Role of Bim in sepsis-induced lymphopenia
Sepsis leads to an annual financial burden in excess of $16 billion in the US alone. In Australia, there has been a four-fold increase in sepsis incidents between 1997 and 2005, owing to an ageing population. Sepsis is defined as the host inflammatory response to severe, life-threatening infection. This response can be divided into two stages, a hyper-inflammatory phase and a hypo-inflammatory phase. During the hyper-inflammatory phase, activated immune cells (mostly the innate immune system) produce copious amounts of inflammatory cytokines, which can lead to multiple organ failure. However, improved treatment protocols have resulted in most patients surviving this stage and entering a protracted immune suppressive phase. This phase is characterized by extensive apoptosis of B cells, and T cells leading to prolonged lymphopenia where the patients are susceptible to nosocomial infections.
Experimental drug therapies for sepsis are at cross roads with more than 30 drug trials failing in the last 25 years. This is largely attributed to the fact that these drugs were aimed at the hyper inflammatory phase of sepsis. Current thinking in the field is to block immune cell apoptosis to prevent lymphopenia. Bim is a critical mediator of immune cell homeostasis. We have recently identified the factor that is released by macrophages during sepsis that kills B and T cells. Efforts are underway to identify the receptor(s) for this factor. Understanding the molecular basis of the interaction between this factor and the receptor will help in developing new therapeutics for sepsis.