Selective emergence of antibody-secreting cells in the multiple sclerosis brain

Background: Although distinct brain-homing B cells have been identified in multiple sclerosis (MS), it is unknown how these further evolve to contribute to local pathology. In this study, we explored B-cell maturation in the central nervous system (CNS) of MS and control brain donors and determined their association with immunoglobulin (Ig) production, T-cell presence and lesion formation. Methods: Ex vivo multicolor flow cytometry was performed on postmortem blood, cerebrospinal fluid (CSF), meninges and white matter from 28 MS and 10 non-demented control donors. MS brain tissue sections were analyzed with immunostainings and laser-capture microdissection to obtain paired lesional rims and perilesional areas. IgG index and CSF oligoclonal bands were measured with nephelometry, isoelectric focusing and immunoblotting. Blood-derived B cells from MS patients and healthy controls were cocultured under T follicular helper-like conditions to evaluate their ASC-differentiating capacity in vitro . Results: ASC versus B-cell ratios were increased in postmortem CNS compartments of MS but not control donors. Local presence of ASCs associated with a mature CD45 low phenotype, focal MS lesional activity, lesional Ig gene expression, and CSF IgG levels as well as clonality. In vitro blood B-cell maturation into ASCs did not differ between MS and control donors. Notably, lesional CD4 + memory T cells positively correlated with the presence of ASCs, which was accompanied by local interaction with T cells. Conclusion: These findings provide evidence that local B cells in MS preferentially mature into ASCs, which are largely responsible for both intrathecal and local Ig production. This is especially seen in active MS white matter lesions and likely depends on the interaction with CD4 + memory T cells that are locally present.