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The Role of Cytokines in Physiopathological processes in the Human Brain.

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Guillaume Sébire
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Preterm birth is defined as any birth occurring before 37 completed weeks of gestation by the World Health Organization. Preterm birth is responsible for perinatal mortality and long-term neurological morbidity. Acute chorioamnionitis is observed in 70% of premature labor and is associated with a heavy burden of multiorgan morbidities in the offspring. Unfortunately, chorioamnionitis is still missing effective biomarkers and early placento- as well as feto-protective and curative treatments. This review summarizes recent advances in the understanding of the underlying mechanisms of chorioamnionitis and subsequent impacts on the pregnancy outcome, both during and beyond gestation. This review also describes relevant and current animal models of chorioamnionitis used to decipher associated mechanisms and develop much needed therapies. Improved knowledge of the pathophysiological mechanisms underpinning chorioamnionitis based on preclinical models is a mandatory step to identify early in utero diagnostic biomarkers and design novel anti-inflammatory interventions to improve both maternal and fetal outcomes.
Guillaume Sébire
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Bacterial infections and hypoxia/ischemia (H/I) are implicated in human neonatal brain damage leading to cerebral palsy (CP). We developed an animal model presenting similar perinatal brain damage by combining bacterial endotoxin and H/I insults. Interleukin (IL)-1beta is a mediator of brain damage and its action(s) is counteracted by its cognate anti-inflammatory IL-1 receptor antagonist (IL-1ra). We tested the hypothesis that the balance between agonist and antagonist in the IL-1 system is shifted towards inflammation in perinatal brains exposed to endotoxin and/or H/I. Lipopolysaccharide (LPS) and/or H/I enhanced both intracerebral IL-1beta mRNA and protein levels, with a maximum increase observed with combined LPS and H/I insults. Conversely, IL-1ra expression was significantly downregulated by LPS, H/I, or both combined, with a maximum magnitude of imbalance between IL-1beta and sIL-1ra noticed with the double hit. The nuclear factor (NF)kappaB component of the signaling pathway activated by IL-1beta-binding to its receptor was activated following exposure to LPS and/or H/I. We show for the first time that, perinatally, bacterial products, H/I, or both combined, induce downregulation in sIL-1ra expression concomitant with upregulation in IL-1beta. The resulting pro-inflammatory orientation in the IL-1/IL-1ra balance might play a role in the initiation of perinatal brain damages.
The brain reacts to injury or disease by cascades of cellular and molecular responses. Evidence suggests that immune-inflammatory processes are key elements in the physiopathological processes associated with brain injury or damage. Cytokines are among major mediators implicated in these processes. Cytokine responses in the initial phase of brain injury might have a role in aggravating brain damage. However, in later stages, these molecular mediators might contribute to recovery or repair. Hemodynamic stabilization and optimalization of oxygen delivery to the brain remain cornerstones in the management of acute brain injury. New approaches might use anticytokine therapy to limit progression and halt or attenuate secondary brain damage. Progress toward such novel neuroprotection strategies, however, awaits better understanding of the optimal timing and dosing of those neuromodulatory therapies and better knowledge of the numerous interactions of those mediators. This also requires understanding of how and when precisely immune mechanisms shift from noxious to protective or restorative actions.
Guillaume Sébire
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Using a model of perinatal brain lesions induced by lipopolysaccharide and hypoxia/ischemia, we hypothesized that interleukin-2 (IL-2), a neurotoxic cytokine, was enhanced within injured brains. We showed that lipopolysaccharide and hypoxia/ischemia enhanced both intracerebral IL-2 mRNA and protein levels, with a maximum increase upon lipopolysaccharide and hypoxia/ischemia. The lack of detectable T lymphocytes suggested the synthesis of IL-2 by neural cells. Lipopolysaccharide and hypoxia triggered IL-2 synthesis by cultured microglia with a peak after exposure to lipopolysaccharide and hypoxia. Double-labeling showed, in vivo and in vitro, that IL-2 immunoreactivity was colocalized with a microglia/macrophage marker. These results disclosed the ability of microglia to produce IL-2 and also suggest the implication of IL-2 in neural cell death triggered by perinatal lipopolysaccharide and hypoxia/ischemia exposures.
