Department of Ophthalmology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.
Department of Ophthalmology, Shiley Eye Institute University of California, San Diego, 9415, USA.
BMC Immunol. 2024 May 11;25(1):31. doi: 10.1186/s12865-024-00613-3.
Thyroid eye disease (TED) is an inflammatory process involving lymphocyte-mediated immune response and orbital tissue damage. The anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies produced by B lymphocytes are involved in the activation of orbital fibroblasts and the inflammatory process of orbital tissue damage in TED. The purpose of this study was to explore the role of IGF-1R in the mechanistic connection between orbital fibroblasts and B lymphocytes in TED.
Orbital fibroblasts sampled from orbital connective tissues and peripheral B lymphocytes isolated from peripheral blood, which were obtained from 15 patients with TED and 15 control patients, were co-cultured at a ratio of 1:20. The level of IGF-1R expression in orbital fibroblasts was evaluated by flow cytometry and confocal microscopy. Transient B lymphocyte depletion was induced with anti-CD20 monoclonal antibody rituximab, while the IGF-1R pathway was blocked by the IGF-1R binding protein. The expression levels of interleukin-6 (IL-6) and regulated upon activation, normal T cell expressed and secreted (RANTES) in the co-culture model were quantified via ELISA.
IGF-1R expression was significantly elevated in TED orbital fibroblasts compared to that of controls. A 24-h co-culture of orbital fibroblasts with peripheral B lymphocytes induced elevated expression levels of IL-6 and RANTES in each group (TED patients and controls), with the highest levels occurring in TED patients (T + T group). Rituximab and IGF-1R binding protein significantly inhibited increased levels of IL-6 and RANTES in the co-culture model of TED patients.
IGF-1R may mediate interaction between orbital fibroblasts and peripheral B lymphocytes; thus, blocking IGF-1R may reduce the local inflammatory response in TED. Rituximab-mediated B lymphocyte depletion played a role in inhibiting inflammatory responses in this in vitro co-culture model, providing a theoretical basis for the clinical application of anti-CD20 monoclonal antibodies in TED.
甲状腺眼病（TED）是一种涉及淋巴细胞介导的免疫反应和眼眶组织损伤的炎症过程。B 淋巴细胞产生的抗胰岛素样生长因子-1 受体（IGF-1R）抗体参与了 TED 中眼眶成纤维细胞的激活和眼眶组织损伤的炎症过程。本研究旨在探讨 IGF-1R 在 TED 中眼眶成纤维细胞与 B 淋巴细胞之间的机制联系中的作用。
从眼眶结缔组织中取样的眼眶成纤维细胞和从外周血中分离的外周 B 淋巴细胞，来自 15 例 TED 患者和 15 例对照患者，以 1:20 的比例共培养。通过流式细胞术和共聚焦显微镜评估眼眶成纤维细胞中 IGF-1R 的表达水平。用抗 CD20 单克隆抗体利妥昔单抗诱导短暂性 B 淋巴细胞耗竭，同时用 IGF-1R 结合蛋白阻断 IGF-1R 途径。通过 ELISA 定量共培养模型中白细胞介素-6（IL-6）和活化正常 T 细胞表达和分泌（RANTES）的表达水平。
与对照组相比，TED 眼眶成纤维细胞中 IGF-1R 的表达明显升高。眼眶成纤维细胞与外周 B 淋巴细胞 24 小时共培养后，各组（TED 患者和对照组）IL-6 和 RANTES 的表达水平均升高，TED 患者组（T+T 组）升高最明显。利妥昔单抗和 IGF-1R 结合蛋白显著抑制了 TED 患者共培养模型中 IL-6 和 RANTES 水平的升高。
IGF-1R 可能介导眼眶成纤维细胞与外周 B 淋巴细胞之间的相互作用；因此，阻断 IGF-1R 可能会减少 TED 中的局部炎症反应。利妥昔单抗介导的 B 淋巴细胞耗竭在抑制该体外共培养模型中的炎症反应中发挥了作用，为抗 CD20 单克隆抗体在 TED 中的临床应用提供了理论依据。
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