Simon H U, Yousefi S, Dommann-Scherrer C C, Zimmermann D R, Bauer S, Barandun J, Blaser K
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Switzerland.
J Exp Med. 1996 Mar 1;183(3):1071-82. doi: 10.1084/jem.183.3.1071.
The mechanisms of sustained overproduction of eosinophils in the idiopathic hypereosinophilic syndrome and in some human immunodeficiency virus (HIV)-1-infected individuals are largely unknown. We hypothesized that T cells may release soluble products that regulate eosinophilia in these patients, as has been previously shown in bronchial asthma. We identified one patient with idiopathic hypereosinophilic syndrome and one HIV-1-infected individual with associated hypereosinophilia who demonstrated high numbers of CD4-CD8- T cells in peripheral blood. CD4-CD8- T cells from both patients, although highly activated, did not express functional Fas receptors. In one case, the lack of functional Fas receptors was associated with failure of Fas mRNA and protein expression, and in another, expression of a soluble form of the Fas molecule that may have antagonized normal signaling of Fas ligand. In contrast to the recently described lymphoproliferative/autoimmune syndrome, which is characterized by accumulation of CD4-CD8- T cells and mutations within the Fas gene, this study suggests somatic variations in Fas expression and function quite late in life. Both genetic and somatic abnormalities in regulation of the Fas gene are therefore associated with failures to undergo T cell apoptosis. Furthermore, the expanded population of CD4-CD8- T cells from both patients elaborated cytokines with antiapoptotic properties for eosinophils, indicating a major role of these T cells in the development of eosinophilia. Thus, this study demonstrates a sequential dysregulation of apoptosis in different cell types.
特发性嗜酸性粒细胞增多综合征以及一些人类免疫缺陷病毒（HIV）-1感染个体中嗜酸性粒细胞持续过度产生的机制在很大程度上尚不清楚。我们推测，正如先前在支气管哮喘中所显示的那样，T细胞可能会释放调节这些患者嗜酸性粒细胞增多的可溶性产物。我们鉴定出一名特发性嗜酸性粒细胞增多综合征患者和一名伴有相关嗜酸性粒细胞增多的HIV-1感染个体，他们外周血中CD4-CD8-T细胞数量较多。两名患者的CD4-CD8-T细胞尽管高度活化，但未表达功能性Fas受体。在一个病例中，功能性Fas受体的缺乏与Fas mRNA和蛋白表达失败有关，而在另一个病例中，Fas分子可溶性形式的表达可能拮抗了Fas配体的正常信号传导。与最近描述的以CD4-CD8-T细胞积聚和Fas基因内突变特征的淋巴增殖性/自身免疫综合征不同，本研究表明Fas表达和功能在生命后期出现体细胞变异。因此，Fas基因调控中的遗传和体细胞异常均与T细胞凋亡失败有关。此外，两名患者中扩增的CD4-CD8-T细胞群体分泌了具有抗嗜酸性粒细胞凋亡特性的细胞因子，表明这些T细胞在嗜酸性粒细胞增多的发生中起主要作用。因此，本研究证明了不同细胞类型中凋亡的顺序失调。
