Aukrust P, Svardal A M, Müller F, Lunden B, Berge R K, Frøland S S
Medical Department A, University of Oslo, National Hospital, Norway.
Blood. 1995 Aug 15;86(4):1383-91.
We have previously shown chronic immune activation and enhanced generation of reactive oxygen species in common variable immunodeficiency (CVI). In the present study, we examined levels of glutathione, the dominant intracellular thiol, that play an important protective role against oxidative and inflammatory stress in plasma and in monocytes and lymphocyte subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes from CVI patients had significantly lower levels of both total and reduced glutathione as well as a lower ratio of reduced to total glutathione compared with healthy controls. This decrease in glutathione levels in CD4+ lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of total glutathione were also significantly decreased in CVI. In contrast, monocytes from CVI patients exhibited increased levels of both total and reduced glutathione compared with blood donor monocytes. CVI patients had significantly raised serum levels of tumor necrosis factor alpha (TNF alpha) and TNF alpha concentration was strongly associated with glutathione depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total and reduced glutathione were found in a subgroup of CVI patients characterized by persistent immune activation in vivo, decreased numbers of CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally, supplementation of cell cultures with glutathione-monoethyl ester did significantly enhance interleukin-2 production from peripheral blood mononuclear cells in CVI patients. These glutathione abnormalities in CVI indicate increased oxidative stress, particularly in CD4+ lymphocytes, and intracellular depletion of reduced glutathione of the demonstrated magnitude may have profound implications for CD4+ lymphocyte function and the immunodeficiency in CVI.
我们之前已经表明，常见可变免疫缺陷（CVI）中存在慢性免疫激活和活性氧生成增强的情况。在本研究中，我们检测了20例CVI患者和16名健康对照者血浆、单核细胞及淋巴细胞亚群中谷胱甘肽（细胞内主要的硫醇，对氧化和炎症应激起重要保护作用）的水平。与健康对照相比，CVI患者的CD4 +淋巴细胞中总谷胱甘肽和还原型谷胱甘肽水平均显著降低，且还原型谷胱甘肽与总谷胱甘肽的比值也较低。CD4 +淋巴细胞中谷胱甘肽水平的降低在CD45RA +亚群中最为明显。CVI患者血浆中的总谷胱甘肽水平也显著降低。相比之下，与献血者的单核细胞相比，CVI患者的单核细胞中总谷胱甘肽和还原型谷胱甘肽水平均升高。CVI患者的血清肿瘤坏死因子α（TNFα）水平显著升高，且TNFα浓度与CD4 +淋巴细胞中的谷胱甘肽耗竭密切相关。此外，在一组体内持续免疫激活、外周血CD4 +淋巴细胞数量减少且脾肿大的CVI患者亚组中，发现总谷胱甘肽和还原型谷胱甘肽水平最低。最后，用谷胱甘肽单乙酯补充细胞培养物确实显著增强了CVI患者外周血单个核细胞中白细胞介素-2的产生。CVI中的这些谷胱甘肽异常表明氧化应激增加，特别是在CD4 +淋巴细胞中，如此程度的细胞内还原型谷胱甘肽耗竭可能对CD4 +淋巴细胞功能及CVI中的免疫缺陷有深远影响。
