Comparison of immunoglobulin G heavy-chain sequences in MS and SSPE brains reveals an antigen-driven response

Objective: To better understand B-cell activation in MS by analyzing the immunoglobulin (Ig) G heavy chain variable region (VH) repertoire found in MS brains and comparing it with brain VH sequences in individuals with subacute sclerosing panencephalitis (SSPE)-a chronic encephalitis produced by measles virus (MV)--and characterized by an antigen-driven oligoclonal IgG response to MV antigens. Background: The specificity of oligoclonal IgG in MS CSF and plaques, and their relevance to the pathogenesis of MS is unknown. Methods: Nested PCR was used to amplify and sequence the rearranged IgG heavy-chain VH repertoire in plaques of three acute MS brains and in three SSPE brains. A representative population of VH sequences from each tissue was aligned to the known 51 functional VH germline segments. From this the authors determined the closest VH family germline segment, and the degree and location of somatic mutations for each unique IgG. Results: As expected for an antigen-driven response against MV antigens, most VH sequences from the SSPE brains were mutated extensively compared with their closest germline segments. Furthermore, SSPE VH sequences accumulated replacement mutations preferentially in the complementary-determining regions (CDRs) relative to framework regions--features normally observed during antigen-driven selection. A comparison of VH family and germline usage also demonstrated that each SSPE brain had its own unique IgG response. When the authors compared the VH response in MS plaques with SSPE, MS VH sequences were also mutated extensively, displayed a preferential accumulation of replacement mutations in CDRs, and were unique in each MS brain. Conclusion: The presence of an antigen-driven response in MS, rather than a nonconventional mechanism of B-cell activation, warrants additional analysis of the specificity of Ige in MS brain and CSF.