Immune Privilege, CNS Autoimmunity, and Clostridium perfringens Epsilon Toxin

The project aims to mechanistically determine how Clostridium perfringens epsilon toxin (ETX) and Bordetella pertussis toxin (PTX) overcome CNS immune privilege to trigger autoimmunity in the context of myelin autoreactive lymphocytes. It also seeks to understand why ETX causes lesions in the forebrain, cerebellum, brainstem, and spinal cord, contrasting with PTX where lesions are more commonly localized to the spinal cord. The central hypothesis is that ETX and PTX trigger CNS autoimmunity by inducing critical dysfunction at CNS barriers necessary for entry of pathogenic lymphocytes. This will be tested by: 1) Determining the effect of cell-specific deletion or introduction of the ETX receptor MAL (Myelin and Lymphocyte Protein) in active immunization models of experimental autoimmune encephalomyelitis (EAE), comparing neuroanatomical location, phenotype, and activation state of immune infiltrates between PTX- and ETX-induced EAE, and exploring the effect of ETX on human lymphocytes. 2) Determining the genes induced and suppressed in CNS-endothelial cells by ETX and PTX and defining their function in overcoming CNS immune privilege through loss-of-function strategies.