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Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory astrocytopathy that has both genetic and environmental causes. A growing body of evidence suggests that the presence of several infectious agents correlates with the development of NMOSD. In this review, we summarize studies that either support or present evidence against the hypothesized association between infection and NMOSD. We will also present an overview of potential mechanisms underlying the pathogenesis of NMOSD. Finally, we provide some beneficial properties that infectious elements may have based on “hygiene hypothesis”. It is of great clinical significance to further investigate the complex mechanisms by which infections may affect autoimmune diseases to develop better strategies to prevent and treat them, although so far no causal link between infectious agents and NMOSD has been established. [ABSTRACT FROM AUTHOR]

Summary: Botulinum neurotoxins (BoNTs) can cause paralysis at exceptionally low concentrations and include seven serotypes (BoNT/A-G). The chimeric BoNT/DC toxin has a receptor binding domain similar to the same region in BoNT/C. However, BoNT/DC does not share protein receptor with BoNT/C. Instead, it shares synaptotagmin (Syt) I and II as receptors with BoNT/B, despite their low sequence similarity. Here, we present the crystal structures of the binding domain of BoNT/DC in complex with the recognition domains of its protein receptors, Syt-I and Syt-II. The structures reveal that BoNT/DC possesses a Syt binding site, distinct from the established Syt-II binding site in BoNT/B. Structure-based mutagenesis further shows that hydrophobic interactions play a key role in Syt binding. The structures suggest that the BoNT/DC ganglioside binding sites are independent of the protein receptor binding site. Our results reveal the remarkable versatility in the receptor recognition of the BoNTs. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by axonal destruction and demyelination, which etiology and immunopathogenesis still remains uncertain. Although several lines of evidence show that myelin-reactive T cells play an essential role in the pathogenesis of MS, recent findings have pointed to the relevance of innate immune system such as Toll-like receptors (TLRs). TLRs have been assigned number 1 to 10 in human with different cellular location. Among them, TLR9 is one of the best studied nucleic acid sensing molecules. In this article, we discuss the role of TLR9 and its signaling pathway in the development of MS and present some therapeutic strategies based on in vivo and in vitro findings. [ABSTRACT FROM AUTHOR]

Cystatin is of interest from biochemical and evolutionary prospective, and also has been applied in biotechnology. In this paper, a novel cystatin was found by EST sequence analysis of the cDNA library of Cyanea capillata tentacle. The sequence of a full-length cDNA clone contained an open reading frame encoding a putative 18-residue signal peptide and a mature protein of 113 amino acids, which showed only 26% identities to Family 2 cystatins and had its own characteristic enzyme-binding motifs, Ser97-Trp98, which had not been found in any other known cystatins. Thus, the novel cystatin cloned from jellyfish was designated as cystatin J, which may belong to a new family of cystatin, called Family 4. The mature cystatin J was produced in Escherichia coli as a thioredoxin (Trx) fusion protein using the pET expression system and purified by affinity and cation exchange chromatography. The recombinant cystatin J of approximately Mr = 12,800 displayed an obvious inhibition of papain (Ki value below 0.5 nM), in competition with substrate. Thus, the recombinant cystatin J was a functional cystatin in spite of relatively lower sequence similarity with other cystatins. Activity of the novel cystatin was stable at pH 4–11 at 4 °C, but unstable at neutral pH at >50 °C. [Copyright &y& Elsevier]

Background Immunoglobulin against myelin oligodendrocyte glycoprotein (MOG-IgG) is a potential demyelinating disease-associated autoantibody. Whether clinical features of MOG antibody-associated demyelinating diseases change with age remains unclear. Object To investigate the different clinical features between pediatric-onset and adult-onset MOG-IgG-seropositive patients in a relatively large cohort. Methods A total of 816 consecutive patients with suspected demyelinating disease were prospectively enrolled from three tertiary academic centers in South China from February 2016 to December 2016. Sixteen pediatric-onset cases (≤14 years old) and 34 adult-onset cases (>14 years old) seropositive for MOG-IgG were identified. Differences in clinical features between the two groups were investigated. Results There was a significant difference in the cumulative incidence of first relapse among the two groups ( P  = .008). Cerebral symptoms were significantly higher in pediatric-onset patients than in adult-onset patients, either at disease onset (pediatric-onset group, 10/16(62.5%); adult-onset group, 8/34(23.53%); P  = .007) or throughout the course of disease (pediatric-onset group, 11/16(68.8%); adult-onset group, 10/34(29.4%); P  = .009). Optic nerve symptoms were more common in adult-onset groups, but no significant difference was found between the two groups. A significantly higher rate of pediatric-onset patients (9/16, 56.3%) met the acute disseminated encephalomyelitis criteria compared with adult-onset patients (2/34, 5.9%) ( P  = .0003), and isolated optic neuritis was mainly diagnosed in adult-onset patients (pediatric-onset group, 2/16(12.5%); adult-onset group, 14/34(41.2%); P  = .043). The MOG-IgG titer showed a significant positive correlation with total protein levels in cerebrospinal fluid, but only in adult-onset patients ( r  = 0.95; P  = .0004). On magnetic resonance imaging, extensive white matter lesions were observed in both groups, and the number was much higher in pediatric-onset (7/15, 46.7%) than in adult-onset patients (4/29, 13.8%) ( P  = .043). At the last follow-up, more pediatric-onset patients (10/16, 62.5%) experienced complete recovery (EDSS 0.0 at last follow up) compared with adult-onset patients (9/34, 26.5%) ( P  = .014). Conclusions Distinctive features are present between pediatric-onset and adult-onset patients with MOG-IgG. Further studies are required to determine the different underlying pathogenesis of MOG antibody at different ages. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are a class of proteins that play essential roles in innate and adaptive immune responses. Recently, accumulating evidence has demonstrated that impairments in the TLR signalling pathway contribute to the development and progression of neuroimmune diseases, such as neuromyelitis optica spectrum disorder (NMOSD). However, the cellular and molecular mechanisms are still largely unknown. In this study, we report a novel variant, C52Y, of canopy FGF signalling regulator 3 (CNPY3) from patients with familial NMOSD and demonstrate that this variant shows a stronger interaction with GP96 and TLRs than with wild-type CNPY3. We find that C52Y has dominant negative effects on TLR4 surface expression. Importantly, the TLR4 surface expression level is decreased in RAW264.7 cells infected with the C52Y virus upon LPS stimulation. We further demonstrate that bone marrow-derived macrophages (BMDMs) from CNPY3C52Y/+ transgenic mice secrete less tumour necrosis factor (TNF) and interleukin (IL)-6 than BMDMs from wild-type mice upon stimulation with LPS. These data suggest that impairment of TLR trafficking may contribute to the development of neuroimmune disorders. • A novel rare variant of canopy FGF signalling regulator 3 (CNPY3) was identified from familial NMOSD. • The variant C52Y has dominant negative effects on TLR2 and TLR4 surface expression in vitro. • The variant C52Y impairs the TLR immune response in vitro and in vivo. [ABSTRACT FROM AUTHOR]