The Role of Innate Response Activator B Cells in Sepsis

Sepsis is a global health problem affecting millions of patients each year. The incidence of sepsis has been rising over the past years due to the increasing age of the population, increasing use and efficacy of immunosuppressive therapy and emerging resistance of causative bacteria. Due to a lack of appropriate therapeutic targets, the mortality of sepsis continues to be unacceptably high despite progress in intensive care medicine. Innate response activator (IRA) B cells are a recently discovered population of innate-like B cells that develop from B1a B cells and are critical for the protection from sepsis in a model of polymicrobial intraperitoneal infection initiated by cecal ligation and puncture. IRA B cells are characterized by the secretion of two major cytokine products i.e. granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-3. The role of IL-3 produced by IRA B cells in sepsis, however, is currently unknown. Similarly, no conclusive data is available on the role of IL-3 in the pathophysiology of sepsis. Unpublished observations show that IL-3/ mice subjected to cecal ligation and puncture completely recover from sepsis and survive the infection. Mechanistically, IL-3/ mice do not develop a cytokine storm, which is a precipitating event causing septic shock and death, but they can nevertheless control bacteremia. Based on these preliminary data, IL-3 and IRA B cells should be considered as a therapeutic target for the treatment of sepsis. The central aim of this proposal is to gain a better understanding of the role of IL-3 produced by IRA B cells in the pathophysiology of sepsis. The studies of this proposed project could open new avenues to modify the systemic inflammatory response to treat sepsis and prevent lethal septic shock which currently results in hundreds of thousands of deaths each year.

Interleukin-3 determines the survival in blood poisoningInterleukin-3 is a soluble factor with which cells communicate between organs via the blood stream. It functions as a protein messenger, which acts on the bone marrow and stimulates the generation of white blood cells and therefore fulfills the function of a growth factor. The cellular source of interleukin-3 and its effects in severe infections such as blood poisoning has previously been unknown, though.We could show that a specific type of so called B cells located in the spleen produces interleukin-3. Interleukin-3 then circulates in the blood and travels to the bone marrow. In the setting of severe infections there is an overwhelming production of interleukin-3 and therefore of white blood cells in the bone marrow. These immune cells are being released to the blood stream to produce additional factors that enhance inflammation resulting in a domino effect that may be lethal.Elevated levels of interleukin-3 in patient samples could predict an increased risk of subsequent death in patients admitted to the intensive care unit because of sepsis. Vice versa, the inhibition of interleukin-3s actions in a mouse model of sepsis improved survival.Our results have broad consequences for the diagnosis and treatment of blood poisoning. On the hand, measurement of interleukin-3 levels in patients blood samples enables a more accurate diagnosis and the identification of individuals with increased risk of a more severe course of the disease prompting early and aggressive treatment. On the other hand, the inhibition of interleukin-3 is a novel and promising approach to treat blood poisoning. On the basis of our results, clinical studies should be started to target interleukin-3 for the treatment of blood poisoning.