Accelerated Lymphocyte Death in Sepsis Occurs by both the Death Receptor and Mitochondrial Pathways

Abstract

Patients with sepsis are immune compromised, as evidenced by their failure to clear their primary infection and their propensity to develop secondary infections with pathogens that are often not particularly virulent in normal healthy individuals. A potential mechanism for immunosuppression in sepsis is lymphocyte apoptosis, which may occur by either a death receptor or a mitochondrial-mediated pathway. A prospective study of blood samples from 71 patients with sepsis, 55 nonseptic patients, and 6 healthy volunteers was undertaken to quantitate lymphocyte apoptosis and determine cell death pathways and mechanisms of apoptosis. Apoptosis was evaluated by flow cytometry and Western blotting. Lymphocyte apoptosis was increased in CD4 and CD8 T cells, B cells (CD20), and NK cells (CD56) in septic vs nonseptic patients. Samples taken sequentially from 10 patients with sepsis showed that the degree of CD3 T cell apoptosis correlated with the activity of his/her sepsis. In septic patients, apoptotic lymphocytes were positive for active caspases 8 and 9, consistent with death occurring by both mitochondrial-mediated and receptor-mediated pathways. In support of the concept that both death pathways were operative, lymphocyte apoptosis occurred in cells with markedly decreased Bcl-2 (an inhibitor of mitochondrial-mediated apoptosis) as well as cells with normal concentrations of Bcl-2. In conclusion, apoptosis occurs in a broad range of lymphocyte subsets in patients with sepsis and correlates with the activity of the disease. Lymphocyte loss occurs by both death receptor and mitochondrial-mediated apoptosis, suggesting that there may be multiple triggers for lymphocyte apoptosis.

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

“…This has been illustrated by the description of increased mortality, decreased bacterial clearance, and altered pro-inflammatory immune response after polymicrobial septic challenge in mice lacking both T and B cells (119,120). A growing body of evidence has now confirmed that the lymphocyte-mediated immune response may be dysfunctional after severe sepsis and may play a major role in the development of a state of immunoparalysis in patients.…”

Role of programmed cell death in the immunopathogenesis of sepsis

“…Le Tulzo et al concluded that lymphocyte apoptosis was rapidly increased in the blood of patients in septic shock and that this development of lymphocyte apoptosis led to a profound and persistent lymphopenia associated with poor outcome [28]. Hotchkiss's group observed that the frequency of apoptosis was substantially increased in CD4 + and CD8 + T-cells, B cells (CD20 + ), and NK cells (CD56 + ) in septic individuals when compared to non-septic patients and that the degree of lymphocyte apoptosis correlated with the severity of sepsis involving both (death receptor and mitochondrial) apoptotic pathways [29]. These experiments clearly supported the concept that lymphocyte apoptosis induced immune suppression during sepsis, mainly through a mechanism of direct depletion of cells of the adaptive immune system.…”

Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

“…Mice with defects in the Fas/Fas ligand signaling pathway through genetic engineering or pharmacological blockade show decreased levels of sepsis-induced lymphocyte apoptosis [111,112], as well as increased survival in the CLP model [113]. Furthermore, immunohistologic analyses and study of caspase activation patterns in apoptotic lymphocytes isolated from baboons with E. coli-induced septic shock [114] as well as a large series of human sepsis patients [115] are consistent with contributions from both the mitochondrial and death-receptor pathways of apoptosis. However, inhibition of B cell apoptosis by specific targeting of FccRII (CD32), an ITIM-containing Fc receptor, was insufficient to reduce mortality in the mouse CLP model, despite leading to a significant drop in apoptotic cells numbers [116].…”