Increased IgG and oligoclonal bands (OGBs) in the CSF and brains of patients with chronic inflammatory or demyelinating CMS disease provide clues to the nature of disease. OGBs appear almost exclusively in chronic infectious diseases of the CNS, and are antibody directed against the disease-causing organism, thus providing a rationale for our hypothesis that in chronic CNS inflammatory or demyelinating diseases of unknown cause, the OGBs target the antigens that trigger disease. We have analyzed the sequences of intrathecally synthesized IgG in subacute sclerosing panencephalitis (SSPE), a fatal chronic measles virus infection of the brain, and demonstrated features of antigen-driven selection. We produced recombinant IgG from these sequences, and demonstrated their high-affinity reactivities to the causative measles virus. We will test the hypothesis that the plasma cells resident in SSPE brain are primarily directed against the cause of disease, and use it as an experimental paradigm to develop strategies and techniques to identify disease- relevant IgG and their corresponding antigens in inflammatory or demyelinating CNS disease of unknown cause. We will use laser capture microdissection and single cell RT-PCR to analyze the IgG response in individual plasma cells and B cells resident in SSPE brain, and biopan phage-displayed SSPE Fab libraries to identify the strongest immune responses. We will characterize the relative strengths of these two compartments to relate them to the specificity and abundance of antigens (disease-relevant and secondarily generated) in the humoral response. Finally, we will develop strategies to detect very rare antigens in situ by immunoblotting, immunoprecipitation, or by selection from phage-displayed libraries. This experimental paradigm in SSPE will develop sensitive immunologic techniques to dissect the humoral immune response in chronic inflammatory CNS disease, and will develop strategies to identify disease- relevant IgG and their disease-relevant antigens in other inflammatory or demyelinating CNS diseases of unknown cause, including multiple sclerosis, acute disseminated encephalomyelitis, sarcoidosis, and CNS vasculitides. Determining the cause of these devastating neurologic diseases will have profound implications not only for early diagnosis but also for prevention of disease.
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