Guillaume Sébire
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A critical issue in animal models of perinatal brain injury is to adapt the pertinent pathophysiological scenarios to their corresponding developmental window in order to induce neuropathological and behavioral characteristics reminiscent to perinatal cerebral palsy (CP). A major problem in most of these animal models designed up to now is that they do not present motor deficits characteristic of CP. Using a unique rat paradigm of prenatal inflammation combined to an early postnatal hypoxia-ischemia pertinent to the context of very early premature human newborns, we were interested in finding out if such experimental conditions might reproduce both histological damages and behavioral deficits previously described in the human context. We showed that exposure to lipopolysaccharide (LPS) or hypoxia-ischemia (H/I) induced behavioral alterations in animals subjected to forced motor activity. When both LPS and H/I aggressions were combined, the motor deficits reached their highest intensity and affected both spontaneous and forced motor activities. LPS+H/I-exposed animals also showed extensive bilateral cortical and subcortical lesions of the motor networks affecting the frontal cortices and underlying white matters fascicles, lenticular nuclei and the substantia nigra. These neuropathological lesions and their associated motor behavioral deficits are reminiscent of those observed in very preterm human neonates affected by subsequent CP and validate the value of the present animal model to test new therapeutic strategies which might open horizons for perinatal neuroprotection.
Guillaume Sébire
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Background: AHEM is a rare form of acute disseminated encephalomyelitis (ADEM) characterized by fulminant encephalopathy with hemorrhagic necrosis and most often fatal outcome. Methods: A case report and review of literature. Results: A 6-year-old girl known SCD presented an acute demyelinating syndrome (ADS) with diplopia due to unilateral fourth nerve palsy. She received (20mg/kg/day for 5 days) of IVMP (intravenous methylprednisolone). Two weeks after steroid weaning, she presented right hemiplegia. Brain MRI showed a left frontal necrotico-hemorrhagic lesion and new areas of demyelination. She showed signs of herniation and underwent craniotomy. Investigations ruled out vascular and infectious process in both events. The deterioration stopped concomitantly to the initiation of IVMP. She was discharged with a longer oral wean. Later, she was diagnosed with Crohn’s disease and primary sclerosing cholangitis. We considered AHEM as the most plausible diagnosis based on the clinical and radiological presentation, the preceding ADS, the exclusion of other etiologies, and the response to IVMP including resolution of non-necrotic lesions. Similar - but fatal - AHEM has been reported in 2 SCD patients. Conclusions: In any ADS occurring in the context of SCD and/or auto-immune condition, we recommend to slowly wean steroids, and to closely monitor the patient after weaning to quickly treat any recurrence with IVMP.
Guillaume Sébire
added 3 research items
Inflammatory molecules are promptly upregulated in the fetal environment and postnatally in brain-damaged subjects. Intrauterine infections and inflammation are often associated with asphyxia. This double-hit effect by combined infection or inflammation and hypoxia is therefore a frequent concomitant in neonatal brain damage. Animal models combining hypoxia and infection were recently designed to explore the mechanisms underlying brain damage in such circumstances and to look for possible neuroprotective strategies. Proinflammatory cytokines are thought to be major mediators in brain injury in neonates with perinatal asphyxia, bacterial infection, or both. Cytokines, however, could also have neuroprotective properties. The critical point in the balance between neurodamaging and neuroprotective effects of cytokines has yet to be unraveled. This understanding might help to develop new therapeutic approaches to counteract the inflammatory disequilibrium observed in the pathophysiologic mechanisms associated with brain injury.
