Imbalance of Circulating B-Cell Subsets Was Associated With Higher Risk of Relapses in RRMS Patients

B-cell aggregates below the meninges have been associated with progression of neurodegeneration in multiple sclerosis (MS). We aimed to investigate the frequency of different B-cell subsets and their relationship with MS severity. Also, we quantified the CXCL13 and neurofilament (NfL) plasma levels.

According to the differential expression of IgD, CD38, CD27, HLA-DR, CD138, IL-10, and IL-17, the frequency of different circulating B-cell (CD19⁺) subsets was evaluated using flow cytometry. Plasma levels of CXCL13 and NfL were quantified using ELISA.

Here, the severity of neurological impairment positively correlated with the percentage of plasmablast (CD138⁺, IL-17⁺IL-10^-, HLA-DR⁺IgD^-) and memory CD27⁺CD38⁺B-cell subsets (IL-17⁺IL-10^- and HLA-DR⁺IgD^-), but negatively correlated with the proportion of HLA-DR^-IgD⁺ and IL-17^-IL-10⁺ among transitional and plasmablasts. The occurrence of new clinical relapses was mainly observed among patients who showed an elevated proportion of CD138⁺⁺ and HLA-DR⁺⁺IgD^- plasmablast and HLA-DR⁺IgD^- memory and CD27⁺CD38⁺B-cell subsets. Further, relapsed patients showed a higher percentage of IL-17⁺IL-10^- cells among transitional, naïve and different memory B cells at baseline. By contrast, elevated frequency of HLA-DR^-IgD⁺⁺ memory B cells and IL-17^-IL-10⁺ among transitional and plasmablasts was observed in nonrelapsed patients over time. CXCL13 levels were higher in relapsed patients, and positively correlated with CD138⁺ plasmablasts and memory B-cell subsets. Finally, plasma levels of NfL correlated positively with both CD138⁺ and HLA-DR⁺IgD^- plasmablasts, but negatively with transitional and naïve B cells with HLA-DR^-IgD⁺ phenotype.

In summary, our findings suggest that increased circulating anergic or immunogenic B-cell subsets could be candidate biomarkers for low- and high-risk of disease activity, respectively.