Bona G, Defranco S, Chiocchetti A, Indelicato M, Biava A, Difranco D, Dianzani I, Ramenghi U, Corrias A, Weber G, De Sanctis V, Iughetti L, Radetti G, Dianzani U
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Medical Sciences, 'A.Avogadro' University of Eastern Piedmont, Novara, Italy.
Clin Exp Immunol. 2003 Sep;133(3):430-7. doi: 10.1046/j.1365-2249.2003.02221.x.
Triggering of the Fas receptor induces T cell apoptosis and is involved in shutting-off the immune response. Inherited defects impairing Fas function cause the autoimmune lymphoproliferative syndrome, and may play a role in other autoimmune diseases. The aim of this work was to analyse the Fas function in paediatric patients with thyroid autoimmunities. We found that T cells from 24/28 patients with Graves' disease (GD) and 12/35 patients with Hashimoto's thyroiditis (HT) displayed defective Fas function. In HT, the defect was more frequent in patients requiring replacement therapy (11/20) than in those not requiring (1/15); moreover, in untreated HT the highest defect was displayed by patients with the highest levels of autoantibodies. Fas was always expressed at normal levels and no Fas mutations were detected. Analysis of the healthy parents of seven Fas-resistant patients showed that several of them were Fas-resistant, which suggests a genetic component. Fusion of Fas-resistant T cells with the Fas-sensitive HUT78 T cell line generated Fas-resistant hybrid cells, which suggests the presence of molecules exerting a dominant negative effect on Fas function. Analysis of Fas-induced activation of caspase-8 and -9 showed decreased activity of both caspases in HT, whereas activity of caspase-9 was increased and that of caspase-8 was decreased in GD. These data suggest that heterogeneous inherited defects impairing Fas function favour the development of thyroid autoimmunities.
Fas受体的激活可诱导T细胞凋亡，并参与免疫反应的终止。遗传性Fas功能缺陷会导致自身免疫性淋巴增殖综合征，可能在其他自身免疫性疾病中也起作用。这项工作的目的是分析患有甲状腺自身免疫性疾病的儿科患者的Fas功能。我们发现，28例格雷夫斯病（GD）患者中的24例以及35例桥本甲状腺炎（HT）患者中的12例的T细胞显示出Fas功能缺陷。在HT中，需要替代治疗的患者（20例中的11例）比不需要替代治疗的患者（15例中的1例）缺陷更常见；此外，在未经治疗的HT中，自身抗体水平最高的患者Fas功能缺陷最为明显。Fas总是以正常水平表达，未检测到Fas突变。对7例Fas抵抗患者的健康父母进行分析发现，他们中的一些人也存在Fas抵抗，这表明存在遗传因素。Fas抵抗性T细胞与Fas敏感性HUT78 T细胞系融合产生了Fas抵抗性杂交细胞，这表明存在对Fas功能发挥显性负效应的分子。对Fas诱导的半胱天冬酶-8和-9激活的分析表明，HT中这两种半胱天冬酶的活性均降低，而GD中半胱天冬酶-9的活性增加，半胱天冬酶-8的活性降低。这些数据表明，损害Fas功能的异质性遗传缺陷有利于甲状腺自身免疫性疾病的发展。
