243 General Discussion macrophage composition towards more pro-healing activity might be a useful therapy to speed up wound healing in patients. BURN INJURY LEADS TO A SHIFT IN LYMPHOCYTE SUBSETS, YET REGULATION OF INFLAMMATION APPEARS LIMITED In general, by the end of the first week after tissue injury, lymphocytes start to respond [26,85], allegedly to ensure specific anti-pathogen reactions and regulation of inflammation [86]. However, evidence on the role of specific lymphocyte subsets including T cells, B cells and NK cells during wound healing is limited [85]. To complement this knowledge, we investigated the levels of B cells, NK cells, T cells and related cytokines in blood and burn wound tissue. Furthermore, we assessed markers that are typical for T cell differentiation towards regulatory (Treg) or inflammatory T helper cells (Th1/Th17). In Chapter 5, we showed that chemokines MIP-1α, MIP-1β, and RANTES were highly increased in burn tissue from patients, especially at post burn week 3. This coincided with increased levels of B cells, NK cells and T cells that were likely attracted by these lymphocyte chemokines [87]. Unexpectedly, blood lymphocyte numbers did not increase in patients (Chapter 4) and even decreased in experimental animals (Chapter 2). Moreover, the neutrophil/ lymphocyte ratio, a marker for systemic inflammatory response syndrome [88], was highly increased during at least the first 9 days after burns in animals. Extreme replenishing of innate immune cells by the bone marrow can lead to a shortage of lymphocytes in the circulation [45], delaying the regulatory response of lymphocytes that occurs during normal wound healing [26,89]. Studies in burn patients reported that persistent leukocytosis in combination with lymphopenia is associated with persistent (systemic) inflammation, arrested wound healing, increased susceptibility to opportunistic infections, and increased mortality [4,90,91]. While the total T cell response appears to be delayed, there was a shift towards more γδ T cells in burn tissue during the first week after injury, supporting the proposal that γδ T cells are involved in the early response to injury [92,93]. Unlike αβ T cells, γδ T cells can interact with antigens directly and are presumably involved in immune surveillance and might produce cytokines and chemokines to recruit immune cells upon sensing damaged cell structures [94]. We showed that from the second week after burn injury onward, a portion of T cells acquired a pro-inflammatory phenotype (Th1 or Th17) (Chapter 4). We also found evidence for Treg differentiation in blood, but this T cell population also showed increased expression of chemokine receptors (CCR4 and CCR6), suggesting that these T cells might be putative pathophysiologic Tregs [95–98]. Tregs represent a versatile 8
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