诱导共刺激分子配体 (ICOSL) 在 Graves 病甲亢患者甲状腺组织中的表达。

Involvement of inducible costimulator ligand (ICOSL) expression in thyroid tissue in hyperthyroidism of Graves' disease patients.

机构信息

Institute of Medical Biotechnology, Medical College of Soochow University, 708 Renmin Road, Suzhou, 215007, Jiangsu, China.

出版信息

J Clin Immunol. 2012 Dec;32(6):1253-61. doi: 10.1007/s10875-012-9711-2. Epub 2012 Jun 17.

DOI:10.1007/s10875-012-9711-2

PMID:22706735

Abstract

BACKGROUND

The role of costimulatory molecules expressed on lymphocytes and thyrocytes in hyperthyroidism has attracted increasing attention and research has shown a close correlation between variant expression of these molecules on lymphocytes and thyrocytes and the development of GD.

MATERIALS AND METHODS

[corrected] Thyroid tissues were collected from GD patients during surgery and from Hashimoto disease (HT) and non-toxic goiter (NTG) patients as controls. ICOSL expression on infiltrated B cells and TFC was detected by flow cytometry (FCM), reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). Variation in ICOSL expression on TFC in primary cultures was analyzed in the absence or presence of cytokines using FCM assays. The role of ICOS-ICOSL signaling in proliferation, thyroid hormone production and thyroglobulin (Tg) release was investigated in primary TFC cultures using ICOS gene transfected L929 cells (ICOS-L929 cells) and the blocking ICOSL antibody (11 C4) in MTT assays and radioimmunoassays.

RESULTS AND DISCUSSION

ICOSL expression on infiltrated B cells and TFC was detected in GD patient tissue. However, ICOSL expression was only detected on infiltrated B cells in control HT and NTG patient tissue. ICOSL expression on TFC was induced in vitro by the proinflammatory cytokines IFN-γ, IL-6 and TNF-α. Compared with mock transfected L929 (mock-L929) control cells, ICOS-L929 cells promoted significant proliferation of primary cultured TFC, with increased thyroid hormone and Tg production (all P < 0.01). TFC proliferation and production of thyroid hormones and Tg were inhibited significantly in the presence of ICOSL blocking antibody (11 C4) (all P < 0.05). Our observations suggest that ICOS-ICOSL signal plays a direct role in proliferation and differentiation of TFC and may exert important effects in the initiation, maintenance and exaggeration of autoimmune responses in local tissue.

摘要

背景

表达在淋巴细胞和甲状腺细胞上的共刺激分子在甲状腺功能亢进症中的作用引起了越来越多的关注，研究表明这些分子在淋巴细胞和甲状腺细胞上的变异表达与 GD 的发生发展密切相关。

材料和方法

手术中从 GD 患者、桥本甲状腺炎（HT）和非毒性甲状腺肿（NTG）患者中采集甲状腺组织作为对照。通过流式细胞术（FCM）、逆转录聚合酶链反应（RT-PCR）和免疫组织化学（IHC）检测浸润 B 细胞和 TFC 上 ICOSL 的表达。在缺乏或存在细胞因子的情况下，通过 FCM 分析检测原发性 TFC 培养物中 TFC 上 ICOSL 的表达变化。通过转染 ICOS 基因的 L929 细胞（ICOS-L929 细胞）和阻断 ICOSL 抗体（11 C4）在 MTT 测定和放射免疫测定中，研究 ICOS-ICOSL 信号在原发性 TFC 培养物中的增殖、甲状腺激素产生和甲状腺球蛋白（Tg）释放中的作用。

结果与讨论

在 GD 患者组织中检测到浸润 B 细胞和 TFC 上 ICOSL 的表达。然而，在对照 HT 和 NTG 患者组织中仅检测到浸润 B 细胞上的 ICOSL 表达。IFN-γ、IL-6 和 TNF-α 等促炎细胞因子可在体外诱导 TFC 上 ICOSL 的表达。与空载转染的 L929（空载-L929）对照细胞相比，ICOS-L929 细胞显著促进原代培养 TFC 的增殖，甲状腺激素和 Tg 产生增加（均 P<0.01）。在存在 ICOSL 阻断抗体（11 C4）的情况下，TFC 增殖和甲状腺激素和 Tg 的产生明显受到抑制（均 P<0.05）。我们的观察表明，ICOS-ICOSL 信号在 TFC 的增殖和分化中发挥直接作用，可能在局部组织中自身免疫反应的启动、维持和加剧中发挥重要作用。