| Background and Objective: The present study was first carried out to explore the different phenotypes of CD19+CD24hiCD38hi Tr B cells in an acute and remission phase with NMOSD.In addition,the potential of Tr B cells in NMOSD to produce IL-10 and IL-6 was studied to assess their role of immune regulation.We also compared the levels of IL-40 in the serum and cerebrospinal fluid(CSF)in different stages of NMOSD,and HCs.We used multicolor flow cytometry to characterize the distribution and functional characteristics of B cells in NMOSD to better understand Tr B cells involvement of NMOSD pathogenesis.Materials and Methods:The numbers and frequencies of circulating CD19+CD24hiCD38hi Tr B cells and their different subsets in an acute and remission phase with NMOSD as well as HCs were examined by flow cytometry(T1 B: CD24hiCD38hiCD27-Ig MhiIg Dlo;T2 B: CD24hiCD38hiCD27-Ig MinIg Din;T3 B: CD24hiCD38hiCD27-Ig MloIg Dlo;CD27+ Tr B: CD24hiCD38hiCD27+).Furthermore,Tr B cells were studied to show their ability for produce IL-6 and IL-10.In addition,the levels of plasma and CSF IL-40 in both NMOSD patients and HCs.Results:(1)Patients with NMOSD in acute relapse phase had fewer numbers and frequencies of Tr B cells than remission phase and HCs.The numbers of mature naive B cells were higher in the patients with NMOSD acute relapse than in the patients with remission phase and HCs.Moreover,the frequencies of memory B cells were lower in the patients with NMOSD acute relapse than in the patients with remission phase and HCs.There was a decrease in the total number but an increase in the frequency of T1 B cells in patients with NMOSD acute relapse phase compared to the remission phase and HCs.Although NMOSD patients in acute relapse phase had significantly less the number of T2 B cells than the remission phase and HCs,there was no difference in the frequency.The frequencies and numbers of T3 B cells in patients with NMOSD acute relapse phase were lower than the remission phase and HCs.Notably,NMOSD patients in acute relapse phase had significantly less the frequency and number of CD27+ Tr B cells than the remission phase and HCs.(2)The frequencies of IL-10–positive B cells were lower in patients with NMOSD acute relapse phase compared with the remission phase and HCs.The frequencies of IL-10–positive transitional B cells were also lower in patients with NMOSD acute relapse phase.The frequencies of IL-10–positive T1 B,T2 B,and CD27+ Tr B cells in patients with NMOSD acute relapse phase were significantly lower than the remission phase and HCs.However,the frequencies of IL-10–positive T3 B cells were lower in patients with NMOSD acute relapse and remission phase compared with the HCs.(3)The frequencies of IL-6–positive B cells were higher in patients with NMOSD acute relapse phase compared with remission phase and the HCs.The frequencies of IL-6–positive Tr B cells were also higher in patients with NMOSD acute relapse phase compared with the remission phase and HCs.The frequencies of IL-6–positive T1 B,T2 B,and T3 B cells in patients with NMOSD acute relapse phase were significantly higher than the remission phase and HCs.However,the frequencies of IL-6–positive CD27+ Tr B cells were higher in the HCs compared with patients with NMOSD remission phase.(4)The levels of plasma IL-40 were higher in patients with NMOSD remission phase than that in acute relapse phase and HCs,but there was no significant difference between in patients with NMOSD acute phase and HCs.Moreover,the levels of CSF IL-40 in patients with NMOSD acute relapse were not significantly different from those in HCs.Furthermore,the frequencies of Tr B cells in patients with NMOSD were positively correlated with the levels of plasma IL-40.(5)The frequencies of Tr B cells in serum AQP4-Ig G–positive NMOSD patients were significantly lower than that of serum AQP4-Ig G–negative NMOSD patients.Among different subpopulations of Tr B cells,only the frequencies of CD27+ Tr B cells were lower in serum AQP4-Ig G–positive NMOSD patients than in the NMOSD patients with serum AQP4-Ig G–negative NMOSD patients,while the frequencies of T1 B,T2 B,and T3 B cells in AQP4-Ig G–positive NMOSD patients were not significantly different from those in serum AQP4-Ig G–negative NMOSD patients.(6)The frequencies of Tr B cells in patients with NMOSD acute relapse phase were negatively correlated with the ARR,but there was no significant correlation with the EDSS.Conclusion:(1)The frequencies of Tr B cells in the patients with NMOSD acute relapse were lower than the HCs,and low expression of IL-10 and high expression of IL-6.Althogh the frequencies of Tr B cells and the expressions of IL-10 in the patients with NMOSD remission phase have no statistical differences compared with HCs,the expressions of IL-6 were lower in the patients with NMOSD remission phase than that of HCs.In NMOSD acute relapse phase,the imbalance between pro-and anti-inflammatory cytokine productions in Tr B cells may affect their functional stability and thus participate in the pathogenesis of NMOSD,but the immune regulatory function of Tr B cells can gradually recover in patients with NMOSD remission phase.(2)The frequencies of Tr B cells in the patients with NMOSD acute relapse were negatively correlated with the ARR,and were lower in serum AQP4-Ig G–positive NMOSD patients and enhanced lesions in MRI.Tr B cells may serve as new biomarkers for evaluating disease relapse.(3)The frequencies of T3 B cells and CD27+ Tr B cells in patients with acute NMOSD were significantly reduced,and the frequencies of CD27+ Tr B cells were lower in serum AQP4-Ig G–positive NMOSD patients than in the NMOSD patients with serum AQP4-Ig G–negative NMOSD patients.Furthermore,the frequencies of IL-6–positive CD27+ Tr B cells were lower in the patients with NMOSD remission phase than that of HCs.CD27+ Tr B cells may play a major role in immunoregulatory functions compared with other Tr B cell subsets.(4)The levels of plasma IL-40 were higher in patients with NMOSD remission phase than that in acute relapse phase and HCs,and the frequencies of Tr B cells in NMOSD patients were positively correlated with the levels of plasma IL-40.IL-40 may be related to the development of Tr B cell. |
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