transcripts of immune-related genes were compared in infected vs. uninfected cells.
The EV genome and antigens were detected only in the cells exposed to AITD-derived virus isolates, not in control cells. Persistent EV infection, while suppressing transcription of several type I IFN and cytokine determinants, was associated with enhanced transcription of NFKB1/RELA, IFNAR1, JAK1/STAT1, i.e., the determinants that play key immunologic roles. Infection also led to upregulation of the CCL2 chemokine and the IL-18 pro-inflammatory interleukin.
As in the case of EV strains obtained from autoimmune diabetes, results show that the EV strains that are present in the thyroid of AITD cases do repress IFN and cytokine pathways. JAK1/STAT1 upregulation supports activation of TLR pathways and aberrant T cell signaling. In the early phases of AITD, our results highlight the potential benefit of interventions aimed at blocking the viral infection and easing the inflammatory response.
桥本甲状腺炎和格雷夫斯病是病因不明的自身免疫性甲状腺疾病（AITD）。甲状腺细胞的肠道病毒（EV）感染被认为可能是细胞损伤和器官特异性自身免疫的起始因素。我们研究了从AITD患者甲状腺组织中分离出的EV毒株持续感染人上皮细胞是否与能够促进免疫病理学的转录变化有关。
用从AITD病例甲状腺组织中分离出的EV毒株感染AV3上皮细胞系。将与无甲状腺自身免疫证据的受试者甲状腺组织的无病毒培养基孵育的AV3细胞用作未感染对照。比较感染细胞与未感染细胞中免疫相关基因的转录本。
仅在暴露于AITD衍生病毒分离株的细胞中检测到EV基因组和抗原，对照细胞中未检测到。持续性EV感染在抑制几种I型干扰素和细胞因子决定簇转录的同时，与NFKB1/RELA、IFNAR1、JAK1/STAT1（即发挥关键免疫作用的决定簇）的转录增强有关。感染还导致CCL2趋化因子和IL-18促炎白细胞介素上调。
与从自身免疫性糖尿病中分离出的EV毒株情况一样，结果表明AITD病例甲状腺中存在的EV毒株确实会抑制干扰素和细胞因子途径。JAK1/STAT1上调支持Toll样受体途径的激活和异常的T细胞信号传导。在AITD的早期阶段，我们的结果突出了旨在阻断病毒感染和减轻炎症反应的干预措施的潜在益处。
