Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the Central Nervous System (CNS) which likely involves an autoimmune mechanism directed against self-myelin associated antigens. There is substantial evidence suggesting that B cells are involved in at least one mechanism of MS pathogenesis. However, both functional and molecular analysis of the immunoglobulins (Ig's) produced by clonally expanded CSF B cells has been limited. We hypothesize that a subset of clonally expanded B cells in the CSF of MS patients is involved in at least one mechanism of MS pathogenesis by producing antibodies that bind to myelin associated antigens. In order to identify complete Ig rearrangements that may play a role in the autoimmune activities evidenced in MS patients and test for their antigenic specificity, we intend to define the Ig repertoires in the CSF of MS patients in order to identify Ig's from clonally expanded B cells. We then plan to determine the antigenic specificity of these unique Ig rearrangements by cloning both the heavy and light chain segments into an expression vector, isolating the resultant Fab fragments, and testing them for their antigenic specificity. We can also use PCR to track the persistence of these clones in the original MS patients. Moreover, we can determine if other MS patients have the same clonally expanded B cells in their CSF. These studies provide the necessary foundation to initiate and assess the potential role of B cells in at least one mechanism of MS pathogenesis, and ultimately will allow us to explore whether generating specific immunotherapies directed against these clonally expanded B cells in the future is warranted. ? ?
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