VH4 Gene Segments Dominate the Intrathecal Humoral Immune Response in Multiple Sclerosis

Abstract

A characteristic feature of the CNS inflammatory response in multiple sclerosis (MS) is the intrathecal synthesis of IgG and the presence of oligoclonal bands. A strong correlation between CD138+ plasma blast numbers in MS cerebrospinal fluid (CeSF) and intrathecal IgG synthesis suggests that these cells are the major Ab-secreting cell type in MS CeSF. Sequencing of V regions from CD138+ cells in MS CeSF has revealed somatically mutated and expanded IgG clonotypes consistent with an Ag-targeted response. In the present study, single-cell RT-PCR analysis of CD138+ cells from 11 MS patients representing differing clinical courses and stages of disease identified expansion of CD138+ cells with functionally rearranged VH4 gene segments as an overriding feature of MS CeSF repertoires. VH4 dominance was attributed to the preferential selection of specific VH4 genes, particularly gene segment VH4-39, which displayed a significant enrichment in CeSF compared with MS peripheral blood B cells. A modest increase in VH4 prevalence among MS peripheral blood IgG memory cells was also noted, suggesting that factors shaping the CD138 repertoire in CeSF might also influence the peripheral IgG memory cell pool. These results indicate a highly restricted B cell response in MS. Identifying the targets of CeSF plasma cells may yield insights into disease pathogenesis.