全身性紅斑性狼瘡病人相關免疫細胞的氧化還原狀態，粒線體功能和陽離子運送之研究

Abstract

全身性紅斑性狼瘡(systemic lupus erythematosus, SLE) 是全身性自體免疫疾病的主要疾病，罹患者除了身體各種器官均會有嚴重影響之可能外，更會對各種感染的感受性增加，也是其造成罹患者的主要致病及死亡原因之一。究其原因，自然是全身性紅斑性狼瘡病人有免疫系統上的眾多異常，而在這些異常中，免疫相關細胞本身功能異常，扮演著關鍵性的角色，其中中性白血球(PMN)和單核性細胞(mononuclear cells, MNC)的功能異常，例如對特異性抗原、裂殖素(mitogen)，和同種及異種細胞的刺激均呈現反應低下(hyporesponsiveness/anergy)的現象，應是重要的原因之一。雖有不少文獻指出SLE患者的單核性細胞的活化，低反應性，及細胞死亡的信息傳遞有異常和缺陷，但其中信息傳遞缺陷的分子機制至今仍不甚清楚，一般認為細胞內的氧化還原反應的狀態(reduction/oxidation, redox)對於各種生物活性，包括信息傳遞，基因表現及細胞增殖有重要的影響。至今有很多對redox敏感的標的分子陸續被發現，而這些標的分子又會影響到離子輸送、鈣離子代謝、基因轉錄、細胞生長和凋亡等生物學上的重要現象。本實驗主要目的，在於研究全身性紅斑性狼瘡病人免疫相關細胞的低反應性之致病因子可能為何，而經由實驗顯示發現SLE-MNC的glutathione peroxidase (GSH-Px)的活性不僅低下而且蛋白分子的聚合性不同，亦即SLE-MNC表現出來的100kDa GSH-Px tetramer的含量比正常MNC少，SLE-MNC hyporesponsiveness及不正常的redox狀態之間應有某些程度的相關。此外粒線體功能和陽離子運送均有異常之情形。 總結而言，我們的研究顯示，全身性紅斑性狼瘡病人的單核細胞對刺激的反應低下可能是來自減損的氧化還原能力，粒腺體功能性下降，粒腺體 DNA 的缺失，與離子轉送有關分子表現的抑制，以及存在於血清中抗雙股DNA自體性抗體所造成不利的影響所致有關。

The systemic lupus erythematosus (SLE) is a main disease of the immune disease. Patients of SLE suffer from various kinds of organs. In addition, it will also have serious influence on the increase of infection, and this is the main pathogenic and cause of death of the disease, too. Susceptibility to common and opportunistic infections is a major cause of morbidity and mortality in these patients.The important factor of this is the functional defects of the immune cells per se. It is well recognized that hyporesponsiveness to stimulation are found in both polymorphonuclear neutrophils (PMN) and mononuclear cells (MNC) of patients with active SLE. In previous reports demonstrated that SLE-PMN was not only defective in IL-8 production but hyporesponsive to IL-8 stimulation. On the other hand, hyporesponsiveness/anergy of SLE-MNC to phytomitogens, specific antigens, allogeneic and autologous cells stimulation were documented in vitro. However, the real cause for SLE-MNC hyporesponsiveness has not been elucidated yet. Recently, many authors have identified a number of aberrated antigen receptor-mediated signal events in T and B lymphocytes from patients with active SLE. Although the TCR- or BCR-mediated increases in protein tyrosine phosphorylation and cytoplasmic free Ca2+, along with T cell receptor zeta chain deficiency is consistent with the presence of active cells in vivo. But this can not explain the defective responsiveness of SLE-MNC to common antigens such as tetanus toxoid in vitro. It is now quite clear that many biological molecules that are critically important in signaling and in the regulation of gene expression are sensitive cell to reactive oxygen species (ROS) at a concentration much lower than require inflict oxidative damage. Oxidation-reduction (redox) based regulation of signal transduction and gene expression is emerging as a fundamental regulatory mechanism in cell biology. A low, physiological concentration of ROS can regulate a variety of key molecular mechanisms linking with immune responses, cell-cell adhesion, cell proliferation, inflammation, metabolism, aging and death.. Based on these facts,we hypothesized that the hyporesponsiveness of MHC and PMN to stimulation signaling in patients with SLE is related to imbalanced redox state.However, more investigations are needed to solve it. This main purpose of this experiment is to study the possible cause of hyporesponsiveness in systemic lupus erythematosus.