Systemic juvenile idiopathic arthritis (sJIA) is a rare, multifactorial, autoinflammatory disease which is one of the gravest chronic diseases in childhood. In addition, sJIA is associated with a life-threatening complication called macrophage activation syndrome. There is no treatment available which can cure sJIA. Treat-AID brings together experts covering all inflammatory mechanisms relevant in sJIA and well-acknowledged clinical partners to develop a complete new treatment strategy for this crippling disease. We have shown that an extraordinarily high expression of the alarmins S100A8 and S100A9 plays a central role in the pathogenesis of sJIA. Recently we have identified peptide sequences of about 15 amino acids within these S100-molecules which are responsible for activation of leukocytes via binding to Toll-like receptor-4 (TLR4). In this proposal we will generate novel therapeutic antibodies specifically inhibiting the S100-TLR4 interaction sites. Since release of alarmins is a key pathogenic mechanism in sJIA targeting molecules of this family is a very promising strategy to control inflammatory processes at a very early stage. To achieve this goal Treat-AID brings together a network with a unique collection of cellular and animal models relevant for sJIA to analyse therapeutic antibodies developed in this project. In conclusion, we have identified a unique and well defined target structure for anti-inflammatory therapies which is highly relevant in sJIA and which activity is restricted to local sites of inflammation minimizing the risk of systemic side effects.