Schistosoma mansoni and α-galactosylceramide:: Prophylactic effect of Th1 immune suppression in a mouse model of Graves' hyperthyroidism
Schistosoma mansoni and α-galactosylceramide:: Prophylactic effect of Th1 immune suppression in a mouse model of Graves' hyperthyroidism
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DOI：
10.4049/jimmunol.173.3.2167
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Rapoport, B
中科院分区：
文献类型：
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作者：
Nagayama, Y;Watanabe, K;Rapoport, B
Graves‘s甲亢是一种由刺激性促甲状腺激素受体(TSHR)自身抗体介导的器官特异性自身免疫性疾病，被认为是Th2显性疾病。然而，最近的数据与鼠标格雷夫斯的模型相互矛盾。例如，我们最近证明，给BALB/c小鼠注射编码TSHR的腺病毒可诱导以针对TSHR的Th1和Th2混合免疫反应为特征的Graves‘甲亢，并且腺病毒瞬时共表达Th2细胞因子IL-4会使Ag特异性免疫反应向Th2倾斜，从而抑制疾病诱导。为了进一步了解免疫极化与Graves病的关系，我们评估了曼氏血吸虫蠕虫感染和α-半乳糖神经酰胺(α-GalCer)对Graves病Th2免疫极化的影响，这两种免疫极化都是已知的偏向Th2的系统免疫反应。曼氏假单胞菌感染首先诱导对可溶性虫体AGS的Th1和Th2混合免疫应答，然后是对可溶性虫卵AGS的Th2应答。先前感染曼氏沙门氏菌可抑制Th1型抗TSHR免疫反应，表现为脾细胞分泌抗原特异性干扰素-γ，降低IgG2a亚类抗TSHR抗体效价，并阻止疾病的发展。同样，α-GalCer抑制抗原特异性的脾细胞分泌干扰素-γ，并防止疾病诱导。然而，一旦完全诱导抗TSHR免疫反应，曼氏沙门氏菌或α-GalCer在治疗疾病方面就无效。这些数据支持Graves病的Th1学说，并表明在抗原启动时抑制Th1型免疫反应可能是抑制致病性抗TSHR免疫反应的关键。
Graves' hyperthyroidism, an organ-specific autoimmune disease mediated by stimulatory thyrotropin receptor (TSHR) autoantibodies, has been considered a Th2-dominant disease. However, recent data with mouse Graves' models are conflicting. For example, we recently demonstrated that injection of BALB/c mice with adenovirus coding the TSHR induced Graves' hyperthyroidism characterized by mixed Th1 and Th2 immune responses against the TSHR, and that transient coexpression of the Th2 cytokine IL-4 by adenovirus skewed Ag-specific immune response toward Th2 and suppressed disease induction. To gain further insight into the relationship between immune polarization and Graves' disease, we evaluated the effect of Th2 immune polarization by helminth Schistosoma mansoni infection and alpha-galactosylceramide (alpha-GalCer), both known to bias the systemic immune response to Th2, on Graves' disease. S. mansoni infection first induced mixed Th1 and Th2 immune responses to soluble worm Ags, followed by a Th2 response to soluble egg Ags. Prior infection with S. mansoni suppressed the Th1-type anti-TSHR immune response, as demonstrated by impaired Ag-specific IFN-gamma secretion of splenocytes and decreased titers of IgG2a subclass anti-TSHR Abs, and also prevented disease development. Similarly, alpha-GalCer suppressed Ag-specific splenocyte secretion of IFN-gamma and prevented disease induction. However, once the anti-TSHR immune response was fully induced, S. mansoni or alpha-GalCer was ineffective in curing disease. These data support the Th1 theory in Graves disease and indicate that suppression of the Th1-type immune response at the time of Ag priming may be crucial for inhibiting the pathogenic anti-TSHR immune response.