Clonal B cell persistence in multiple sclerosis: A longitudinal immune repertoire study

Objective: Determine the stability of CSF B cell clonotypes during disease course in multiple sclerosis (MS). Background: The efficacy of anti-CD20 therapy in MS highlights the need for further understanding the role of B cells in multiple sclerosis. At a single time point, CSF B cells of MS patients are clonally related to peripheral blood B cells. We investigated whether B cell clonotypes can be found in the CSF over time. Design/Methods: IgM and IgG B cell receptor (BCR) heavy chain variable region (IgG/M-VH) immune repertoires were generated on an Ion Personal Genome Machine from CSF and peripheral blood of nine MS patients at an initial, untreated time point (a) and again on average 434 (+/− 108.2 S.D., range 262–668) days later (b). A custom bioinformatics pipeline based on MiXCR (Bolotin et al Nature Methods 2015) was used to identify IGHJ/V germline segments and CDR3 sequence. Clonally related BCRs in different compartments and at different time points were identified by comparing sequences using a distance metric approach. Results: Seven of the nine patients were treated with an approved disease-modifying drug following the first CSF sample. Four of five patients who experienced clinical relapses had clonally related CSF B cells at the subsequent LP. Conversely, three of four relapse-free patients were not found to have any clonally related CSF B cells. Conclusions: To our knowledge, this is the first longitudinal B cell immune repertoire study in the CSF compartment of patients with MS. We found clonally related CSF B cells over time in the majority of patients with active relapsing disease. This may suggest recurring recruitment or intrathecal persistence of disease-associated B cells. Larger follow-up studies are needed to assess whether persistence of B cell clones correlates with treatment and treatment response. Disclosure: Dr. Greenfield has nothing to disclose. Dr. Eggers has nothing to disclose. Dr. Wu has nothing to disclose. Dr. Laurent has nothing to disclose. Dr. Michel has nothing to disclose. Dr. Harkin has nothing to disclose. Dr. Pierson has nothing to disclose. Dr. Cree has received personal compensation for activities with AbbVie, Biogen, EMD Serono, Novartis and Shire as a consultant. Dr. Wilson has nothing to disclose. Dr. Hauser has received personal compensation for activities with Annexon, Symbiotix, Bionure as a scientific advisory board member and from F. Hoffmann-La Roche Ltd. Dr. von Budingen has received personal compensation for activities with F. Hoffman-La Roche as an employee.