lymphocyte apoptosis has been increasingly recognized as an important step in the pathogenesis of sepsis , by inducing a state of ' immune paralysis ' that renders the host vulnerable to invading pathogens . sepsis is an important clinical problem , affecting more than 700,000 people each year in the united states alone , of whom 20% to 30% die . this paradigm led to the development of agents aimed at blocking key mediators of inflammation , such as bacterial lipopolysaccharide , interleukin-1 , and/or tumor necrosis factor- among others . however , when many of these agents were tested in large phase iii randomized controlled trials they failed to demonstrate a beneficial effect [ 4 - 6 ] . thus , therapeutic strategies aimed at suppressing inflammation in sepsis have been disappointing . over the past decade , studies in experimental models and in patients suggested that the immune response of sepsis follows a biphasic pattern , with an initial ' hyperinflammatatory ' phase characterized by high levels of pro - inflammatory cytokines , and a second phase characterized by decreased responsiveness of immune cells to inflammatory stimuli  the ' immunoparalysis ' phase . the immunoparalysis phase is an extremely vulnerable period when patients are at particular risk from invading bacteria . the mechanism for this immune paralysis appears to involve apoptosis of immune cells , in particular lymphocytes . in a seminal study , wang et al .   found that the intra - peritoneal injection of gram - negative bacteria to mice was followed by apoptosis of cd4+cd8 + lymphocytes in the thymus . hotchkiss et al .   used a murine model of cecal ligation and puncture to show that lymphocyte apoptosis also involves lymphocytes from the spleen and most other vital organ systems , and later demonstrated that extensive lymphocyte apoptosis is also present in humans with sepsis . studies using loss - of - function approaches suggested that the mechanisms of lymphocyte apoptosis in sepsis involve both the receptor - mediated and the mitochondrial pathways of apoptosis , with the later playing the predominant role ( reviewed in ) . now extend these laboratory observations to the bedside , by demonstrating accelerated apoptosis in circulating lymphocytes ( cd4 , cd8 and cd19 ) from patients with severe sepsis , but not in non - septic , critically ill patients . this study is important because it confirms a pattern of activation of bcl-2 family members predicted by animal studies , and sets the basis for further studies aimed at modulating lymphocyte apoptosis in sepsis . one particularly interesting finding in weber and colleagues ' study is that the pro - apoptotic molecule bim was markedly upregulated in the lymphocytes of patients with severe sepsis . this is important because , of the different components of the apoptosis cascade that have been tested in animal models ( fadd , bid , bcl2 , caspases ) , only deletion of bim is associated with complete protection from apoptosis . however , it is important to note that blockade of lymphocyte apoptosis is not always protective in sepsis . for example , septic mice lacking myd88 have decreased lymphocyte apoptosis but a significant increase in mortality . myd88 is an important proximal component of the main pathogen recognition pathways , suggesting that inhibition of lymphocyte apoptosis is protective only when the ability of the host to identify and respond to pathogens is preserved . patients were enrolled 4 hours after presentation , which may have been too early in the hospital course to catch the period of maximal apoptosis . also , information on the effects of severe sepsis on the receptor - mediated pathway of apoptosis , particularly fadd and caspase 8 , would have been interesting . in summary , the study by weber and colleagues reaffirms and advances our knowledge of specific pathways involved in lymphocyte apoptosis in patients suffering from severe sepsis , raising hopes for potential therapeutic targets that improve mortality in this patient population .