Date Published: February 7, 2018
Publisher: Public Library of Science
Author(s): Katrin Schmoeckel, Daniel M. Mrochen, Jochen Hühn, Christian Pötschke, Barbara M. Bröker, John S Tregoning.
Sepsis is frequently complicated by a state of profound immunosuppression, in its extreme form known as immunoparalysis. We have studied the role of the adaptive immune system in the murine acute peritonitis model. To read out adaptive immunosuppression, we primed post-septic and control animals by immunization with the model antigen TNP-ovalbumin in alum, and measured the specific antibody-responses via ELISA and ELISpot assay as well as T-cell responses in a proliferation assay after restimulation. Specific antibody titers, antibody affinity and plasma cell counts in the bone marrow were reduced in post-septic animals. The antigen-induced splenic proliferation was also impaired. The adaptive immunosuppression was positively correlated with an overwhelming general antibody response to the septic insult. Remarkably, antigen “overload” by non-specific immunization induced a similar degree of adaptive immunosuppression in the absence of sepsis. In both settings, depletion of regulatory T cells before priming reversed some parameters of the immunosuppression. In conclusion, our data show that adaptive immunosuppression occurs independent of profound systemic inflammation and life-threatening illness.
Sepsis is difficult to treat and causes high morbidity and mortality . The dissemination of bacteria and their products elicits a systemic inflammation response (SIRS, systemic inflammatory response syndrome), resulting in multiple organ failure and shock [2,3]. This can be therapeutically addressed by adequate antibiotic therapy as well as supportive measures, such as hemodynamic stabilization. An even greater therapeutic problem is anti-inflammatory counter-regulation (CARS, compensatory anti-inflammatory response syndrome), which sets in after or even simultaneously with SIRS. During CARS, the anti-bacterial effector mechanisms are seriously impaired such that the immune system cannot clear the primary infection and is highly susceptible to secondary infections [2–4]. More than 70% of sepsis patients die because of immunosuppression, which in its extreme form is referred to as immunoparalysis [2,5–7].
We studied inhibition of the adaptive immune response during sepsis by using primary immunization with antigen and adjuvant as a second hit and observed reduction of the antigen-specific humoral (antibody and ASC) and cellular responses (T cells). Remarkably, NSI induced a similar suppression of the adaptive immune response, showing that it can occur independently of surgical trauma and systemic bacterial dissemination, which in sepsis cause life-threatening illness.