Temporal progression of gene regulation of peripheral white blood cells explains gender dimorphism of critically ill patients after trauma.
BACKGROUND
The 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.


METHODS
We 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.


RESULTS
This 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.


CONCLUSIONS
A 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.
['Kolte|Amol|A|', 'König|Rainer|R|']
D000293:Adolescent D000328:Adult D016638:Critical Illness D004734:Energy Metabolism D005260:Female D015870:Gene Expression D005786:Gene Expression Regulation D006801:Humans D007962:Leukocytes D008137:Longitudinal Studies D008297:Male D008875:Middle Aged D009102:Multiple Organ Failure D012737:Sex Factors D014947:Wounds and Injuries D055815:Young Adult
Gender Trauma Clustering Gene set enrichment analysis Sepsis Sex Systemic infection Transcriptomics