Abstract
BackgroundRegulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS). Novel regulatory B cell subsets CD19+CD24hiCD38hi cells and CD19+PD-L1hi 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.AimTo characterize repopulated B cell subsets and elucidate alemtuzumab’s mechanism of action in B cell perspective.MethodsThe 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.ResultsWe found deficiency of CD19+CD24hiCD38hi cells during relapse compared to remission and HC (relapse vs remission: p = 0.0006, relapse vs HC: p = 0.0004). CD19+PD-L1hi 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+CD24hiCD38hi 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+CD24hiCD38hi 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-L1hi 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-L1hi cells at 12 M was significantly higher than 9 M (p = 0.0311). We further pinpoint that CD19+CD24hiCD38hi cells were deficient at severe relapses following alemtuzumab infusion and restored during recovery.ConclusionsOur results highlight the preferential reconstitution of Bregs as a possible mechanism of action of alemtuzumab and CD19+CD24hiCD38hi cells as a potential biomarker for disease activity.
Highlights
Regulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS)
We found deficiency of CD19+CD24hiCD38hi cells during relapse compared to remission and healthy controls (HC)
CD19+PD-L1hi cells were deficient during relapse than remission and HC
Summary
Regulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS). 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. A novel Breg subset that was originally known as immature transitional B cells (CD19+CD24hiCD38hi) has been described to have regulatory capacity through interleukin-10 production [7]. Alemtuzumab is a highly effective treatment in relapsing MS It provides a long-lasting suppression of disease activity by altering the proportion of lymphocyte subsets with preferential increase of regulatory T cells (Treg) [10, 11]. In contrast to alemtuzumab’s documented efficacy, alemtuzumab’s mechanism of action is not fully understood and information about the composition of the repopulating B cell pool, especially Breg, is scarce
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