Complement Biosynthesis in the Central Nervous System

Barnum, Scott R.

doi:10.1177/10454411950060020301

Cited by 187 publications

(107 citation statements)

References 101 publications

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“…Local CNS production of complement components and their contributing role in traumatic brain injury were suggested previously (Barnum, 1995;Kossmann et al, 1997;Rancan et al, 2003). Increased C3 and complement activation have also been detected in models of traumatic injury, endotoxemia, ischemia, viral encephalitis, and in human brain injury patients (Nadeau and Rivest, 2001;Schafer et al, 2000;Speth et al, 2001;Van Beek et al, 2000).…”

Section: Discussionmentioning

confidence: 82%

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist

Sewell

Nacewicz

Liu

et al. 2004

Journal of Neuroimmunology

124

111

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The role of complement components in traumatic brain injury is poorly understood. Here we show that secondary damage after acute cryoinjury is significantly reduced in C3 −/− or C5 −/− mice or in mice treated with C5a receptor antagonist peptides. Injury sizes and neutrophil extravasation were compared. While neutrophil density increased following traumatic brain injury in wild type (C57BL/6) mice, C3-deficient mice demonstrated lower neutrophil extravasation and injury sizes in the brain. RNase protection assay indicated that C3 contributes to the induction of brain inflammatory mediators, MIF, RANTES (CCL5) and MCP-1 (CCL2). Intracranial C3 injection induced neutrophil extravasation in injured brains of C3 −/− mice suggesting locally produced C3 is important in brain inflammation. We show that neutrophil extravasation is significantly reduced in both C5 −/− mice and C5a receptor antagonist treated cryoinjured mice suggesting that one of the possible mechanisms of C3 effect on neutrophil extravasation is mediated via downstream complement activation products such as C5a. Our data indicates that complement inhibitors may ameliorate traumatic brain injury.

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Section: Discussionmentioning

confidence: 82%

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist

Sewell

Nacewicz

Liu

et al. 2004

Journal of Neuroimmunology

124

111

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“…On the other hand, microglia produce a multitude of factors which may be toxic to neurons thereby contributing to cell death in the CNS upon activation (Block and Hong 2005). In addition, glial cells may express most if not all of the activation and regulatory proteins of the complement system (Barnum 1995;Barnum 2002) and microglia up-regulate complement factor C1q in response to transient ischemia in the brain (Schafer et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Rohrer

Demos

Frigg

et al. 2007

Experimental Eye Research

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Misregulation of the innate immune response and other immune-related processes have been suggested to play a critical role in the pathogenesis of a number of different neurodegenerative diseases, including age related macular degeneration. In an animal model for photoreceptor degeneration, several genes of the innate and acquired immune system were found to be differentially regulated in the retina during the degenerative process. In addition to this differential regulation of individual genes, we found that in the rd1 retina a significantly higher number of genes involved in immune-related responses were expressed at any given time during the degenerative period. The peak of immune-related gene expression was at postnatal day 14, coinciding with the peak of photoreceptor apoptosis in the rd1 mouse. We directly tested the potential involvement of acquired and innate immune responses in initiation and progression of photoreceptor degeneration by analyzing double mutant animals. Retinal morphology and photoreceptor apoptosis of rd1 mice on a SCID genetic background (no mature T-and B-cells) or in combination with a RAG-1 (no functional B-and T-cells) or a C1qα (no functional classical complement activation pathway) knockout was followed during the degenerative process using light microscopy or TUNEL staining, respectively. Although complement factor C1qα was highly up-regulated in the rd1 retina concomitantly with the degenerative process, lack of this protein did not protect the rd1 retina. Similarly, retinal degeneration and photoreceptor apoptosis appeared to proceed normally in the rd1 mouse lacking functional Band T-cells. Our results suggest that both, the classical complement system of innate immunity and a functional acquired immune response are not essential for the degenerative process in the rd1 mouse retina.

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“…The quiescent CNS compartment in which NMO-IgG initially encounters AQP4 lacks the C1q component of complement essential for Ig-dependent (classical) pathway activation (18). In that environment, rapid down-regulation of surface M1 would protect the astrocyte from subsequent lysis by its own up-regulated production of complement components (16) (a consequence that we predict would be initiated by surface cross-linking of AQP4).…”

Section: Discussionmentioning

confidence: 99%

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Hinson¹,

Romero²,

Popescu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

291

274

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The astrocytic aquaporin-4 (AQP4) water channel is the target of pathogenic antibodies in a spectrum of relapsing autoimmune inflammatory central nervous system disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG. Neuromyelitis optica is the most severe of these disorders. The two major AQP4 isoforms, M1 and M23, have identical extracellular residues. This report identifies two novel properties of NMO-IgG as determinants of pathogenicity. First, the binding of NMO-IgG to the ectodomain of astrocytic AQP4 has isoform-specific outcomes. M1 is completely internalized, but M23 resists internalization and is aggregated into larger-order orthogonal arrays of particles that activate complement more effectively than M1 when bound by NMO-IgG. Second, NMO-IgG binding to either isoform impairs water flux directly, independently of antigen down-regulation. We identified, in nondestructive central nervous system lesions of two NMO patients, two previously unappreciated histopathological correlates supporting the clinical relevance of our in vitro findings: (i) reactive astrocytes with persistent foci of surface AQP4 and (ii) vacuolation in adjacent myelin consistent with edema. The multiple molecular outcomes identified as a consequence of NMO-IgG interaction with AQP4 plausibly account for the diverse pathological features of NMO: edema, inflammation, demyelination, and necrosis. Differences in the nature and anatomical distribution of NMO lesions, and in the clinical and imaging manifestations of disease documented in pediatric and adult patients, may be influenced by regional and maturational differences in the ratio of M1 to M23 proteins in astrocytic membranes.T he most abundant water channel in the central nervous system (CNS) is aquaporin-4 (AQP4), which is confined to astrocytes and ependyma; is enriched at glial-pial and glialendothelial interfaces; and surrounds nodes of Ranvier and paranodes, adjacent oligodendroglial loops, and synapses (1). In 2005, we identified AQP4 as the target of pathogenic autoantibodies in a spectrum of inflammatory CNS disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG (2, 3). These disorders are now recognized collectively as IgG-mediated autoimmune astrocytopathies. Before discovery of this antibody, NMO spectrum disorders were misclassified as multiple sclerosis variants. NMOIgG is centrally involved in the pathogenesis of NMO spectrum disorders. Its detection predicts frequent relapses that cause cumulative neurological impairment. Lesions characteristically affect the spinal cord and optic nerve, but do not spare the brain. Independent laboratories have demonstrated that NMO-IgG binding initiates AQP4 down-regulation with accompanying endocytosis of its physically associated glutamate transporter, EAAT2, complement activation, impairment of blood-brain barrier integrity, inflammation, and astrocyte injury (4-8). Demyelination is a proposed consequence of both pa...

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Complement Biosynthesis in the Central Nervous System

Cited by 187 publications

References 101 publications

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

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