191: Impaired antigen presentation following Systemic Inflammatory Response Syndrome (SIRS) is caused by the local induction of a paralysis program in developing dendritic cells

Abstract

Systemic Inflammatory Response Syndrome (SIRS) is a common condition associated with systemic or severe infections, trauma, burns or haemorrhage. It is characterised by the release of inflammatory cytokines whose main function is to activate the innate and acquired arms of the immune system to fight infection and/or to limit and repair tissue damage. Paradoxically, this enhanced state of responsiveness is followed by a period of immunosuppression that can last for several weeks, long after resolution of the infection or tissue damage that triggered SIRS. The immunosuppressed patients are at risk of suffering secondary or opportunistic infections which are the main cause of mortality and morbidity in critical care patients. Malaria infection can also cause SIRS and immunosuppression, probably contributing to the poor efficacy of vaccination against malaria and other pathogens, and to high incidence of Epstein Barr Virus-induced tumours, in malaria-endemic areas. We show that pseudoinfection of mice with TLR ligands, or infection with the malaria parasite, induces local changes in the tissues where dendritic cells (DC) develop, leading to continuous formation of paralysed DC for several weeks, until the local environment gradually returns to the state pre-SIRS. Paralysed DC have poor antigen capture and (cross) presentation capacity. We have (i) characterised the mechanisms responsible for these defects; (ii) identified a unique genetic program induced in paralysed DC that is responsible for their impaired antigen presenting functions; (iii) discovered extracellular cytokines responsible for induction of paralysed DC, which can be targeted with neutralising mAb to prevent paralysis; (iv) devised strategies to overcome the impaired antigen presenting function of paralysed DC, helping to restore immunocompetence quickly after SIRS. Understanding the mechanisms of SIRS-induced DC paralysis could lead to the development of new therapies to prevent secondary infections and death in intensive care patients, and to improve vaccine design in malarious areas.