Complement-dependent bystander injury to neurons in AQP4-IgG seropositive neuromyelitis optica

Duan, Tianjiao; Smith, Alex J.; Verkman, A. S.

doi:10.1186/s12974-018-1333-z

Cited by 64 publications

(48 citation statements)

References 41 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Complement proteases interact with receptors C3Ra and C5aR, so-termed anaphylatoxin receptors, to form a membrane attack complex that targets cells and causes cell lysis. The same complement attack complex C5b9 is implicated in neuronal damage [183]. The membrane attack complex leads to inflammatory cell chemotaxis, opsonization and cell lysis.…”

Section: Viral Complement Control Proteinsmentioning

confidence: 99%

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Yaron

Zhang

Guo

et al. 2020

JCM

View full text Add to dashboard Cite

Viruses are widely used as a platform for the production of therapeutics. Vaccines containing live, dead and components of viruses, gene therapy vectors and oncolytic viruses are key examples of clinically-approved therapeutic uses for viruses. Despite this, the use of virus-derived proteins as natural sources for immune modulators remains in the early stages of development. Viruses have evolved complex, highly effective approaches for immune evasion. Originally developed for protection against host immune responses, viral immune-modulating proteins are extraordinarily potent, often functioning at picomolar concentrations. These complex viral intracellular parasites have “performed the R&D”, developing highly effective immune evasive strategies over millions of years. These proteins provide a new and natural source for immune-modulating therapeutics, similar in many ways to penicillin being developed from mold or streptokinase from bacteria. Virus-derived serine proteinase inhibitors (serpins), chemokine modulating proteins, complement control, inflammasome inhibition, growth factors (e.g., viral vascular endothelial growth factor) and cytokine mimics (e.g., viral interleukin 10) and/or inhibitors (e.g., tumor necrosis factor) have now been identified that target central immunological response pathways. We review here current development of virus-derived immune-modulating biologics with efficacy demonstrated in pre-clinical or clinical studies, focusing on pox and herpesviruses-derived immune-modulating therapeutics.

show abstract

Section: Viral Complement Control Proteinsmentioning

confidence: 99%

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Yaron

Zhang

Guo

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…A recent study provided evidence that in rat brain and astrocyte‐neuron cocultures, AQP4‐IgG and complement kill neurons through a complement bystander mechanism instead of injuring neurons directly. This proposed mechanism involves the diffusion of activated soluble complement components from complement‐injured astrocytes to nearby cells, leading to early neuronal injury near astrocytes even before gross plasma membrane permeabilization and uptake of the dead cells are observed . Using whole‐genome sequencing and genome‐wide SNP array, a recent genetic study identified three HLA alleles that are highly correlated with AQP4‐IgG‐seropositive patients .…”

Section: Complement‐dependent Cytotoxicitymentioning

confidence: 99%

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder

Chang

2019

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorderNeuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system that preferentially targets the spinal cord and optic nerve. Following the discovery of circulating antibodies against the astrocytic aquaporin 4 (AQP4) water channel protein, recent studies have expanded our knowledge of the unique complexities of the pathogenesis of neuromyelitis optica and its relationship with the immune response. This review describes and summarizes the recent advances in our understanding of the molecular mechanisms underlying neuromyelitis optica disease pathology and examines their potential as therapeutic targets. Additionally, we update the most recent research by proposing major unanswered questions regarding how peripheral AQP4 antibodies are produced and their entry into the central nervous system, the causes of AQP4-IgG-seronegative disease, why peripheral AQP4-expressing organs are spared from damage, and the impact of this disease on pregnancy.

show abstract

“…The complement system plays a pivotal role in the innate immunity of CNS in aging and disease progression (16,23,48). The complement pathway is an important regulatory factor of innate immunity.…”

Section: Introductionmentioning

confidence: 99%

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Huang

Zhang

Lin³

et al. 2019

Brain Pathology

View full text Add to dashboard Cite

Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/β-catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/ kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2 + oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28-day septic rats. The number of PLP + and MBP + cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g-ratios were higher. This was coupled with an increase in number of NG2 + cells and decreased number of CC1 + cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above-mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/β-catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/β-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination. Huang et al C3a induces hypomyelination in the septic brain

show abstract

Complement-dependent bystander injury to neurons in AQP4-IgG seropositive neuromyelitis optica

Cited by 64 publications

References 41 publications

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

Contact Info

Product

Resources

About