MS is the most common human demyelinating disease. Although its cause is unknown, a clue to the nature of disease lies in the presence of increased IgG and oligoclonal bands (OGBs) in MS CSF. We hypothesize that the OGBs in MS CSF are antibody directed against the antigen that triggered disease. The rationale for this hypothesis is that in various viral and granulomatous CNS infections, OGBs can be removed by incubation of CSF with the disease-causing organism. It is likely that the MS antigen, including its cognate mRNA, persists in MS brain, a notion supported by serial MRI brain scanning of MS patients which reveals continuous plaque formation in the absence of clinical disease, by the intrathecal synthesis and persistence of OGBs in MS CSF, and by the presence of IgG in MS plaques. To identify an MS-specific antigen or transcript and to characterize its mRNA, we will: (1) construct directionally cloned cDNA libraries in an expression vector from plaque and periplaque areas of MS brain; (2) identify by nucleic acid hybridization screening (after subtractive hybridization), MS-specific clones; or by immunological screening, MS-specific clones whose expression products react specifically with MS CSF, but not with CSF containing OGBs from other inflammatory and infectious diseases of the CNS; and show that protein extracts from these candidate MS-specific clones are capable of removing the OGBs in MS CSF, but not OGBs in control CSF; (3) screen CSF and sera from MS and control patients for antibody directed against the candidate MS-specific antigen; and (4) characterize, using molecular biologic techniques, MS-relevant clones, and study their pattern and level of expression in MS brain. To carry out these studies we have: (a) pathologically-verified MS brains, non-MS neurologic disease brains, and brains from normal autopsied subjects; (b) MS CSF and CSF from patients with known CNS inflammatory and infectious diseases, both containing OGBs; (c) the expertise in molecular biology to characterize an unknown mRNA. Identification of an MS-specific antigen will have wide applicability, not only for early, definitive diagnosis, but also to develop strategies for modulation, if not prevention, of disease.
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