Cerebrospinal fluid C9 in demyelinating disease

Compston, D. A. S.; Morgan, B. Paul; Oleesky, D A; Fifield, R.; Campbell, Anthony K.

doi:10.1212/wnl.36.11.1503

Cited by 46 publications

(18 citation statements)

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“…The concentrations of SC5b-9 were significantly correlated with neurological disability measured by expanded disability scale system (EDSS) and MBP levels in spinal fluid (55). Low levels of C9 in the spinal fluid have been correlated with MS disease activity, indicating C9 consumption during active demyelination (56,57). These findings suggest that complement activation and C5b-9 assembly take place in the spinal fluid when there is breakdown in the blood brain barrier.…”

Section: Complement Activation and Multiple Sclerosismentioning

confidence: 85%

C5b‐9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection

2005

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Complement system activation plays an important role in innate and acquired immunity. Activation of complement leads to the formation of C5b-9 terminal complex. While C5b-9 can promote cell lysis, sublytic assembly of C5b-9 on plasma membranes induces cell cycle activation and survival. Multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE) are inflammatory demyelinating diseases of the central nervous system (CNS) mediated by activated lymphocytes, macrophages/microglia and the complement system. Complement activation may contribute to the pathogenesis of these diseases through its dual role: the ability of activated terminal complex C5b-9 to promote demyelination and the capacity of sublytic C5b-9 to protect oligodendrocytes (OLG) from apoptosis. By inducing EAE in C5-deficient mice, we showed that complement C5 promotes remyelination and protects oligodendrocytes from apoptotic cell death. These findings indicate that activation of complement C5b-9 plays a pro-inflammatory role in the acute phase of the disease, but may also be neuroprotective during the chronic phase of the disease.

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Section: Complement Activation and Multiple Sclerosismentioning

confidence: 85%

C5b‐9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection

2005

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“…A role for the complement system in MS has been established and is reviewed in Ingram 2010 [3]. Evidence implicating complement in MS came from studies measuring complement proteins in MS CNS tissue, plasma and CSF [4–6]. Numerous immunohistochemistry studies described the presence of complement proteins in and around areas of pathology in MS WM; however, analyses were generally limited to one or a few complement proteins and small numbers of cases [7–13].…”

Section: Introductionmentioning

confidence: 99%

Complement activation in multiple sclerosis plaques: an immunohistochemical analysis

Ingram¹,

Loveless

Howell

et al. 2014

acta neuropathol commun

142

120

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IntroductionInflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. This study aims to bring clarity to these questions.ResultsWe describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease. Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation. Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue. C1q staining was present in all plaques suggesting a dominant role for the classical pathway. Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons.ConclusionsThe findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-53) contains supplementary material, which is available to authorized users.

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“…IL2 and its receptor; IL7 and its receptor) were identified. Complement, a key component of the innate immune system, has an established role in the pathogenesis of MS (for review see Ingram et al 9 ); however, despite evidence from pathological, 10,11 functional 12,13 and animal 14 models, the extent and precise nature of complement activation in MS, and its contribution to disease phenotype and long-term outcome, remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Systemic complement profiling in multiple sclerosis as a biomarker of disease state

et al. 2012

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Background:There is increasing evidence of significant and dynamic systemic activation and upregulation of complement in multiple sclerosis (MS), which may contribute to disease pathogenesis.Objective:We aimed to investigate the pathological role of complement in MS and the potential role for complement profiling as a biomarker of MS disease state.Methods:Key components of the classical, alternative and terminal pathways of complement were measured in plasma and cerebrospinal fluid (CSF) of patients with MS in different clinical phases of disease and in matched controls.Results:Increased plasma levels of C3 (p<0.003), C4 (p<0.001), C4a (p<0.001), C1 inhibitor (p<0.001), and factor H (p<0.001), and reduced levels of C9 (p<0.001) were observed in MS patients compared with controls. Combined profiling of these analytes produced a statistical model with a predictive value of 97% for MS and 73% for clinical relapse when combined with selected demographic data. CSF-plasma correlations suggested that source of synthesis of these components was both systemic and central.Conclusion:These data provide further evidence of alterations in both local and systemic expression and activation of complement in MS and suggest that complement profiling may be informative as a biomarker of MS disease, although further work is needed to determine its use in distinguishing MS from its differential.

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Cerebrospinal fluid C9 in demyelinating disease

Cited by 46 publications

References 0 publications

C5b‐9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection

C5b‐9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection

Complement activation in multiple sclerosis plaques: an immunohistochemical analysis

Systemic complement profiling in multiple sclerosis as a biomarker of disease state

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