130 Chapter 4 DISCUSSION Here, we performed a longitudinal study on 20 severely burned patients and investigated the effects of severe burn injury on the systemic immune response. We reveal that upon burn injury there is an immediate surge of innate immune cells, with initially a large contribution of immature neutrophils, but no increase in lymphocyte numbers. These cellular responses could not be correlated to the patient’s TBSA, which might indicate maximum response levels. Notably, only patients submitted to the ICU were included in this study. Simultaneously with the cellular influx, increased levels of various pro-inflammatory cytokines were found. This innate immune and cytokine response decreased to some extent over time, but persisted for at least three weeks. From the second week onward, shifts in T cell subpopulations were observed: within the T cell population, there was an increase of CCR4 and CCR6 expressing cells and although Treg numbers increased as well, the overall phenotype of the CD4+ T cells and Tregs appeared to be rather pro-inflammatory than anti-inflammatory. The increase in granulocytes could mainly be attributed to neutrophils, and within this population both mature and immature neutrophils were increased. In the first week after injury, mature neutrophil counts correlated with IL-17A, which is known to accelerate neutrophil recruitment [27]. Moreover, levels of IL-6 and IL-8 were increased over the complete study period and could be correlated to the number of immature neutrophils in the third week post injury. IL-6 and IL-8 are involved in neutrophil recruitment and chemotaxis [27,28]. In a healthy situation, immature neutrophils are usually absent in the circulation as neutrophils normally mature within the bone marrow before they are released to the bloodstream [29]. The early release of immature neutrophils can be caused by an emergency response of the immune system to acute inflammation, such as trauma, burn or sepsis [25,30,31]. During acute inflammation, neutrophils produce ROS, elastase, myeloperoxidase and release neutrophil extracellular traps (NETs) which can damage tissues by their cytotoxicity and can cause ischemia through thrombocytosis [10,32]. In other studies of patients with large burn injuries (>15% TBSA), expression of CD11b on neutrophils was increased in the first week while expression of CD16 was reduced [33,34]. Other studies also reported a fast decrease of CD16 expression due to the immaturity of neutrophils [35,36]. We also observed reduced CD16 expression on immature neutrophils (data not shown). It has been shown that continuous release of neutrophils into the circulation can lead to bone marrow exhaustion that in turn can lead to compromised innate immunity [37–39]. Although literature on the functions or activities of immature neutrophils is conflicting, some papers state that immature neutrophils are underdeveloped and that high numbers and their active state might induce tissue damage causing secondary progression of the burn injury [13,37,38]. Other
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