Lisheng Peng

Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder

Objective: To screen cytokines and chemokines and determine their dynamic changes in the serum and cerebrospinal fluid (CSF) of patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: Eight NMOSD with seropositive aquaporin-4 antibody (AQP4-IgG) were enrolled, as well as 8 matched patients with multiple sclerosis (MS) and 8 with noninflammatory neurological diseases, who were included as controls. In total, 102 cytokines and 34 chemokines were detected in the CSF and serum of NMOSD patients and controls. Results: CSF interleukin (IL)-17A levels were significantly higher in NMOSD patients in the relapsing phase (27.15 ± 11.33) than in those in the remitting phase (10.04 ± 3.11, p = 0.0017), and patients with MS (14.72 ± 3.20, p = 0.0283) and other controls (10.39 ± 11.38, p = 0.0021). CSF IL-6 levels were higher in the NMOSD patients in the relapsing phase (12.23 ± 3.47) than in those in the remitting phase (5.87 ± 2.78, p = 0.0001), and MS patients (7.38 ± 2.35, p = 0.0033) and other controls (7.50 ± 0.37, p = 0.0043). CSF CCL19 levels were also significantly higher in NMOSD patients in the relapsing phase (35.87 ± 27.07) than in those in the remitting phase (10.71 ± 3.62, p = 0.0215). Serum IL-19 levels were lower in NMOSD patients in the relapsing phase (6.23 ± 1.95) than in those in the remitting phase (10.72 ± 4.46, p = 0.0092). Further, there was a positive, significant correlation between serum IL-9 concentration and the Expanded Disability Status Scale score in the NMOSD patients in the relapsing phase (p = 0.04). Conclusion: In addition to IL-6 and IL-17A, IL-16 and CCL19 act as proinflammatory cytokines/chemokines, while IL-19 plays a protective role in NMOSD pathogenesis.

TLR9 and its signaling pathway in multiple sclerosis

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.

Exacerbation of oxygen-glucose deprivation-induced blood brain barrier disruption: potential pathogenic role of interleukin 9 in ischemic stroke

Interleukin (IL)-9 exerts a variety of functions in autoimmune diseases. However, its role in ischemic brain injury remains unknown. The present study explored the biological effects of IL-9 in ischemic stroke (IS). We recruited 42 patients newly diagnosed with IS and 22 age- and sex-matched healthy controls. The expression levels of IL-9 and percentages of IL-9-producing T cells, including CD3+CD4+IL-9+ and CD3+CD8+IL-9+ cells, were determined in peripheral blood mononuclear cells (PBMCs) obtained from patients and control individuals. We also investigated the effects of IL-9 on the blood-brain barrier (BBB) following oxygen-glucose deprivation (OGD) and the potential downstream signaling pathways. We found that patients with IS had higher IL-9 expression levels and increased percentages of IL-9-producing T cells in their PBMCs. The percentages of CD3+CD4+IL-9+ and CD3+CD8+IL-9+ T cells were positively correlated with the severity of illness. In in vitro experiments using bEnd.3 cells, exogenously administered IL-9 exacerbated the loss of tight junction proteins (TJPs) in cells subjected to OGD plus reoxygenation (RO). This effect was mediated via activation of IL-9 receptors, which increased the level of endothelial nitric oxide synthase (eNOS), as well as through up-regulated phosphorylation of signal transducer and activator of transcription 1 and 3 and down-regulated phosphorylatedxa0protein kinase B/phosphorylated phosphatidylinositol 3-kinase signaling. These results indicate that IL-9 has a destructive effect on the BBB following OGD, at least in part by inducing eNOS production, and raise the possibility of targetting IL-9 for therapeutic intervention in IS.

High salt-induced activation and expression of inflammatory cytokines in cultured astrocytes

ABSTRACT Salt (sodium chloride, NaCl) accumulation in the brain is associated with various diseases of central nervous system (CNS). Activation of astrocytes is an important manifestation of pathophysiological processes in the CNS. However, the direct impact of high salt (HS) environment on astrocytes is unclear. In the current study, we found that high salt treatment can induce activation of astrocytes both in vivo and in vitro, manifested as morphological alteration coupled with increased expression of glial fibrillary acidic protein (GFAP). Additionally, HS upregulated the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and vascular endothelial growth factor (VEGF); however, its effects on transforming growth factor-β (TGF-β) expression were not evident. Furthermore, HS treatment induced increased phosphorylation of signal transducer and activator transcription 3 (STAT 3). Inhibition of Janus kinase 2 (JAK 2) by specific pharmacological antagonists, AG490, attenuated the activation of JAK2/STAT3 pathway and induction of GFAP and other pro-inflammatory factors, respectively. The results suggest that the aforementioned multiple inflammatory cytokines and mediators that may be linked to the HS induced pathogenesis of CNS via the JAK2/STAT3 signaling pathways.

