ABSTRACT

Ataxia-Telangiectasia (A-T) is characterized by cerebellar neurodegeneration and immunodeficiency. Recent studies suggest that very low glucocorticoids (GCs) doses may help improve A-T neurological phenotype in some patients. Interestingly, in GCs studies an unexpected improvement of lymphocytes proliferation in some A-T patients has been observed. GCs are able to upregulate IL-7 Rα expression and rescue it from the recycling. In this study, we compared several immunological functions, including PBMC proliferative responses, cell activation events and IL-7/IL-7 Rα axis functionality, with the neurological behavior during an in-vivo GCs treatment between the most Responder patient to GC and the Non-Responder at all. During in-vivo GC treatment, we observed an increase of lymphocyte proliferation upon stimulation with PHA or IL-7 only in the Responder. This finding paralleled the increase in the surface expression of IL-7 R and up-regulation of the CD69 T-cell activation marker. Internalization and recycling of IL-7 R occurred properly only in the Responder. Microarray analysis revealed a remarkable difference in the DE-genes levels among Responder and Non-Responder, mostly concerning miRNAs and Multiple Complex families. Our findings suggest that the improvement of lymphocyte functionality, which correlates to the neurological behavior, is mediated through an effect of GCs on the IL-7/IL-7 Rα axis.

摘要

共济失调毛细血管扩张症 (AT) 的特征是小脑神经变性和免疫缺陷。最近的研究表明，非常低的糖皮质激素 (GCs) 剂量可能有助于改善某些患者的 AT 神经表型。有趣的是，在 GC 研究中，已经观察到一些 AT 患者淋巴细胞增殖的意外改善。GC 能够上调 IL-7 Rα 表达并将其从回收中拯救出来。在这项研究中，我们比较了几种免疫学功能，包括 PBMC 增殖反应、细胞活化事件和 IL-7/IL-7 Rα 轴功能，以及在体内GCs 治疗期间对 GC 最有反应的患者和完全不响应。在体内在 GC 处理中，我们观察到仅在响应者中用 PHA 或 IL-7 刺激后淋巴细胞增殖增加。这一发现与 IL-7 R 表面表达的增加和 CD69 T 细胞活化标志物的上调平行。IL-7 R 的内化和再循环仅在响应者中正确发生。微阵列分析显示响应者和非响应者的 DE 基因水平存在显着差异，主要涉及 miRNA 和多重复杂家族。我们的研究结果表明，与神经行为相关的淋巴细胞功能的改善是通过 GC 对 IL-7/IL-7 Rα 轴的影响介导的。