Notable Increased Cerebrospinal Fluid Levels of Soluble Interleukin-6 Receptors in Neuromyelitis Optica

Wang, Honghao; Wang, Kai; Zhong, Xiaonan; Dai, Yongqiang; Qiu, Wei; Wu, Ai-Min; Hu, Xueqiang

doi:10.1159/000339302

Cited by 38 publications

(21 citation statements)

References 55 publications

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“…In agreement with our previous reports [8,9], we show here that CSF levels of cytokines such as IL-6 and IL-17A, which prefer B-cell activation, survival, and AQP4-IgG production, are elevated in NMOSD patients. Th2-mediated humoral autoimmunity is critical in NMOSD pathogenesis, with eosinophil infiltration in NMOSD lesions being frequently observed [10,11].…”

Section: Discussionsupporting

confidence: 93%

Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder

Wang

Zhou²,

Sun³

et al. 2016

Neuroimmunomodulation

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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.

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Section: Discussionsupporting

confidence: 93%

Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder

Wang

Zhou²,

Sun³

et al. 2016

Neuroimmunomodulation

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“…12,13 BBB dysfunction mediated by AQP4 internalization and the inflammatory phenotype of astrocytes as described here is complement-independent and we speculate that this mechanism is distinct and relates to sublytic lesions in patients. Endothelial cells do not express transmembrane IL-6 binding receptor, but higher levels of sIL-6R in CSF from patients with NMO were also observed, 32 suggesting that abundant intrathecal sIL-6R in patients with NMO is available for complexing with IL-6 in the course of pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Effects of neuromyelitis optica–IgG at the blood–brain barrier in vitro

Takeshita

Obermeier

Cotleur

et al. 2017

Neurol Neuroimmunol Neuroinflamm

142

105

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Objective:To address the hypothesis that physiologic interactions between astrocytes and endothelial cells (EC) at the blood–brain barrier (BBB) are afflicted by pathogenic inflammatory signaling when astrocytes are exposed to aquaporin-4 (AQP4) antibodies present in the immunoglobulin G (IgG) fraction of serum from patients with neuromyelitis optica (NMO), referred to as NMO-IgG.Methods:We established static and flow-based in vitro BBB models incorporating co-cultures of conditionally immortalized human brain microvascular endothelial cells and human astrocyte cell lines with or without AQP4 expression.Results:In astrocyte–EC co-cultures, exposure of astrocytes to NMO-IgG decreased barrier function, induced CCL2 and CXCL8 expression by EC, and promoted leukocyte migration under flow, contingent on astrocyte expression of AQP4. NMO-IgG selectively induced interleukin (IL)-6 production by AQP4-positive astrocytes. When EC were exposed to IL-6, we observed decreased barrier function, increased CCL2 and CXCL8 expression, and enhanced leukocyte transmigration under flow. These effects were reversed after application of IL–6 neutralizing antibody.Conclusions:Our results indicate that NMO-IgG induces IL-6 production by AQP4-positive astrocytes and that IL-6 signaling to EC decreases barrier function, increases chemokine production, and enhances leukocyte transmigration under flow.

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“…Testing for a positive MRZ reaction (defined as intrathecal IgG synthesis against at least two of the three pathogens) can be useful for differentiating between NMO and MS, as it is frequently positive in MS but not in NMO [1, 115]. More recently, concentrations of interleukin-6 (IL-6) and of the soluble IL-6 receptor (sIL-6R) were found to be higher in the CSF of NMO patients than of MS patients, and these may prove to be useful markers for differentiating NMO from other demyelinating diseases [116–118]. Whether measurements of glial fibrillary acidic protein (GFAP) in serum and/or CSF are of differential diagnostic value in NMO remains to be clarified [119–124].…”

Section: Clinical Evaluation When Nmo Is Suspectedmentioning

confidence: 99%

Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS)

et al. 2013

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Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.

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Notable Increased Cerebrospinal Fluid Levels of Soluble Interleukin-6 Receptors in Neuromyelitis Optica

Cited by 38 publications

References 55 publications

Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder

Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder

Effects of neuromyelitis optica–IgG at the blood–brain barrier in vitro

Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS)

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