Study of the placentae of patients with neuromyelitis optica spectrum disorder

Previous studies have shown that circulating AQP4-IgG may lead to negative consequences during pregnancy in patients with neuromyelitis optica spectrum disorder (NMOSD). The objective of this study was to explore whether AQP4-IgG influences pregnancy by affecting AQP4 expression and inducing placental inflammation in patients with NMOSD. We prospectively collected clinical data from six pregnant AQP4-IgG-seropositive NMOSD patients and their infants, and investigated AQP4 expression and placental inflammatory infiltration by comparing hematoxylin and eosin and immunohistochemical (AQP1, AQP4, C5b-9, IgG, CD3, CD8, CD20, and CD68) staining results with three normal controls. Four patients were term pregnant and their infants were normal for development, serum AQP4-IgG was positive at the time of birth, and three infants were negative for AQP4-IgG after 3u202fmonths. Two patients underwent induced abortion; one because of NMOSD relapse and another because of fetal malformation. Histological investigation showed normal structure of the chorionic villi, and no significant difference in the intensity of the immunohistochemical staining for AQP1, AQP4, and inflammatory markers in placentae of patients and the controls. Our results showed that there was no significant decrease in placental AQP4 expression, and no obvious placental inflammation or signs of damage in term placentae of NMOSD patients seropositive for AQP4-IgG.

Infections in neuromyelitis optica spectrum disorder

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.

Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Growing evidence has proven that T helper 17 (Th17) cells are one of the regulators of neuroinflammation mechanisms in MS disease. Researchers have demonstrated that some microRNAs (miRNAs) are associated with disease activity and duration, even with different MS patterns. miRNAs regulate CD4+ T cells to differentiate toward various T cell subtypes including Th17u2009cells. In this review, we discuss the possible mechanisms of miRNAs in MS pathophysiology by regulating CD4+ T cell differentiation into Th17u2009cells, and potential miRNA targets for current disease-modifying treatments.

Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis

Cystatin C (CysC) is associated with many neurodegenerative disorders and autoimmune diseases, but its relationship with anti‐N‐Methyl‐D‐aspartate receptor (anti‐NMDAR) encephalitis is unknown.

Risk Factors and Clinical Manifestations of Juxtacortical Small Lesions: A Neuroimaging Study

Background and objective White matter hyperintensities can be easily identified by brain imaging. Juxtacortical small lesion (JCSL) is a special type of white matter lesion, defined as no greater than 5u2009mm in diameter and adjacent to the cerebral cortex in location. We notice lately that JCSLs alone may be associated to various neurological symptoms. Here, we design the present study to determine the risk factors for JCSLs and their clinical manifestations in patients in our neurology clinic. Methods 206 participants suffered from neurological disorders and completed magnetic resonance imaging (MRI) examinations were divided into two groups: patients with JCSLs and patients without lesions on MRI. Meanwhile, 129 age- and sex-matched healthy volunteers were also recruited. Laboratory examinations and the phenotypes and distributions of the symptoms of the three groups were compared. Results The serum levels of apoB and homocysteine (HCY) were independently related to the appearance of JCSLs and HCY level was also associated with the number of JCSLs. Patients with JCSLs might present with headache, insomnia, and/or anxiety/depression, which were related with the anatomical locations of the lesions. Conclusion These data suggest that JCSLs are symptomatic and might in result fromarteriole atherosclerosis, which should raise our attention.

Different features between pediatric-onset and adult-onset patients who are seropositive for MOG-IgG: A multicenter study in South China

BACKGROUNDnImmunoglobulin 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.nnnOBJECTnTo investigate the different clinical features between pediatric-onset and adult-onset MOG-IgG-seropositive patients in a relatively large cohort.nnnMETHODSnA 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 (≤14u202fyears old) and 34 adult-onset cases (>14u202fyears old) seropositive for MOG-IgG were identified. Differences in clinical features between the two groups were investigated.nnnRESULTSnThere was a significant difference in the cumulative incidence of first relapse among the two groups (Pu202f=u202f.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%); Pu202f=u202f.007) or throughout the course of disease (pediatric-onset group, 11/16(68.8%); adult-onset group, 10/34(29.4%); Pu202f=u202f.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%) (Pu202f=u202f.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%); Pu202f=u202f.043). The MOG-IgG titer showed a significant positive correlation with total protein levels in cerebrospinal fluid, but only in adult-onset patients (ru202f=u202f0.95; Pu202f=u202f.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%) (Pu202f=u202f.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%) (Pu202f=u202f.014).nnnCONCLUSIONSnDistinctive 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.