Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
The University of Oslo, Faculty of Medicine, Oslo, Norway.
J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1763-e1774. doi: 10.1210/clinem/dgaa958.
The origin of Graves disease (GD) remains elusive. However, evidence of an association between GD and viral infections is emerging. Human leukocyte antigen (HLA) class I presents viral antigens to circulating immune cells and plays a crucial role in the defense against viral infections.
This work aimed to investigate HLA class I expression, enterovirus presence, and the viral immune response proteins signal transducer and activation of transcription 1 (STAT1) and protein kinase R (PKR) in thyroid tissue from GD patients.
We collected thyroid tissue from core needle biopsies or surgical specimens from 48 GD patients and 24 controls. Standard immunohistochemistry was used to detect HLA class I and enteroviral capsid protein 1 (VP1) on formalin-fixed and paraffin-embedded tissue. STAT1 and PKR were examined by combined immunofluorescence staining. HLA class I expression score was the main outcome measure.
The HLA class I expression score, which takes both proportion and intensity of immunostaining into account, was significantly higher in GD patients (3.1 ± 3.3) than in controls (0.5 ± 0.9) (P < .001). Significantly more VP1 positive thyroid cells were found GD samples (50.1 ± 30.5%) than in controls (14.9 ± 10.5%) (P < .001). STAT1 and HLA class I were found within the same thyroid cells and PKR and VP1 were also colocalized within thyroid cells.
HLA class I is upregulated in GD and enterovirus protein is prevalent in thyroid tissue. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an antiviral tissue response. These findings support the concept of a link between viral infections and GD.
格雷夫斯病（GD）的病因仍不清楚。然而，GD 与病毒感染之间存在关联的证据正在出现。人类白细胞抗原（HLA）I 类将病毒抗原呈递给循环免疫细胞，并在抵抗病毒感染中发挥关键作用。
本研究旨在研究 GD 患者甲状腺组织中 HLA Ⅰ类表达、肠道病毒存在情况以及病毒免疫反应蛋白信号转导和转录激活因子 1（STAT1）和蛋白激酶 R（PKR）。
我们收集了 48 例 GD 患者和 24 例对照者的甲状腺组织，这些组织来自核心针活检或手术标本。采用标准免疫组织化学方法检测福尔马林固定和石蜡包埋组织中的 HLA Ⅰ类和肠道病毒衣壳蛋白 1（VP1）。采用免疫荧光联合染色法检测 STAT1 和 PKR。主要观察指标为 HLA Ⅰ类表达评分。
考虑到免疫染色的比例和强度，GD 患者的 HLA Ⅰ类表达评分（3.1±3.3）明显高于对照组（0.5±0.9）（P<.001）。GD 患者甲状腺组织中 VP1 阳性细胞的比例（50.1±30.5%）明显高于对照组（14.9±10.5%）（P<.001）。STAT1 和 HLA Ⅰ类存在于同一甲状腺细胞内，PKR 和 VP1 也存在于甲状腺细胞内共定位。
GD 中 HLA Ⅰ类表达上调，甲状腺组织中肠道病毒蛋白普遍存在。HLA Ⅰ类与 STAT1 的共定位以及 VP1 与 PKR 的共定位提示存在抗病毒的组织反应。这些发现支持病毒感染与 GD 之间存在关联的概念。
