Dissecting the "end game": clinical relevance, molecular mechanisms and laboratory assessment of apoptosis.

BACKGROUND: Apoptosis, the process of cell death, is a complex subject. In this review we highlight recent developments in the regulation and dysregulation of apoptosis in health and disease and summarize common laboratory techniques used to assess the process. METHODS: We accessed MEDLINE publications within the past 10 years, that reported on the clinical relevance, molecular mechanisms and laboratory assessment of apoptosis. PRINCIPAL FINDINGS: Apoptosis is a physiological event essential for normal biologic processes at all stages of life, including embryogenesis, tissue remodelling, cell turnover, reproduction and regulation of immune responses. Dysregulation of apoptosis, either excessive or inadequate, features prominently in the pathophysiology of many diseases, ranging from congenital anomalies to degenerative disorders, ischemic and reperfusion injury, chronic inflammatory or autoimmune diseases, certain infections and malignant disease. CONCLUSION: Improved understanding of the molecular mechanisms underlying apoptosis and its laboratory assessment is critical for reversing the pathophysiological processes associated with dysregulation of apoptosis.

Temporal sequence and functional implications of V beta-specific T cell receptor down-regulation and costimulatory molecule expression following in vitro stimulation with the staphylococcal superantigen Toxic shock syndrome toxin-1.

The superantigen toxic shock syndrome toxin-1 (TSST-1) is implicated as the major cause of staphylococcal toxic shock syndrome. The temporal sequence of early signaling events in human peripheral blood mononuclear cells following TSST-1 stimulation was examined. TSST-1 induced rapid and complete down-regulation of V beta 2-specific T cell receptor (TCR), followed by transient CD154 expression on CD4(+) lymphocytes. This was sequentially followed by the up-regulation of CD86, CD80, CD40, and human leukocyte antigen-DR expression on CD14(+) monocytes. In contrast, S14N, a TSST-1 mutant toxin with a single amino acid substitution that is known to be impaired in interleukin (IL)--2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha secretion, was deficient in both V beta 2-TCR down-regulation and CD154 and CD80/CD86 expression. Furthermore, pretreatment with monoclonal antibodies against V beta 2-TCR, CD80/CD86, and CD154 significantly inhibited TSST-1-induced IL-2, IFN-gamma, and TNF-alpha secretion. Taken together, these results indicate that early V beta-specific TCR activation, along with CD80/CD86 and CD154 costimulation, are key determinants of the TSST-1-induced proinflammatory cytokine response.