Interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) are increasingly recognized as key participants in various autoimmune diseases, including multiple sclerosis. Although sets of transcription factors and cytokines are known to regulate T(H)-17 differentiation, the role of noncoding RNA is poorly understood. Here we identify a T(H)-17 cell-associated microRNA, miR-326, whose expression was highly correlated with disease severity in patients with multiple sclerosis and mice with experimental autoimmune encephalomyelitis (EAE). In vivo silencing of miR-326 resulted in fewer T(H)-17 cells and mild EAE, and its overexpression led to more T(H)-17 cells and severe EAE. We also found that miR-326 promoted T(H)-17 differentiation by targeting Ets-1, a negative regulator of T(H)-17 differentiation. Our data show a critical role for microRNA in T(H)-17 differentiation and the pathogenesis of multiple sclerosis.

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Adenosine is a key endogenous signaling molecule that regulates immune responses. A2B adenosine receptor (AR) is a relatively low-affinity receptor for adenosine, and the activation of A2BAR is believed to require pathological level of adenosine that is associated with ischemia, inflammation, trauma, or other types of stress. The role of A2BAR in the pathogenesis of multiple sclerosis (MS) is still unclear. In this study, we discovered that A2BAR was upregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of experimental autoimmune encephalomyelitis (EAE) mice. A2BAR-specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the CNS from immune damage. A2BAR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A2BAR inhibited Th17 cell differentiation by blocking IL-6 production from APCs such as dendritic cells. In dendritic cells, A2BAR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A2BAR significantly reduced adenosine-mediated IL-6 production. The phospholipase Cβ–protein kinase C and p38 MAPK pathways were found to be involved in the A2BAR-mediated IL-6 production. Our findings not only revealed the pathological role of A2BAR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs.

Background: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B pathogenic mutations. The symptoms of WD can be effectively prevented if the affected individuals are identified and intervened early. However, clinical utility of this molecular analysis is challenging due to hundreds of variants with various clinical effects in the gene. Here, we aim to describe the spectrum of ATP7B variants and assess their clinical effects in the Han Chinese population.Methods: The ATP7B gene was directly sequenced in 632 unrelated WD patients and 503 unrelated healthy individuals. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Different frequency of variants observed in both cases and controls were tested using Chi-square or Fisher's exact tests.Results: We detected 161 non-synonymous variants in these 632 WD patients, 58 of which were novel. Among these variants, 78, 64, 8, 4, and 7 were classified as 'pathogenic variants', 'likely pathogenic variants', 'variants with uncertain significance', 'likely benign variants', and 'benign variants', respectively. Ninety percent (569/632) of these WD patients can be genetically diagnosed with two or more 'pathogenic' or 'likely pathogenic' variants. The 14 most common disease-causing variants were found at least once in 94% (537/569) of genetically diagnosed patients.Conclusions: These data expand the spectrum of ATP7B variants and facilitate effective screening for ATP7B variants for early diagnosis of WD and development of individualized treatment regimens.