| Objective:To study the humoral immune dysfunction of neuromyelitis optica (NMO) during remission, and explore its differences with neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS). Meanwhile, observe clinical efficacy of Bushenyisui Capsules (BSYSC) of neuromyelitis optica during remission, and its effect on humoral immune function.Methods:1.28 NMO patients,5 NMOSD patients and 25 MS patients during remission visiting in Traditional Chinese Medicine Department of Beijing Tiantan Hospital in June 2013-December 2014 were enrolled in this study, and recruited 22 volunteers as Health control (HC). Record basic information of patients, including the age of onset, course, frequency of recurrence, lesion site, the last relapse time, and expanded disability status scale (EDSS) score. And detect the proportion of CD19+B cells, CD19+CD27+memory B cells (mB), CD19intCD27highCD38highCD180- plasmablast (PB), CD4+CXCR5+ T helper cells (Th), CD19+CD24highCD38high regulatory B cells (Breg) and CD3-CD16+CD56+ natural killer cells (NK) in peripheral blood by application of flow cytometry. The CXCL13 and BAFF levels in serum were detected by enzyme-linked immunosorbent assay (ELISA), and Interleukin-6 (IL-6) level was detected by cytometric bead array (CBA). Compare differences of indices between groups, and analyze the correlation between different indices, and the correlation between indices and the clinical data.2.26 NMO patients during remission with deficiency of kidney-liver yin syndrome were enrolled and treated with BSYSC for three months. Eventually, 4 cases fall off and 22 cases completed. Record basic informations of patients, including name, gender, age, the age of onset, lesion site (imaging data), course, frequency of recurrence, the last relapse time and combined medication. Record EDSS score and traditional chinese medicine symptoms (TCMS) score, meanwhile, detect the proportion of CD19+B cells, CD19+CD27+mB, CD19intCD27highCD38highCD180- PB, CD4+CXCR5+Th, CD19+CD24highCD38high Breg, CD3-CD16+CD56+ NK in peripheral blood, and the CXCL13, BAFF, IL-6 levels in serum before and after treatment. We followed up medication and relapse of patients after the end of treatment (three months one time).Results:1.The NMO patients during remission:(1) The ratio of male to female were 1:27, its relapse frequency (P=0.006) and EDSS score (P=0.005) were significantly higher than patients with MS; (2) There were no significantly differences of the CD19+B cells proportion in lymphocytes between NMO group and HC group (P=0.794), MS group (P=0.103), NMOSD group (P=0.659); (3) The differences of CD19+CD27+/CD19+were not statistically significant between NMO group and HC group (P=0.927), MS group (P=0.244), NMOSD group (P=0.937); (4) The proportion of CD19intCD27highCD38highCD180- PB in CD19+ B cells of NMO patients is not higher than HC group (P=0.620), MS group (P=0.661) and NMOSD group (P= 0.212); (5) The levels of CXCL13 in serum of NMO patients were significantly higher than that of HC group (P=0.000) and MS group (P=0.002), but it was no significantly different with NMOSD group (P=0.514). It was negatively correlated with the length to the last time of onset (months) (r=-0.401, P=0.034); (6) There were no significant differences of serum BAFF levels between NMO group and HC group (P=0.197), MS group (P=0.415), NMOSD group (P=0.545). The serum BAFF levels of NMO patients without immunotherapy were higher than that of treatment group (P=0.003) and HC group (P=0.001); (7) The contents of serum IL-6 of NMO patients were significantly higher than that of HC group (P=0.009), MS group (P=0.001), but no significant difference with NMOSD patients (P=0.131); (8) The proportion of CD4+CXCR5+Th cells in the peripheral blood accounted for lymphocyte in NMO group increased compared with HC group (P=0.001), MS group (P=0.000), and were higher than that of NMOSD group (P=0.014); (9) The ratio of CD3-CD16+CD56+/CD3- in peripheral blood of NMO patients was significantly lower than HC group (P=0.000) and MS group (P=0.027), but there was no statistical difference between NMO and NMOSD group (P=0.132); (10) The proportion of CD19+CD24highCD38highcells in CD19+ cells in NMO group was significantly lower than HC group (P=0.019), MS group (P=0.031), no significant difference was found between NMO and NMOSD group (P=0.815). The Breg ratio in peripheral blood of NMO patients using hormones and/or immunosuppressive therapy had a lower tendency than unused patients.2. Treat NMO patients during remission with BSYSC:(1) The EDSS score and TCMS score decreased after treatment (P=0.024,0.000). The annual relapse rate was lower after treatment (P=0.000); (2) There were no significant differences of CD19+/lymphocytes (%), CD19+CD27-/CD19+(%), CD19+CD27-/CD19+(%), and CD19intCD27highCD38highCD180-/ CD19+(%) proportions in peripheral blood of NMO patients before and after treatment, P values were 0.973,0.394,0.322 and 0.860; (3) After treatment, serum CXCL13 level didn’t change significantly (P=0.942), but BAFF level elevated compared with level before treatment (P=0.031). Before treatment, serum BAFF content and oral steroid dose (mg) was negatively correlated (r=-0.823, P=0.000), the greater the dose of hormones was, BAFF expression was lower. After treatment, they also had a significant negative correlation (r=-0.627, P=0.002). During treatment,11 patients with oral steroid had different degrees extenuation; (4) Serum IL-6 contents of NMO patients after treatment decreased, and the difference was statistically significant (P=0.000); (5) After treatment, the ratio of peripheral blood CD4+CXCR5+ Th cells in lymphocyte (%) had downward trend, but the difference was not statistically significant (P=0.083); (6) CD19+CD24highCD38high/CD19+(%) proportion rised compared with that before treatment. This proportion of NMO patients in immune inhibitor group was lower than that of patients who didn’t use immune inhibitor (P=0.027) before treatment, and there was also the same tread (P=0.081) after treatment; (7) The proportion of CD3-CD16+CD56+/CD3-in peripheral blood was significantly higher after treatment (P=0.027).Conclusion:1. The humoral immune function of NMO patients during remission is abnormal. There is no significant increase of CD19+ Bcells, memory B cells and antibody-secreting B cells in peripheral blood, but the levels of CXCL13, BAFF, IL-6 and CXCR5+CD4+Th cells promoting B cell maturation are still higher. The proportion of NK cells failed to restore, and Breg cells playing negative regulatory role in humoral immunity are still below normal. The level of serum CXCL13 will decrease when the time to recurrence prolong. Hormones drugs and immuno-suppressants can inhibit expression of BAFF, but may damage Breg cells at the same time. The humoral immune disorders of NMOSD patients are similar to NMO patients. The CXCL13 level in serum of MS patients has a higher trend.2. Bushenyisui Capsules (superimposed treatment) can improve neurological dysfunction and clinical symptoms of patients with NMO, and reduce annual relapse rate. Its effect on peripheral blood B cells, mB, PB is not obvious. But it can lower serum IL-6 level, and promote the repair of Breg and the increase of the number of NK cells, thereby promote immune function to restore balance in NMO remission. Immunosuppressants can signifycantly inhibit Breg. Hormone drugs have great effects on BAFF, the greater the dose, the stronger the inhibition.
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