Till Örebro universitet

Dysregulated immune response is a key characteristic of sepsis immunology, with the current view recognizing concurrent proinflammatory and immunosuppressive responses. Monocytes are central to the immune and inflammatory responses in sepsis, and immunosuppressive monocytes observed in the blood of septic patients are linked to immunosuppression and adverse clinical outcomes. This thesis explores monocyte responses in inflammation and immunosuppressionin sepsis, utilizing a combination of in vitro and in silico monocyte models along with a cohort study of sepsis patients.

In the studied cohort, a more general set of immune markers did not improve sepsis identification whether alone or in combination with previously established screening tools based on clinical parameters, possibly due to the high collinearity between clinical and molecular parameters. A more targeted approach for identifying markers associated with immunosuppressive monocytes was applied by establishing an endotoxin tolerance model. We demonstrated a response profile consisting of soluble markers and upstream regulators in immunosuppressed primary human monocytes following repeated LPS stimulations. These response markers were then evaluated in the sepsis cohort, where lower levels of HLA-DRA expression and reduced TNF/IL-10 ratios were seen to be associated with sepsis. Notably, elevated levels of many of the investigated molecules could be detected before the clinical presentation of septic shock. Lastly, we established a computational model of human monocytes to study and demonstrate, in more detail, the interplay between TNF and IL-10. In conclusion, we demonstrated a response profile of the immunosuppressed monocytes, with molecules associated with sepsis and septic shock.