The aim of this study was to determine, with the use of a rat model, the expression of tumor necrosis factor (TNF)-alpha, its receptors, and TNF-alpha-converting enzyme in perinatal brain lesions of early premature neonates. Lipopolysaccharide (LPS) was injected intraperitoneally in pregnant rats at the end of gestation. At postnatal day 1, the right carotid artery was ligated and followed by exposure to hypoxia. Forebrains (n = 220) were collected to study the TNF-alpha system. LPS alone or combined with hypoxia-ischemia (HI) led to a slight decrease of intracerebral TNF-alpha, whereas sole HI induced no variation. TNF-alpha-converting enzyme followed the same pattern of expression as TNF-alpha. TNF receptor 1 was up-regulated in forebrains that were submitted to LPS alone or combined with HI. No variation was observed in TNF receptor 2 expression. The minimal expression of the TNF-alpha system that we observed may indicate that this pathway is not central in the pathogenesis of brain lesions in early premature neonates.
Objective The observation of the dramatic response to intravenous immunoglobulin (IVIG) of a child from our center with intractable epilepsy (IE) due to focal cortical dysplasia (FCD) prompted us to perform a meta-analysis on the efficacy of IVIG in this condition. Background FCD is a common cause of IE. Microglial activation and up-regulation of neuroinflammatory pathways have been documented in brain specimen from surgically treated IE/FCD patients. IVIG was used for decades to treat patients with IE, however there is no evidence regarding its efficacy, possibly due to the pathophysiological heterogeneity of patients included in most of the previous studies. Design/Methods A search for studies in patients from 0-18 years was performed in databases. We found 4 observational studies - prospective or retrospective - including FCD patients with IE treated by IVIG. The primary outcome was reduction of seizure frequency by more than 50%. Results A total of 8 patients were included in this meta-analysis. The IVIG doses ranged from 0.2 to 1 g/kg/day repeated from three to six times over 1 to 14 months (median: 5 months). IVIG was associated with reduced seizure frequency in six out of eight patients (p<0.05). Among these six patients, the reduction of seizure frequency lasted for 9 months to 9 years (median: 3.7 years). There were either no or mild adverse effects of IVIG infusion including post-infusion paresthesia (n=1), and transient increase in temperature (n=1). Conclusions Despite obvious limitations, mainly due to small number of patients, and to selection biases, this study suggests that based on the available data IVIG might be effective in the treatment of IE secondary to FCD. Further therapeutic trials are mandatory to further clarify the efficacy of IVIG in this condition.
Guillaume Sébire
added 2 research items
Dysfunction in vital brainstem centers, including those controlling cardiorespiratory- and sleep/arousal pathophysiology, is reported in sudden infant death syndrome (SIDS). Biological mechanisms underlying SIDS, however, remain unclear. Cytokines are inter-cellular signaling chemicals. They can interact with neurotransmitters and might thus modify neural and neuroimmune functions. Cytokines could therefore act as neuromodulators. Interleukin (IL)-2 is a major immune-related cytokine. It has not been previously depicted in vital brainstem centers. We detected intense neuronal IL-2 immune-reactivity in the SIDS brainstem, namely in vital neural centers. This IL-2 overexpression might interfere with neurotransmitters in those critical brainstem centers, causing disturbed homeostatic control of cardiorespiratory and arousal responses, possibly leading to SIDS.
Acute transverse myelitis (ATM) is a potentially devastating immune-mediated disorder of the spinal cord that affects all ages. The onset is often unaccompanied by any identifiable cause, and although the results of immediate treatment may be effective in moderating the damage, long-term sequelae in children are common. Because of its rarity, the causes, optimal treatment, and outcomes for ATM in children are poorly known. Typical ATM is a monofocal and monophasic inflammatory disorder targeting primarily the spinal cord, resulting in motor, sensory, and autonomic dysfunction. Approximately 1400 new cases are diagnosed in the United States each year (1–8 per million inhabitants per year), resulting in a prevalence of around 34,000 people with residual disabilities related to ATM [1,2]. Only about 20% of these patients are diagnosed with ATM before the age of 18 years [3]. Similarly, the recent population-based Canadian Paediatric Surveillance Program evaluated the incidence of ATM at 0.2 per 100,000 children [4]. In this study, incidence did not differ according to season, the female:male ratio was 0.81:1, and occurrence was similar whether ATM started before or after the age of 10 years [4]. When classified as a sub-group of acute disseminated encephalomyelitis (ADEM), ATM accounted for 30% of the topographic spectrum of central nervous system (CNS) involvements [5]. If only a single episode of ATM in childhood was considered, the prevalence was 10 times lower than for pediatric multiple sclerosis (MS).
