Multiple sclerosis (MS) is a human demyelinating condition which immune- mediated damage to central nervous system (CNS) myelin is implicated and experimental allergic encephalomyelitis (EAE) is its major laboratory model in which autoimmunity to myelin and T cell involvement are well proven. The present proposal will deal with structural and molecular events related to lymphocyte recognition and adhesion occurring at the level of the blood brain barrier and within the CNS parenchyma, at the level of the myelin/oligodendrocyte complex. The hypothesis to be tested is that immune system molecules are expressed selectively and periodically on CNS vessels and oligodendroglial cells during chronic, inflammatory demyelination and that their expression orchestrates events responsible for lesion formation. With the aid of a series of experiments employing immunocytochemistry in combination with light and electron microscopy on appropriately preserved tissue from cases of MS at different stages and from mice with adoptively transferred chronic relapsing EAE, the present proposal will seek further insight on the immunopathogenesis of the MS plaque. Morphologic evaluation of molecular expression will be supplemented with quantitative assays using immunoblots. The major probes to be used will be monoclonal antibodies against a large battery of human and mouse adhesion molecules and their receptors, cytokines, heat shock proteins and T cell receptor chains. In addition to the examination of proposed innovative mechanisms in the trafficking of immune system cells into the CNS via adhesion-related events, a novel facet of oligodendroglial cell protection and/or pathology in MS, that heat shock protein expression on oligodendrocytes may play a role in lesion growth in MS, and that developmental regulation of heat shock proteins might occur on oligodendrocytes during myelination. These experiments might further elucidate the extent to which components of the CNS interact with the immune system in the creation of the demyelinated plaque.
Showing the most recent 10 out of 109 publications
