An alarmin is a preformed molecule with a specific given intracellular cellular function but which can be released extracellularly as an inflammatory distress signal when cellular homeostasis is threatened. Our project studies whether therapeutic extracellular neutralization of the prototypical alarmin HMGB1, a common nuclear protein in all cells of the animal and plant kingdom, offers a possibility to improve the outcome of severe inflammatory systemic diseases, which are currently without effective therapy. We were instrumental in identifying HMGB1 as a key alarmin in 1999 and have since dedicated our research to HMGB1 biology. We have recently, for the first time ever, developed a neutralizing human anti-HMGB1 monoclonal antibody with impressive therapeutic efficacy in several different disease models mediated by HMGB1-TLR4 signaling. A typical example of such a disease is systemic inflammatory response syndrome (SIRS) caused by severe trauma or sepsis. This antibody will be brought to clinical trials with the financial support of a US academic institution. HMGB1 may also mediate tissue damage via interaction with RAGE receptors, where a better understanding of the mechanisms of action is required, which we aim to explore. We intend to select an HMGB1-specific Affibody® molecule to block RAGE binding.Typical diseases with this molecular background are systemic lupus erythematosus and several important neurodegenerative diseases.