Background

By the late 1970s, the idea that mature, bloodstream neutrophils were terminally differentiated, end-of-line cells was being questioned. In a series of experiments by McCall and colleagues (1973, 1979), the biochemical properties of ‘toxic’ neutrophils – that is, neutrophils isolated from the bloodstream of patients with acute bacterial infections -were characterised. Compared to normal neutrophils isolated from healthy controls, these ‘toxic’ neutrophils exhibited increased oxidative metabolism, phagocytosis, chemotaxis and 2-deoxyglucose transport. They also had increased cellular levels of alkaline phosphatase and showed toxic granulation. Two possibilities could account for these enhanced functions: either the bacterial infection caused the release from the bone marrow of a more active neutrophil population, or the infection somehow changed the activity of the circulating cells. If the latter explanation was the case, then the concept that neutrophils were terminally differentiated was probably incorrect.

At around this time, the synthetic formylated oligopeptides, thought to be analogous to bacterial-derived products, were being characterised. Remarkably, it was shown that the pretreatment of normal neutrophils in vitro with 2 × 10−8 M fMet-Leu-Phe for 15 min could alter the function of these cells so that they resembled ‘toxic’ neutrophils. The conclusion, therefore, was that factors induced by the bacterial infection (either derived from the bacteria themselves or else generated by the host in response to the infection) could up-regulate the function of mature, circulating neutrophils.

It was later shown that substimulatory concentrations of many types of neutrophil agonists could also induce this up-regulation of function. Because the concentrations of these compounds that were required did not activate the neutrophil per se, the phenomenon was referred to as ‘priming’.