Role for Complement in the Development of Seizures following Acute Viral Infection

Libbey, Jane E.; Kirkman, Nikki J.; Wilcox, Karen S.; White, H. Steve; Fujinami, Robert S.

doi:10.1128/jvi.00422-10

Cited by 49 publications

(48 citation statements)

References 47 publications

(70 reference statements)

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“…Complement activation in the CNS is increasingly recognised to be associated with exacerbation and progression of tissue injury in degenerative and inflammatory diseases [21,22]. Dysregulation of the complement system in epilepsy has been observed both in human and animal studies [23][24][25][26][27]. For example, sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioural and electrographic seizures as well as neurotoxicity, suggesting a direct role for the complement system in epileptogenesis [28].…”

Section: Introductionmentioning

confidence: 99%

Complement system biomarkers in epilepsy

Kopczynska

Zelek

Vespa

et al. 2018

Seizure

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Purpose: To explore whether complement dysregulation occurs in a routinely recruited clinical cohort of epilepsy patients, and whether complement biomarkers have potential to be used as markers of disease severity and seizure control. analysis were used to test whether combinations of complement analytes were predictive of epilepsy diagnoses and seizure occurrence. Correlation between number and type of antiepileptic drugs (AED) and complement analytes was also performed. Methods Results:We found: 1) significant differences between all epilepsy patients and controls for TCC (p˂ 0.01) and FH (p˂ 0.01) after performing univariate analysis.2) multivariate analysis combining six analytes (C3, C4, Properdin, FH, C1Inh, Clu) to give a predictive value (area under the curve) of 0.80 for differentiating epilepsy from controls.3) significant differences in complement levels between patients with controlled seizures (n=65) in comparison with uncontrolled seizures (n=87). Levels of iC3b, Properdin and Clu were decreased and levels of C4 were increased in patients with uncontrolled seizures. 4) no correlation was found between the level of complement biomarkers and the number of AEDs taken, but an association between some analyte levels and drug therapy was seen in patients taking sodium valproate, clobazam, and perampanel. Complement biomarkers in EpilepsyPage 3 Conclusion: This study adds to evidence implicating complement in pathogenesis of epilepsy and may allow the development of better therapeutics and prognostic markers in the future.Replication in a larger sample set is needed to validate the findings of the study. Highlights:• Plasma complement biomarkers distinguish epilepsy patients from controls (area under the curve: 0.8).• Plasma complement biomarkers differ between controlled and uncontrolled epilepsy patients.• The data implicate complement dysregulation and inflammation in the pathogenesis of epilepsy.

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Section: Introductionmentioning

confidence: 99%

Complement system biomarkers in epilepsy

Kopczynska

Zelek

Vespa

et al. 2018

Seizure

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“…We previously found that tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) and concomitant inflammatory changes in the brain contribute to the development of acute seizures (5,7). Further, we have shown the importance of complement component 3 (C3) activation in the central nervous system (CNS) for the development of acute seizures (9). C3 activation within the brain in response to viral infection may help drive inflammation and cytokine production, ultimately leading to seizures.…”

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confidence: 99%

“…Our earlier studies concentrated on innate immune contributions to the development of seizures (5,7,9). We previously found that tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) and concomitant inflammatory changes in the brain contribute to the development of acute seizures (5,7).…”

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confidence: 99%

Lack of Correlation of Central Nervous System Inflammation and Neuropathology with the Development of Seizures following Acute Virus Infection

Libbey

Kennett

Wilcox

et al. 2011

J Virol

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“…Our recent work demonstrated an important role for microglia and macrophages in acute seizures (15,16,19). PCR arrays and antibody depletion studies were used to determine that monocyte-derived cells were important in the development of acute seizures (16).…”

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Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Cusick

Libbey

Patel

et al. 2013

J Virol

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101

173

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b Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-␣ and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-␣ than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

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Role for Complement in the Development of Seizures following Acute Viral Infection

Cited by 49 publications

References 47 publications

Complement system biomarkers in epilepsy

Complement system biomarkers in epilepsy

Lack of Correlation of Central Nervous System Inflammation and Neuropathology with the Development of Seizures following Acute Virus Infection

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

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