The pathogenesis of multiple sclerosis (MS), an autoimmune disease affecting the brain and spinal cord, remains poorly understood. Patients with MS typically present with recurrent episodes of neurological dysfunctions such as blindness, paresis, and sensory disturbances. Studies on experimental autoimmune encephalomyelitis (EAE) animal models have led to a number of testable hypotheses including a hypothetical role of altered gut microbiota in the development of MS. To investigate whether gut microbiota in patients with MS is altered, we compared the gut microbiota of 20 Japanese patients with relapsing-remitting (RR) MS (MS20) with that of 40 healthy Japanese subjects (HC40) and an additional 18 healthy subjects (HC18). All the HC18 subjects repeatedly provided fecal samples over the course of months (158 samples in total). Analysis of the bacterial 16S ribosomal RNA (rRNA) gene by using a high-throughput culture-independent pyrosequencing method provided evidence of a moderate dysbiosis in the structure of gut microbiota in patients with MS. Furthermore, we found 21 species that showed significant differences in relative abundance between the MS20 and HC40 samples. On comparing MS samples to the 158 longitudinal HC18 samples, the differences were found to be reproducibly significant for most of the species. These taxa comprised primarily of clostridial species belonging to Clostridia clusters XIVa and IV and Bacteroidetes. The phylogenetic tree analysis revealed that none of the clostridial species that were significantly reduced in the gut microbiota of patients with MS overlapped with other spore-forming clostridial species capable of inducing colonic regulatory T cells (Treg), which prevent autoimmunity and allergies; this suggests that many of the clostridial species associated with MS might be distinct from those broadly associated with autoimmune conditions. Correcting the dysbiosis and altered gut microbiota might deserve consideration as a potential strategy for the prevention and treatment of MS.

Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19 ^int CD27 ^high CD38 ^high CD180 ⁻ phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse. We also demonstrate that interleukin 6 (IL-6), shown to be increased in NMO, enhanced the survival of PB as well as their AQP4-Ab secretion, whereas the blockade of IL-6 receptor (IL-6R) signaling by anti–IL-6R antibody reduced the survival of PB in vitro. These results indicate that the IL-6–dependent B-cell subpopulation is involved in the pathogenesis of NMO, thereby providing a therapeutic strategy for targeting IL-6R signaling.

Objective: To evaluate the safety and efficacy of a humanized anti–interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO). Methods: Seven patients with anti–aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year. We evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue. Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells. Results: Six females and one male with NMO were enrolled. After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p < 0.005). The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly. The ameliorating effects on intractable pain exceeded expectations. Conclusion: Interleukin-6 receptor blockade is a promising therapeutic option for NMO. Classification of evidence: This study provides Class IV evidence that in patients with NMO, TCZ reduces relapse rate, neuropathic pain, and fatigue.

Human Vα24⁺ NK T cells are a unique subset of lymphocytes expressing the Vα24JαQ invariant TCR chain. Because they can rapidly produce large amounts of regulatory cytokines, a reduction of NK T cells may lead to the development of certain autoimmune diseases. Using a single-strand conformation polymorphism method, we demonstrate that a great reduction of Vα24JαQ NK T cells in the peripheral blood is an immunological hallmark of multiple sclerosis, whereas it is not appreciable in other autoimmune/inflammatory diseases such as chronic inflammatory demyelinating polyneuropathy. The chronic inflammatory demyelinating polyneuropathy lesions were often found to be infiltrated with Vα24JαQ NK T cells, but multiple sclerosis lesions only rarely expressed the Vα24JαQ TCR. It is therefore possible that the extent of NK T cell alteration may be a critical factor which would define the clinical and pathological features of autoimmune disease. Although the mechanism underlying the NK T cell deletion remains largely unclear, a remarkable contrast between the CNS and peripheral nervous system diseases allows us to speculate a role of tissue-specific elements such as the level of CD1d expression or differences in the CD1d-bound glycolipid.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3⁺ regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ⁻IL-17A⁻Foxp3⁺CD4⁺ T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4⁺ T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.

Significance: We have compared gut microbiomes in the different stages of multiple sclerosis (MS) based on both microbial and functional analyses using fecal samples. Together with microbial composition data, metagenomic functional and metabolite data revealed a reduced level of microbial butyrate and propionate biosynthesis in the gut of relapsing remitting MS (RRMS). On the other hand, in the gut of secondary progressive MS (SPMS), we revealed an enhancement in microbial DNA mismatch repair, which was consistent with excessive fecal oxidation shown in sulfur metabolomic analysis. As elevated oxidative stress is closely associated with chronic neuroinflammation and neurodegeneration, the present result opens a way to microbiome data-assisted management of MS, useful for prevention of disease progression.