These data show that circulating exosomes have a distinct RNA profile in RRMS. Because putative targets for these miRNAs include the signal transducer and activator of transcription 3 and the cell cycle regulator aryl hydrocarbon receptor, the data suggest a disturbed cell-to-cell communication in this disease. Thus, exosomal miRNAs might represent a useful biomarker to distinguish multiple sclerosis relapse. Ann Neurol 2017;81:703-717.

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Exosomes isolated outside CNS tissue expressed myelin proteins, and the presence of MOG correlated strongly with disease activity. We conclude that exosomes might enhance and/or perpetuate anti-myelin immune reactions in MS and may provide novel markers of disease activity.

Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory demyelinating diseases of the central nervous system (CNS) that cause optic neuritis, transverse myelitis, and some other CNS syndromes. Recently, diagnosis and understanding of these diseases has been markedly enhanced by the discovery that serum autoantibodies that target aquaporin-4 (AQP4) are strongly associated with the disease. This spectrum includes also a potential subset of patients with a phenotype of NMOSD who have anti-myelin oligodendrocyte glycoprotein (MOG) antibody. Although steroids and immunosuppressive drugs have been widely used for NMOSD treatment, until recently there was no approved therapy for these diseases. With improved understanding of the pathophysiology of NMOSD, numerous new therapeutic strategies have recently been evaluated. The results of these studies, involving monoclonal antibodies (mAbs) inhibiting terminal complement protein cleavage interfering with interleukin-6 receptor (IL-6 R) signaling and depleting CD19-positive B cells, have been published in recent months. All of these new therapeutics have shown a high degree of efficacy in diminishing NMOSD activity and inhibiting disability progression. At the same time, all these mAbs have demonstrated favorable safety and tolerability profiles, with a limited rate of adverse events. The first of these new drugs, eculizumab, have been approved in USA and Europe for NMOSD treatment within the last couple of months and it is expected that the other novel, effective and safe treatments for NMOSD will be approved in the near future.

Background and ObjectivesTo investigate the total circular RNA (circRNA) profile in patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs).MethodsHybridization microarray was used to define the circRNA profile in peripheral blood mononuclear cells (PBMCs) from 20 untreated patients with RRMS (10 in relapse and 10 in remission) and 10 HCs. We analyzed close to 14,000 individual circRNAs per sample. The discovery set data were validated using quantitative reverse transcription-PCR with an independent cohort of 47 patients with RRMS (19 in relapse and 28 in remission) and 27 HCs.ResultsMicroarray analysis revealed 914 transcripts to be differentially expressed between patients with RRMS in relapse and HCs (p < 0.05). We validated 3 circRNAs from 5 showing highest levels of differential expression in the RRMS relapse vs HC group: hsa_circRNA_101348, hsa_circRNA_102611, and hsa_circRNA_104361. Their expression was significantly increased during relapse in RRMS (p = 0.0002, FC = 2.9; p = 0.01, FC = 1.6; and p = 0.001, FC = 1.5, respectively) and in patients showing gadolinium enhancement on brain MRI (hsa_circRNA_101348, p = 0.0039, FC = 2.4; hsa_circRNA_104361, p = 0.029, FC = 1.7). Bioinformatic analysis revealed 15 microRNAs interacting with these circRNAs in a complementary manner and led to the discovery and validation of 3 protein-coding RNAs upregulated in patients with RRMS during relapse. Two of these, AK2 and IKZF3, have previously been implicated in B-cell function.DiscussioncircRNAs display a distinct profile in PBMCs from patients with RRMS, and our results may implicate circRNA in the known disturbed B-cell activity in RRMS and thus represent a novel biomarker for monitoring relapse activity.