Role of vascular cell adhesion molecules and leukocyte apoptosis in the lymphopenia and thrombocytopenia of patients with severe acute respiratory syndrome (SARS).

The immunopathogenesis of leukopenia and thrombocytopenia in patients with severe acute respiratory syndrome (SARS) is unclear. In order to explore the leukopenia mechanism, we studied 15 SARS patients who were previously healthy, and 15 age-matched normal controls in a paired design. Soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble Fas ligand (sFasL) in plasma were measured by ELISA, and intracellular activated caspase-3 fragment in different leukocytes was determined by flow cytometry. Patients with SARS had significantly lower lymphocyte and platelet counts and significantly higher sVCAM-1 and sFasL levels compared to healthy controls. sVCAM-1 levels correlated negatively with total leukocytes and platelet counts, but positively with plasma sFasL levels. Intracellular cleaved caspase-3 expression was also significantly higher in lymphocytes from SARS patients in acute phase than in convalescent stage. Lymphopenia and thrombocytopenia in SARS patients may be caused, in part, by enhanced vascular sequestration associated with increased sVCAM-1 levels. However, lymphopenia may be due to enhanced cell death. Inhibition of cell adhesion and caspase-3 activation could, therefore, have prevented SARS patients from developing thrombocytopenia and lymphopenia.

Altered p38 mitogen-activated protein kinase expression in different leukocytes with increment of immunosuppressive mediators in patients with severe acute respiratory syndrome.

Severe acute respiratory syndrome (SARS) has spread to a global pandemic, especially in Asia. The transmission route of SARS has been clarified, but the immunopathogenesis of SARS is unclear. In an age-matched case-control design, we studied immune parameters in 15 SARS patients who were previously healthy. Plasma was harvested for detection of virus load, cytokines, and nitrite/nitrate levels, and blood leukocytes were subjected to flow cytometric analysis of intracellular mitogen-activated protein kinases (MAPKs) in different leukocytes. Patients with SARS had significantly higher IL-8 levels (p = 0.016) in early stage, and higher IL-2 levels (p = 0.039) in late stage than normal controls. Blood TNF-alpha, IL-6, and IL-10, and nitrite/nitrate levels were not significantly elevated. In contrast, TGF-beta and PGE(2) levels were significantly elevated in SARS patients. Five of the 15 SARS patients had detectable coronaviruses in blood, but patients with detectable and undetectable viremia had no different profiles of immune mediators. Flow cytometric analysis of MAPKs activation by phospho-p38 and phospho-p44/42 (extracellular signal-regulated kinase) expression showed that augmented p38 activation (p = 0.044) of CD14 monocytes associated with suppressed p38 activation (p = 0.033) of CD8 lymphocytes was found in SARS patients. These results suggest that regulation of TGF-beta and PGE(2) production and MAPKs activation in different leukocytes may be considered while developing therapeutics for the SARS treatment.