There is a considerable body of work concerning active lesions which supports the contention that MS is an immune mediated inflammatory demyelinating disease. To set the stage for these findings it is important to keep in mind that the CNS, an immunologically priviledged tissue free of lymphoid cells with limited MHC class I and II antigen expression, actually "sees" the immune system. It is "patrolled" by activated lymphocytes ( activated to any antigen, not necessarily a CNS antigen), which can up-regulate intrinsic MHC expression, and respond to appropriately presented antigen. With this brief introduction, consider the following selected summary of some recent literature regarding MS. New lesions are characterized by altered microvascular permeabliltiy, perivenous infiltrates composed predominantly of T lymphocytes and macrophages with variable numbers of B lymphocytes and plasma cells. Plasma proteins including complement and immunoglobulins are also present in the tissue. Actual myelin removal is accomplished by microglia/macrophage lineage cells apparently via a clathrin coated pit uptake mechanism which is typical of receptor mediated uptake. Microglia/macrophages exhibit focal IgG surface staining consistent with IgG receptor mediated activation and ligand uptake. These cells also have complement receptors which may be activated. Activation of Ig and C receptors can result in the release of a myriad of locally destructive elements. In response to cytokines released from activated lymphocytes, ie., IL-2, gamma interferon and tumor necrosis factor alpha, endothelial cells display surface activation marker molecules such as: HLA-DR, ICAM-1,VCAM-1. These are important for the movement of circulating cells into the tissues. Soluble factors from activated lymphocytes also induce the expression of MHC class II antigen and essential co-stimulatory molecules, such as B7, by brain perivascular macrophages and ramified microglia. These brain marcophage lineage cells may thus become competent antigen presenting cells, capable of presenting local antigens to systemic T Cells. Reactive astrocytes appear and seem to engulf some oligodendroglia cells. They also make and release a variety of immunomodulatory molecules, such as TGF beta. Now the key question is what sets the whole thing going? What excites each new round of lesions? What limits lesions size, ends each round? Why do some people have only a single episode, others progressive disease and most relapsing and remitting disease? Here maybe a good place to insert into your "equations" mechanisms of T cell apoptosis, like fas/fas ligand, and the expression of other anti-apoptotic proteins such as Bcl-2. Food for thought! Work for your generation.