Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway
Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway
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DOI：
10.4049/jimmunol.170.12.6348
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发表时间：
2003-06-15
影响因子：
4.4
通讯作者：
Smith, TJ
中科院分区：
文献类型：
--
作者：
Pritchard, J;Han, R;Smith, TJ
Graves病（GD）与T细胞浸润有关，但淋巴细胞运输的机制仍不清楚。我们以前报道过GD患者的成纤维细胞表达IL-16（一种CD 4特异性趋化因子）和RANTES（一种C-C趋化因子），以响应GD特异性IgG（GD-IgG）。我们意外地发现，这些反应是由GD-IgG和胰岛素样生长因子（IGF）-I受体（IGF-IR）之间的功能性相互作用引起的。IGF-I和IGF-IR特异性IGF-I类似物des（1-3）模拟GD-IgG的作用。GD-IgG和IGF-I均不激活来自无GD供体的对照成纤维细胞中的化学引诱物表达。用特异性受体阻断抗体阻断IGF-IR功能或用显性阴性突变IGF-IR瞬时阻断成纤维细胞完全减弱GD-IgG引起的信号传导。此外，GD-IgG取代特异性I-125标记的IGF-I与成纤维细胞的结合，并减弱通过流式细胞术的IGF-IR检测。这些发现确定了一种新的疾病机制，涉及功能性GD-IgG/IGF-IR桥，这可能解释了GD中的T细胞浸润。阻断这一途径可能是一种特殊的治疗策略。
Graves' disease (GD) is associated with T cell infiltration, but the mechanism for lymphocyte trafficking has remained uncertain. We reported previously that fibroblasts from patients with GD express IL-16, a CD4-specific chemoattractant, and RANTES, a C-C chemokine, in response to GD-specific IgG (GD-IgG). We unexpectedly found that these responses result from a functional interaction between GD-IgG and the insulin-like growth factor (IGF)-I receptor (IGF-IR). IGF-I and the IGF-IR-specific IGF-I analog, des(1-3), mimic the effects of GD-IgG. Neither GD-IgG nor IGF-I activates chemoattractant expression in control fibroblasts from donors without GD. Interrupting IGF-IR function with specific receptor-blocking Abs or by transiently transfecting fibroblasts with a dominant negative mutant IGF-IR completely attenuates signaling provoked by GD-IgG. Moreover, GD-IgG displaces specific I-125-labeled IGF-I binding to fibroblasts and attenuates IGF-IR detection by flow cytometry. These findings identify a novel disease mechanism involving a functional GD-IgG/IGF-IR bridge, which potentially explains T cell infiltration in GD. Interrupting this pathway may constitute a specific therapeutic strategy.