This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multiple Sclerosis (MS) is an inflammatory and demyelinating degenerative disease of the human central nervous system (CNS). It is a worldwide disease that affects approximately 300,000 persons in the United States; it is a disease of young adults, with 70-80% having onset between 20-40 years old. MS is a heterogeneous disorder based on clinical course, magnetic response imaging (MRI) scan assessment, and pathology analysis of biopsy and autopsy material. The disease manifests itself in a large number of possible combinations of deficits, including spinal chord, brainstem, cranial nerve, cerebellar, cerebral and cognitive syndromes. Progressive disability is the fate of most patients with MS, especially when a 25-year perspective is included. Half of MS patients require a cane to walk within 15 years of disease onset. MS is a major cause of neurological disability in young and middle-aged adults and, until the past decade, has had no known beneficial treatments. There are no approved therapies for primary progressive MS and no treatments effective for the prevention of long-term disability. Substantial evidence exists for a pathogenic role of antibodies and B-cell lymphocytes in the pathogenesis of MS and identifies B-cells as an appropriate target for novel immunotherapies for the treatment of MS. Rituximab specifically ablates B-cells and has a well-characterized safety profile that makes it a potentially attractive pharmacological agent to further elucidate the role of B-cells and their functions in MS pathophysiology and to test the therapeutic potential of a B-cell depleting therapy.