Distinct B Cell Functions In Multiple Sclerosis And Neuromyelitis Optica

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are representative demyelinating diseases of central nervous system (CNS) and classical organ-specific autoimmune diseases. Myelin basic protein auto-reactive T cell was largely accepted as the mediator in the pathogenesis of multiple sclerosis in the past few decades, but recently the excellent results of CD20monoclonal antibody (rituximab) in treating MS indicats the important role of B cell. NMO was regarded as a subtype of MS and now NMO is stilled called optic-spinal multiple sclerosis (OSMS) sometimes, though there are many differences in clinical presentations and treatment strategies between NMO and MS. Thus, it is very necessary to make better understanding of the difference in immuno logical pathogenesis between these two diseases. In this study, we focused on B cell by measuring the percentages of peripheral CD19+CD27+memory B cell, CD19+BAFF-R+B cell, the B cells with abilities to traffic through blood brain barrier into CNS (CD19+CXCR5+, CD19+VLA-4+), regulatory B cells (CD19+CD5+CD1dhi, CD19+CD24hiCD38hi), regulatory T cell (CD4+CD25bi) and Th17cell by flowcytometry in42RRMS,51NM0and37healthy controls. The secretion of IL-10and IFN-y by B cell was also evaluated. In some patients, the detection was made duplicate before and after two weeks of high dose intra-venous methylprednisolone. We also detected the level of BAFF and CXCL13in cerebral spinal fluid (CSF) and IFN-y, TNF-a, IL-10, IL-4in serum by ELISA. A significant higher percentage of CD19+BAFF-R+and CD19+CXCR5+B cell and a notable defect in quantity of regulatory B cells were found in NMO patients. B cells of NMO also secreted less IL-10and more IFN-γ than RRMS and healthy controls. Meanwhile, the CSF titre of BAFF and CXCL13of NMO was also higher than that of RRMS and controls. The percentage of CD19+IL-10+and CD19+CD24hiCD38hi B cell in NMO-IgG positive NMO patients was even lower than that in NMO-IgG negative NMO patients. Contrary to NMO, the B cell abnormalities in RRMS were not so eminent. RRMS patients only tended to have a higher percentage of peripheral CD19+BAFF-R+B cell and higher CSF CXCL13titre not exceeding that of NMO. But they were characterized by a significant predominance of peripheral Th17cells and elevated serum IFN-y titre. After two weeks’high dose methylprednisolone infusion, the percentage of peripheral CD19+CD27+memory B cell, CD19+BAFF-R+and CD19+CXCR5+B cells were elevated, while the percentage of CD19+CD5+CDldhi and CD19+CD24hiCD38hi regulatory B cells were unchanged and in some patients, declined. The IFN-y production of B cells was inhibited but the IL-10secretion was not altered. Nevertheless, the percentage of CD4+CD25hi regulatory T cell was elevated and the Th17cells decreased significantly after methylprednisolone treatment. Our results confirmed that NMO characterized by prominent B cell dysfunction and MS by prominent T cell (especially Th17cell) dysfunction are two distinct diseases. The negative immuno-regulatory function of B cell in NMO-IgG positive NMO patient was even weaker than that in NMO-IgG negative NMO patient. Two weeks’ high dose methylprednisolone infusion induced disadvantageous phenotypic conversion of B cell:the percentage of pathogenic memory B cell was elevated while regulatory B cell decreased. On the contrary, methylprednisolone rectified T cell dysfunction significantly. Thus it is a good choice for acute attack of MS. The mechanism of methylprednisolone in NMO therapy might be its inhibition of other inflammatory cells and pathogenic antibody/cytokines secretion. The dynamic observation of a rituximab treated NMO patient revealed that rituximab deleted the pathogenic B cells and rectified the immuno-dysfuntion of T cells first; restored the advantageous distribution of B cells afterwards. As a result, the patient’s clinical and radiological presentations improved greatly. Thus it may be a new effective treatment of NMO. The effectiveness will last for a certain period, related to the duration of the maintenance of improved B cell distribution.