The objectives of this proposal are to develop an understanding of how people infected with an environmental agent acquire immune-mediated neurologic disease. The most common demyelinating disease in man is multiple sclerosis (MS), an immune-mediated neurologic disease of the central nervous system (CNS). Since MS has not been unequivocally associated with an environmental agent (such as a virus) one approach to understanding its pathogenesis is to study immune-mediated diseases of the CNS associated with known environmental agents. One such disease is HAM/TSP (HTLV-I associated myelopathy/tropical spastic paraparesis). In HAM/TSP, patients infected with HTLV-I (human T-lymphotropic virus type I) develop neurologic, immunologic and pathologic abnormalities that can be seen in MS. In fact, most HAM/TSP patients were initially diagnosed with chronic MS. Both MS and HAM/TSP patients develop CNS damage associated with CNS infiltration by immune cells. How inflammatory cells damage the CNS is unclear, but cellular and antibody-mediated immune responses are involved. Preliminary data indicate that HAM/TSP patients develop antibodies (IgG) to HTLV-I that cross react with a normal protein expressed in uninfected neurons. We hypothesize that the cross reactivity between HTLV-I and a neuronal protein implicates molecular mimicry as playing a role in the pathogenesis of HAM/TSP, an immune mediated disease that mimics some forms of MS. Molecular mimicry is characterized by an immune response to an environmental antigen (such as a virus) that cross reacts with a host antigen, with the resultant autoimmunity leading to organ damage and disease. The purpose of the proposed research is to establish the requirements for molecular mimicry by completing the following specific aims: 1. Identify the neuronal self protein recognized by HAM/TSP IgG and compare its sequence to HTLV-I. 2. Determine the epitope specificity of HAM/TSP IgG for HTLV-I and the neuronal self protein. 3. Determine the specificity of HAM/TSP IgG for neuronal tissue.
