The cerebrospinal fluid immunoglobulin transcriptome and proteome in XXXX reveals central nervous system-specific B cell populations.

@entity1652 @entity1 @entity6220 @entity3951
BACKGROUND: @entity1652 ( @entity1652 ) is a severe demyelinating @entity6220 (CNS) associated with the presence of an autoimmune antibody response ( @entity3951 -IgG) against the water channel aquaporin-4 ( @entity3951 ). It remains unclear whether pathologic @entity3951 -IgG in the CNS is produced entirely by peripheral plasma cells or is generated in part by infiltrating B cells. To determine the overlap of @entity3951 -IgG idiotypes between the CNS and periphery, we compared the immunoglobulin G (IgG) transcriptome of cerebrospinal fluid (CSF) plasmablasts with the CSF and serum IgG proteomes in 7 @entity3951 -seropositive @entity1652 @entity1 following exacerbation. METHODS: CSF variable region Ig heavy- (VH) and light-chain (VL) transcriptome libraries were generated for each @entity1 from CSF plasmablasts by single cell sorting, reverse transcriptase polymerase chain reaction (RT-PCR), and DNA sequencing. Recombinant antibodies were generated from clonally expanded, paired VH and VL sequences and tested for @entity3951 -reactivity by cell-binding assay. CSF and serum IgG fractions were searched for sequences that matched their respective CSF IgG transcriptome. Matching peptides within the same @entity1 's CSF and serum IgG proteomes were also identified. RESULTS: In each @entity1652 @entity1 , we recovered CSF IgG VH and VL sequences that matched germline-mutated IgG protein sequences from the @entity1 's CSF and serum IgG proteomes. Although a modest variation was observed between @entity1 , the overlap between the transcriptome and proteome sequences was found primarily, but not exclusively, within the CSF. More than 50% of the CSF IgG transcriptome sequences were exclusively found in the CSF IgG proteome, whereas 28% were found in both the CSF and blood IgG proteome, and 18% were found exclusively in the blood proteome. A comparable distribution was noted when only @entity3951 -specific IgG clones were considered. Similarly, on average, only 50% of the CSF IgG proteome matched corresponding peptide sequences in the serum. CONCLUSIONS: During @entity1652 exacerbations, a substantial fraction of the intrathecal Ig proteome is generated by an intrathecal B cell population composed of both novel and peripherally-derived clones. Intrathecal CSF B cell clones may contribute to @entity1652 disease exacerbation and lesion formation and may be an important target for preventative therapies.
