Autoimmunity and allergy are the clinical manifestations of loss of tolerance to either self or to innocuous foreign antigens. While research efforts have so far focused on the effector phase of these diseases, we are interested in investigating the breaking of tolerance during the initiation phase of the mouse model of Multiple Sclerosis (MS), the Experimental Autoimmune Encephalomyelitis (EAE). We therefore created several novel models that allow us to investigate the triggering phase of different neuroinflammatory pathologies. We generated a transgenic mouse model, the iDTR strain (Buch et al 2005), that allows through the use of Cre-expressing mouse lines targeted expression of diphtheria toxin receptor by specific cell lineages. Injection of diphtheria toxin into such mice leads to ablation of the marked cell type. In our experiments we use this mouse line in combination with a myelin- specific Cre line (MOGi-cre) to test whether widespread ODC death, induced by diphtheria toxin injection, results in a neuroinflammatory disease. We were able to use this model for showing that mere ODC degeneration is an unlikely initiator of CNS autoimmunity (Locatelli et al., 2012). Using the MOGi-cre strain we expressed luciferase specifically in ODCs under control of the actin β promoter to investigate the response of ODCs to different types of myelin damage. Our results indicate a strong resilience of ODCs against myelin damaging events with a pronounced physiological response (Locatelli et al. 2015). In our attempts to understand the role of oligodendrocytes in neuroinflammation more deeply we are also analysing the role of the IGF-1 axis. IGF-1 has long attracted attention as a potential drug for suppressing ODC apoptosis. As part of our attempts to understand the initiation phase of EAE, we are also investigating the role of Toll-like receptors (TLRs) in the EAE model. TLRs are a key components of innate immune system and play a prominent role in recognizing microbial products. TLR signaling via adaptor proteins MyD88 and TRIF results not only in induction but also inhibition of autoimmune diseases. Emerging studies from both animal models and human studies suggest an important role for TLRs in autoimmunity. Therefore, it is of great interest to study how manipulation of TLRs influences the autoimmune condition. In order to study the contribution of TLRs to the disease induction and progression in EAE model, we are using TLR23479-/- knock out mice in which five TLRs are missing. We are further investigating the role of members of the Interleukin-1 receptor family in EAE as along with TLRs, some IL1R family members utilize MyD88 adaptor protein for their downstream signaling.