Our understanding of the pathophysiology and neurodegenerative processes of MS has led to the development of novel therapeutic strategies. Since the early 1990s, diseasemodifying drugs have been introduced for the selective management of MS, including IFNβ and glatiramer acetate (GA), which have become the standard treatment for relapsing/remitting MS [95] . Most recommendations previously made by the Multiple Sclerosis Therapy Consensus Group (MSTCG) on the use of disease-modifying drug therapies remain valid [96, 97] . Hermmer and Hartung have published an apparent review of the development of rational therapies in MS [98] . Therefore, we will discuss four domains of novel immunomediated therapeutics used for MS and their current status. The first domain includes immunosuppressive agents, such as mitoxantrone, laquinimod (ABR-215062), cladribine (Mylinax ), and teriflunomide (probably via the suppression of TNFα and IL2 production). The second domain includes immunomodulatory agents: (1) cytokine inhibitors such as IFNβ; (2) agents that deplete specific immune cell subsets, such as alemtuzumab (a human monoclonal antibody [mAb] that targets CD52 expressed by T and B cells, producing long-term T-cell depletion) [99, 100] and rituximab (which targets CD20 to deplete human B cells) [99, 101] ; (3) agents that selectively block coreceptors and costimulators, such as daclizumab (an anti-CD25 mAb that inhibits activated T cells and induces regulatory immune cells) [102] . The third domain involves the development of migration-modifying therapies: (1) agents that affect adhesion molecules, such as natalizumab (an mAb that blocks very late antigen 4 [VLA-4]) and (2) sphingosine 1phosphate receptor (S1PR) agonists: fingolimod (FTY720). The fourth domain includes neuroprotective agents associated with immunomodulation, including broad-spectrum immunomodulators such as statins, PPAR agonists (e.g., pioglitazone, gemfibrozil), the sex hormone estriol (E3), fumarate, minocycline, and erythropoietin (EPO), all of which have been effective in the treatment of both EAE, and MS. IFNβ has been clinically introduced to treat patients with MS based on its ability to shift a Th1-mediated response to a Th2-mediated response [92] . However, microarray studies have indicated that a number of genes in patients with MS are upregulated by the cytokines associated with the differentiation of cells into Th1 lymphocytes rather than into Th2 lymphocytes, suggesting that this shift may not be the only therapeutic mechanism of IFNβ in MS [103] . IFNβ therapy also reduces IL23 mRNA levels [104] . IFNβ inhibits human Th17 cell differentiation, so the Th17 axis could be another target of IFNβ therapy [105] . IFNβ-mediated IL27 production by innate immune cells has been shown to play a critical role in the immunoregulatory role of IFNβ in EAE by inhibiting Th17 cells in EAE mice and MS patients [91, 106, 107] . Besides, Galligan et al. evidence further that IFNβ(−/−) mice exhibited an earlier disease onset and a more rapid progression of EAE compared to IFNβ(+/+) mice of EAE and IFNβ(−/−) mice of EAE had increased 7 numbers of CD11b(+) leukocytes infiltrating affected brains and an increased percentage of Th17 cells in the CNS with augmentation of autoreactive T cells,suggesting that IFNβ acts to suppress the production of autoimmune-inducing Th17 cells during the development of disease as well as modulating proinflammatory [108] . In addition, the therapeutic effect of IFNβ is probably attributable to the induction of the regulatory cytokine IL10 [104] . Furthermore, Axtell et al. design a delicate study to further clarify the role of IFNβ in MS/EAE [109] . Likewise, They demonstrate that IFNβ was effective in reducing EAE symptoms transferred by Th1 cells transfer but exacerbated disease by Th17 cells transfer and effective treatment of IFNβ in Th1-induced EAE correlated with augmented IL10 production; differently, in Th17-induced EAE, the amount of IL10 was unaffected by treatment of IFNβ. Likewise, a high IL17F level in the serum of people with RRMS is associated with fail of IFNβ therapy. This characteristic of IFNβ might contribute to explore some logical biomarkers for predictive assessment of the response to a popular therapy for MS [109, 110] . Although, B cells may have a dual role in the pathogenesis of MS that they contribute to the induction of the autoimmune response but also mediate the resolution of the CNS inflammatory infiltrate [111, 112] . However, Ramgolam et al. demonstrate further that supernatants transferred from IFNβ-1b-treated B cells inhibited Th17 cell differentiation, as they suppressed gene expression of the RORC and IL-17A and secretion of IL-17A. Likewise, IFNβ-1b also induces B cells' IL-10 secretion which may mediate their regulatory potent [113] . Thus, IFNβ-1b exerts its therapeutic effects at least in part by targeting B cells' functions that contribute to the autoimmune pathogenesis of RR MS, which may uncover extra mechanisms of the B-cell contribution to the autoimmune effects and provide novel targets for future selective treatment of MS [113] .