It is hypothesized that a primary role of the meninges, tissues the surround the brain and spinal cord and enclose the cerebral spinal fluid, is to serve as a first line defense against infections that threaten the CNS. However, there is compelling evidence that the meninges have an important role in regulating the inflammatory processes that lead to the breach of the BBB in both MS and EAE. In addition to mast cell activation, we have demonstrated that there is an impressive accumulation of myelin specific T cells and other inflammatory cells in the meninges prior to any clinical manifestations of EAE. The resulting cell-cell interactions lead to a break down in the BBB as well as an amplified and more pathogenic immune response. Our laboratory is investigating how this immune cell cross-talk makes cells more pathogenic and how we can develop therapies that interfere with this cross-talk.