Search

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-alpha in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-alpha in SLE patients' plasma.

Rabies virus (RABV) is able to induce apoptotic death of target cells. The molecular pathway of RABV-induced cell death is partially known. In the present study, cDNA array analysis was used as a tool to screen for pro-apoptotic genes that may be involved in RABV induction. RNA was extracted from the infected CNS and from mock-infected controls. When the mean gene expression was compared between the infected group and controls, 21 potential apoptotic genes were identified that exhibited more than 2.5-fold difference in their expression levels. These 21 genes can be grouped into two groups, those genes that participate in the commitment phase and those that play a role as executioners. Examples of genes in commitment phase were death receptors (Fas-L receptor, TNF-receptor), lysosomal proteases, calpain, caspase-1, signaling molecules (ERK, p38MAPK) and bcl-2 family members. Cytochrome c and caspase-3 were representatives of executioners. Based on types of genes activated during the commitment phase, two independent apoptotic mechanisms may be activated in response to the RV infection. The first is immune-mediated death which may operate through the receptor-ligand pathway activated by caspase-1 and the pro-inflammatory cytokine, IL-1beta. The other mechanism is a protease-mediated process which involves lysosomal proteases and calcium-dependent neutral proteases. These two stimulating pathways were followed by Bad, Bak, Bid activation and subsequently the upregulation of cytochrome c and caspase-3. In addition, mobilization of K+ ion and other accessory apoptotic genes such as annexins and clusterin were also upregulated.