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Background  Regulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS). Novel regulatory B cell subsets CD19 + CD24 hi CD38 hi  cells and CD19 + PD-L1 hi  cells, with disparate regulatory mechanisms have been defined. Alemtuzumab provides a long-lasting suppression of disease activity in MS. In contrast to its documented efficacy, alemtuzumab’s mechanism of action is not fully understood and information about the composition of repopulating B cell pool is scarce.    Aim  To characterize repopulated B cell subsets and elucidate alemtuzumab’s mechanism of action in B cell perspective.    Methods  The frequency and the absolute number of Bregs were studied in peripheral blood mononuclear cells (PBMC) of 37 MS patients and 11 healthy controls (HC). Longitudinal analysis of the frequency and the absolute number of Bregs in PBMC of 11 MS patients was evaluated, before and at 6, 9, and 12 months post alemtuzumab.    Results  We found deficiency of CD19 + CD24 hi CD38 hi  cells during relapse compared to remission and HC (relapse vs remission:  p  = 0.0006, relapse vs HC:  p  = 0.0004). CD19 + PD-L1 hi  cells were deficient during relapse than remission and HC (relapse vs remission:  p  = 0.0113, relapse vs HC:  p  = 0.0007). Following alemtuzumab, the distribution of B cells shifts towards naïve phenotype and Breg deficiency is restored. The frequency of CD19 + CD24 hi CD38 hi  cells was significantly increased at 6 M and 9 M compared to 0 M (6 M vs 0 M:  p  = 0.0004, 9 M vs 0 M:  p  = 0.0079). At 9 M, the frequency of CD19 + CD24 hi CD38 hi  cells started to decrease and by 12 M the frequency was reduced compared to 6 M, although it was significantly higher than baseline level (12 M vs 0 M:  p  = 0.0257). The absolute number was significantly increased at 6 M and 9 M post-alemtuzumab (6 M vs 0 M:  p  = 0.0063, 9 M vs 0 M:  p  = 0.02). The frequency of CD19 + PD-L1 hi  cells significantly increased until 12 M (6 M vs 0 M:  p  = 0.0004, 12 M vs 0 M:  p  = 0.0036). The frequency of CD19 + PD-L1 hi  cells at 12 M was significantly higher than 9 M ( p  = 0.0311). We further pinpoint that CD19 + CD24 hi CD38 hi  cells were deficient at severe relapses following alemtuzumab infusion and restored during recovery.    Conclusions  Our results highlight the preferential reconstitution of Bregs as a possible mechanism of action of alemtuzumab and CD19 + CD24 hi CD38 hi  cells as a potential biomarker for disease activity.

Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis