Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica

Tradtrantip, Lukmanee; Yao, Xiaoming; Su, Tao; Smith, Alex J.; Verkman, A. S.

doi:10.1007/s00401-017-1734-6

Cited by 56 publications

(40 citation statements)

References 40 publications

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“…These findings support the contention that NMOSD can be distinguished from MS by the use of plasma complement biomarkers and that trials of anti-complement therapies may help elucidate the role of complement activation in NMOSD [30]. Recent data support a complement bystander mechanism for the assembly of C5b-9 and for early OLG injury and demyelination in NMO [33]. This publication [33] presents evidence for a complement “bystander mechanism” to account for early OLG injury in NMO, in which the activation complement following aquaporin 4 (AQP4)-IgG binding to astrocyte AQP4 results in the deposition of terminal complement C5b-9 on nearby OLG, and finally in cell lysis.…”

Section: Introductionsupporting

confidence: 72%

“…Recent data support a complement bystander mechanism for the assembly of C5b-9 and for early OLG injury and demyelination in NMO [33]. This publication [33] presents evidence for a complement “bystander mechanism” to account for early OLG injury in NMO, in which the activation complement following aquaporin 4 (AQP4)-IgG binding to astrocyte AQP4 results in the deposition of terminal complement C5b-9 on nearby OLG, and finally in cell lysis.…”

Section: Introductionmentioning

confidence: 89%

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The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

et al. 2017

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Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The complement system has an established role in the pathogenesis of MS, and evidence suggests that its components can be used as biomarkers of disease-state activity and response to treatment in MS. Plasma C4a levels have been found to be significantly elevated in patients with active relapsing-remitting MS (RRMS), as compared to both controls and patients with stable RRMS. C3 levels are also significantly elevated in the cerebrospinal fluid (CSF) of patients with RRMS, and C3 levels are correlated with clinical disability. Furthermore, increased levels of factor H can predict the transition from relapsing to progressive disease, since factor H levels have been found to increase progressively with disease progression over a 2-year period in patients transitioning from RRMS to secondary progressive (SP) MS. In addition, elevations in C3 are seen in primary progressive (PP) MS. Complement components can also differentiate RRMS from neuromyelitis optica. Response gene to complement (RGC)-32, a novel molecule induced by complement activation, is a possible biomarker of relapse and response to glatiramer acetate (GA) therapy, since RGC-32 mRNA expression is significantly decreased during relapse and increased in responders to GA treatment. The predictive accuracy of RGC-32 as a potential biomarker (by ROC analysis) is 90% for detecting relapses and 85% for detecting a response to GA treatment. Thus, complement components can serve as biomarkers of disease activity to differentiate MS subtypes and to measure response to therapy.

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Section: Introductionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 89%

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

et al. 2017

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“…The ensuing BBB breakdown and secretion of pro-inflammatory cytokines and chemokines results in the recruitment of granulocytes, macrophages and eosinophils that further disrupt the BBB and secondarily damage oligodendrocytes (which do not express AQP4), causing demyelination, neuron loss and consequential neurological deficit [1,[11][12][13][14]. Additionally, through 'bystander' mechanisms, APQ4-IgGinduced CDC and ADCC in astrocytes may also damage oligodendrocytes and neurons directly [15,16].…”

Section: Introductionmentioning

confidence: 99%

Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder

Frampton

2020

Drugs

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The terminal complement protein (C5) inhibitor eculizumab (Soliris ® ) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive and (in the EU only) for those with a relapsing course of disease. In the phase III PREVENT trial, eculizumab significantly reduced the risk of adjudicated relapse relative to placebo in patients with AQP4-IgG-seropositive NMOSD, approximately a quarter of whom did not receive concomitant immunosuppressive therapies. The beneficial effect of eculizumab was seen across all patient subgroups analysed and was accompanied by improvements in neurological and functional disability assessments, as well as generic health-related quality of life measures; it was sustained through 4 years of treatment, according to combined data from the PREVENT trial and an interim analysis of its ongoing open-label extension study. The safety profile of eculizumab in AQP4-IgG-seropositive NMOSD was consistent with that seen for the drug in other approved indications. Thus, eculizumab provides an effective, generally well tolerated and approved treatment option for this rare, disabling and potentially life-threatening condition. Eculizumab: clinical considerations in AQP4-IgG-seropositive NMOSDFirst agent to be specifically approved for this rare, disabling and potentially life-threatening condition Reduces relapse risk, including in patients not receiving other immunosuppressive therapies Common adverse events include upper respiratory tract infection, headache, nasopharyngitis and nausea Patients must be vaccinated against meningococcal disease (and administered appropriate prophylactic antibiotics if necessary)

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“…The mechanism of complement bystander killing involves local diffusion of activated, soluble complement proteins following AQP4‐IgG binding to astrocyte AQP4, which leads to deposition of the complement membrane attack complex (MAC) on nearby non‐AQP4‐expressing cells (Figure A). In an initial study, primary cocultures of rat astrocytes and mature oligodendrocytes exposed to AQP4‐IgG and complement showed early death of oligodendrocytes in close contact with astrocytes, which was not seen in pure oligodendrocyte cultures or when astrocytes were damaged by a complement‐independent mechanism . Remarkably, astrocyte–oligodendrocyte cocultures exposed to AQP4‐IgG and complement showed prominent MAC deposition on oligodendrocytes in contact with astrocytes, whereas C1q, the initiating protein in the classical complement pathway, was deposited only on astrocytes.…”

Section: Scientific Advances Utilizing Nmo Animal Modelsmentioning

confidence: 99%

“…Adapted from Ref. 55. B. ADCC bystander killing produced by AQP4‐IgG binding to AQP4 on astrocytes, involving activation of leukocytes (NK cell shown) through Fcγ receptor interaction, and killing of bystander cells by release of toxic granules.…”

Section: Scientific Advances Utilizing Nmo Animal Modelsmentioning

confidence: 99%

Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

Duan

2019

Brain Pathology

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Neuromyelitis optica spectrum disorders (NMOSD) is a heterogeneous group of neuroinflammatory conditions associated with demyelination primarily in spinal cord and optic nerve, and to a lesser extent in brain. Most NMOSD patients are seropositive for IgG autoantibodies against aquaporin-4 (AQP4-IgG), the principal water channel in astrocytes. There has been interest in establishing experimental animal models of seropositive NMOSD (herein referred to as NMO) in order to elucidate NMO pathogenesis mechanisms and to evaluate drug candidates. An important outcome of early NMO animal models was evidence for a pathogenic role of AQP4-IgG. However, available animal models of NMO, based largely on passive transfer to rodents of AQP4-IgG or transfer of AQP4-sensitized T cells, often together with pro-inflammatory maneuvers, only partially recapitulate the clinical and pathological features of human NMO, and are inherently biased toward humoral or cellular immune mechanisms. This review summarizes current progress and shortcomings in experimental animal models of seropositive NMOSD, and opines on the import of advancing animal models.

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Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica

Cited by 56 publications

References 40 publications

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder

Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

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