Guillaume Sébire
added 2 research items
HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61-4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99-222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25-4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00-1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99-4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26-273·85) or CSF oligoclonal bands (6·33, 3·35-11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. Canadian Multiple Sclerosis Scientific Research Foundation.
Guillaume Sébire
added a research item
Solitary tumefactive demyelination is rare in children, and the diagnosis is often conferred after brain biopsy. The authors report 3 children with solitary tumefactive demyelination and provide clinical and paraclinical clues to aid the clinician in reaching a diagnosis using a noninvasive approach.
Guillaume Sébire
added a research item
New therapeutic strategies are needed to protect neonates, especially premature newborns, against brain injury and associated neurobehavioral deficits. The role of pro-inflammatory cytokines, especially IL-1β, in the pathophysiological pathway leading to neonatal brain damage is increasingly recognized and represents an attractive therapeutic target. We investigated the therapeutic potential of postnatal systemic administration of the interleukin (IL)-1 receptor antagonist (IL-1Ra) in an animal model of perinatal brain injury using the insults most common to human neonates, i.e. prenatal exposure to inflammation and/or postnatal hypoxia-ischaemia (HI). We found that postnatal administration of IL-1Ra preserved motor function and exploratory behavior after either prenatal exposure to inflammatory agent lipopolysaccharide (LPS) or postnatal HI insult. The deleterious effect of combined prenatal LPS and postnatal HI on brain development was also alleviated by administration of IL-1Ra, as seen by the protected neural stem cell population, prevention of myelin loss in the internal capsule, decreased gliosis, and decreased neurobehavioral impairment. This study showed the distinct pattern of functional deficits induced by prenatal inflammation as compared to postnatal HI and the therapeutic potential of IL-1Ra administration against neonatal brain injury. Furthermore, our results highlight the potential for postnatal treatment of prenatal inflammatory stressors.
Private Profile
added 2 research items
Cytokines interact with neurotransmitters and modify neuronal and neuroimmune functions. Intense in situ neuronal IL-2 immunoreactivity was detected in vital human brainstem neuronal centers which are principally implicated in cardio-respiratory control mechanisms. These observations were made in critically-ill aging adult as well as in young infant patients dying from various clinico-pathological conditions. We suggested that this in situ cytokine over-expression might tip a delicate balance in molecular interactions in those vital neuro-vegetative centers, causing disturbed homeostatic control of cardio-respiratory functions and impaired arousal responses; we further hypothesized that this IL-2-induced neuro-molecular disequilibrium in the brainstem microenvironment might thus be part of a final common pathway leading to death.
Recent studies reported over-expression of a cytokine (Interleukin (IL)-18) in the serum of sporadic amyotrophic lateral sclerosis (sALS) patients. Here, we report on the first-time detection of in-situ expression of activated IL-18 in the human brain in sALS patients. We also detected cerebral in-situ expression of key-molecules known to be closely related to the molecular network associated with the activation/secretion of IL-18 cytokine, namely, the receptor-interacting serine/threonine-protein kinase 3 (RIPK3 or RIP3), NOD-like receptor pyrin domain containing 3 (NLRP3)-inflammasome, and activated caspase-1. These findings suggest and allow to hypothesize that there might be a role for this cytokine network in molecular mechanisms associated with or implicated in the physiopathology of this neurodegenerative disorder.