Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis

Greenfield, A. L.; Dandekar, R.; Ramesh, A.; Eggers, E. L.; Wu, H.; Laurent, S.; Harkin, W.; Pierson, N. S.; Weber, M. S.; Henry, R. G.; Bischof, A.; Cree, B. A. C.; Hauser, S. L.; Wilson, M. R.; von Büdingen, H.- C.

doi:10.1101/490938

bioRxiv · 10.1101/490938

Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis

Greenfield, A. L.·Dandekar, R.·Ramesh, A.·Eggers, E. L.·Wu, H.·Laurent, S.·Harkin, W.·Pierson, N. S.·Weber, M. S.·Henry, R. G.·Bischof, A.·Cree, B. A. C.·Hauser, S. L.·Wilson, M. R.·von Büdingen, H.- C.

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Abstract

B-cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B-cells exist in the cerebrospinal fluid (CSF), meninges, and central nervous system (CNS) parenchyma of MS patients. Longitudinally stable CSF oligoclonal band (OCB) antibody patterns suggest some local CNS B-cell persistence; however, the longitudinal B-cell dynamics within and between the CSF and blood remain unknown. We sought to address this by performing immunoglobulin heavy chain variable region repertoire sequencing on B-cells from longitudinally collected blood and CSF samples of MS patients (n=10). All patients were untreated at the time of the initial sampling; the majority (n=7) were treated with immune modulating therapies 1.2 (+/-0.3 SD) years later during the second sampling. We found clonal persistence of B-cells in the CSF of five patients; these B-cells were frequently immunoglobulin (Ig) class-switched and CD27+. We identified specific blood B-cell subsets that appear to provide input into CNS repertoires over time. We demonstrate complex patterns of clonal B-cell persistence in CSF and blood, even in patients on high-efficacy immune modulating therapy. Our findings support the concept that peripheral B-cell activation and CNS-compartmentalized immune mechanisms are in part therapy-resistant.

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Greenfield, A. L., Dandekar, R., Ramesh, A., Eggers, E. L., Wu, H., Laurent, S., Harkin, W., Pierson, N. S., Weber, M. S., Henry, R. G., Bischof, A., Cree, B. A. C., Hauser, S. L., Wilson, M. R., von Büdingen, H.- C.. 2018-12-09. Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis. https://doi.org/10.1101/490938

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