BackgroundThe immune response of the critically ill after severe trauma is sex-specific and may explain the different progression of the disease. This may be explained by a different gene regulatory program of their peripheral immune cells. We investigated the progression of the transcription profiles of peripheral immune cells of the patients to elucidate their distinct physiological response and clinical course.MethodsWe compared transcription profiles of whole blood of male and female patients from a larger longitudinal study of critically ill patients after trauma. We developed a statistical analysis pipeline that synchronized the time lapse of the profiles based on the temporal severity score of each patient.ResultsThis enabled to categorize the temporal progression of the disease into two pre-acute, an acute and two post-acute phases. Comparing gene regulation of male and female patients at each phase, we identified distinctively regulated molecular processes mainly in the immune response, but also in the regulation of metabolism allowing to cluster these discriminative gene sets into sets of highly related cellular processes. Compared to male patients and healthy controls, female patients showed upregulation of gene sets of innate immunity in the early phase, upregulation of wound healing processes during the acute phase and upregulation of adaptive immunity in the late phase indicating early recovery. In turn, during the pre-acute and acute phase, male patients showed less suppression of gene sets coding for enzymes of energy metabolism and anabolism, most prominently the tricarboxylic acid cycle and β-oxidation, and cellular maintenance, such as cell cycle, DNA replication and damage response, and RNA metabolism.ConclusionsA stronger innate immune response at the very early phase of the disease may support early clearance of the pathogen and its associated molecular patterns. Upregulation of wound healing processes may explain reduced multiple organ failure during the acute phase. Down regulated energy metabolism during the acute phase may make female patients less susceptible to oxidative stress, the upregulated adaptive immune system reflects an earlier recovery and rebuilding of the adaptive immune system that may protect them from secondary infections. Follow up studies need to be performed confirming these observations experimentally.

中文翻译：

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外周白细胞基因调控的时间进程解释了创伤后危重患者的性别二态性

背景严重创伤后危重病人的免疫反应具有性别特异性，可以解释疾病的不同进展。这可能是通过其外周免疫细胞的不同基因调控程序来解释的。我们研究了患者外周免疫细胞转录谱的进展，以阐明其独特的生理反应和临床过程。方法我们比较了来自创伤后危重患者的更大规模纵向研究的男性和女性患者全血的转录谱。我们开发了一个统计分析流程，根据每位患者的时间严重程度评分来同步档案的时间推移。结果这使得能够将疾病的时间进展分为两个急性期、一个急性期和两个急性后期。比较男性和女性患者在每个阶段的基因调控，我们确定了主要在免疫反应中以及在代谢调控中的独特调控的分子过程，从而将这些有区别的基因集聚集成高度相关的细胞过程集。与男性患者和健康对照相比，女性患者在早期表现出先天免疫基因组的上调，在急性期伤口愈合过程上调，在晚期表现出适应性免疫的上调，表明早期恢复。反过来，在急性前期和急性期，男性患者对编码能量代谢和合成代谢酶的基因组表现出较少的抑制，最显着的是三羧酸循环和β-氧化，以及细胞维护，例如细胞周期、DNA复制和损伤反应以及RNA代谢。结论在疾病的早期阶段更强的先天免疫反应可能支持病原体及其相关分子模式的早期清除。伤口愈合过程的上调可以解释急性期多器官衰竭减少的原因。急性期能量代谢的下调可能使女性患者不易受到氧化应激的影响，适应性免疫系统的上调反映了适应性免疫系统的早期恢复和重建，可以保护她们免受继发感染。需要进行后续研究以通过实验证实这些观察结果。