Altered vaccine-induced immunity in children with Dravet syndrome.

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Posted on 27/8/2019, 22:33

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Epilepsia. 2018 Apr;59(4):e45-e50. doi: 10.1111/epi.14038. Epub 2018 Mar 7.
Altered vaccine-induced immunity in children with Dravet syndrome.
Auvin S1,2, Jeljeli M3, Desnous B1,2, Soussi-Yanicostas N1, Dournaud P1, Sterkers G3.
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1PROTECT, INSERM, Paris Diderot University, Sorbonne Paris Cité, Paris, France.2APHP, Pediatric Neurology Department, Robert-Debré University Hospital, Paris, France.3APHP, Clinical Immunology Department, Robert-Debré University Hospital, Paris, France.
Abstract

Dravet syndrome (DS) is a refractory epileptic syndrome. Vaccination is the trigger of the first seizure in about 50% of cases. Fever remains a trigger of seizures during the course of the disease. We compared ex vivo cytokine responses to a combined aluminium-adjuvanted vaccine of children with DS to sex- and age-matched heathy children. Using ex vivo cytokine responses of peripheral-blood mononuclear cells and monocytes, we found that vaccine responsiveness is biased toward a proinflammatory profile in DS with a M1 phenotype of monocytes. We provide new insight into immune mechanisms associated with DS that might guide research for the development of new immunotherapeutic agents in this epilepsy syndrome.
www.ncbi.nlm.nih.gov/pubmed/29512885
ATTENZIONE ARTICOLO TRADOTTO CON https://www.translatetheweb.com/?from=&to=...bmed%2F29512885
Immunità alterata indotta dal vaccino nei bambini con sindrome di Dravet.
Auvin S1,2, Jeljeli M3, Desnoo B1,2, Soussi-Yanicostas N1, Dournaud P1, Sterkers G3.
Informazioni sull'autore
1PROTECT, INSERM, Università Diderot di Parigi, Sorbona Paris Cité, Parigi, Francia.2APHP, Dipartimento di Neurologia Pediatrica, Ospedale Universitario Robert-Debré, Parigi, Francia.3APHP, Reparto di Immunologia Clinica, Ospedale Universitario Robert-Debré, Parigi, Francia.
astratto
La sindrome di Dravet (DS) è una sindrome epilettica refrattaria. La vaccinazione è l'innesco del primo sequestro nel circa il 50% dei casi. La febbre rimane un trigger di convulsioni durante il decorso della malattia. Abbiamo confrontato le risposte delle citochine ex vivo a un vaccino combinato a base di alluminio di bambini con DS con bambini con sesso e di arieda corrispondenti all'età. Utilizzando le risposte di citochine ex vivo di cellule mononucleari e monociti del sangue periferico, abbiamo scoperto che la reattività del vaccino è orientata verso un profilo proinfiammatorio in DS con un fenotipo M1 di monociti. Forniamo nuove informazioni sui meccanismi immunitari associati alla DS che potrebbero guidare la ricerca per lo sviluppo di nuovi agenti immunoterapeutici in questa sindrome dell'epilessia.
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Posted on 27/8/2019, 22:36

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Altered vaccine‐induced immunity in children with Dravet syndrome
Summary
Dravet syndrome (DS) is a refractory epileptic syndrome. Vaccination is the trigger of the first seizure in about 50% of cases. Fever remains a trigger of seizures during the course of the disease. We compared ex vivo cytokine responses to a combined aluminium‐adjuvanted vaccine of children with DS to sex‐ and age‐matched heathy children. Using ex vivo cytokine responses of peripheral‐blood mononuclear cells and monocytes, we found that vaccine responsiveness is biased toward a proinflammatory profile in DS with a M1 phenotype of monocytes. We provide new insight into immune mechanisms associated with DS that might guide research for the development of new immunotherapeutic agents in this epilepsy syndrome.
1 INTRODUCTION
Dravet syndrome (DS) is a refractory epileptic syndrome starting before the age of 1. The first seizure is typically a febrile status epilepticus. Shortly thereafter other seizures occur leading to diagnosis in an otherwise normal infant. Later, myoclonus, atypical absences, and partial seizures are observed. Developmental delay becomes apparent within the second year of life. Mutations in the voltage‐gated sodium channel gene SCN1A are the cause of DS in 70%‐80% of the patients. Fever is the most common trigger of seizures during the course of the disease.1, 2 Vaccination is the trigger of the first seizure in about 50% of cases.3, 4 However, precipitation of seizure onset by immunization does not affect the course of the disease.5

A growing body of evidence implicates a link between inflammation and epileptic disorders.6, 7 Most studies analyzed the baseline levels of proinflammatory cytokines in tissue, sera, or cerebrospinal fluid (CSF).6, 8 A restricted number of studies evaluated cytokine levels following ex vivo stimulation of immune cells with nonspecific activators.9 Ex vivo responses to vaccine antigens reflecting in vivo priming with vaccines avoid seizure‐induced cofounding factors. Despite evidence for vaccine‐related seizure onset in DS, nothing is known about cytokine response to vaccines in these patients. In DS, experimental studies have shown that the SCN1A mutation results in a modified neuronal excitability, which is sensitive to the increase in body temperature.10 Whether inflammation contributes to seizure occurrence has not yet been investigated. Here, we explored if vaccinated patients with DS might be prone to an altered cytokine response to the vaccine.

2 POPULATIONS AND METHODS

We compared ex vivo cytokine responses to a combined aluminium‐adjuvanted vaccine (diphtheria‐tetanus‐pertussis‐poliomyelitis‐haemophilus‐B hepatitis; Infanrix‐hexa, GlaxoSmithKline Biologicals, Brentford, UK) of children with DS (Table S1) to sex‐ and age‐matched heathy children (HC). Inclusion criteria were completion of vaccinations and availability of residual cryopreserved peripheral‐blood mononuclear cells (PBMCs) from blood samples collected for standard care in stable clinical conditions (DS) at least 15 days from any fever/infection episode or for biological investigations in healthy bone marrow donors before the gift (HC). The study was approved by our hospital's institutional review board (Robert‐Debré Hospital, Paris, France). Informed consent was obtained from the parents of all children. Table S2 reports the main characteristics of DS.

Cryopreserved PBMCs from DS and HC were simultaneously thawed and seeded (106/mL) into Roswell Park Memorial Institute culture medium supplemented with pooled human sera (10%), glutamine (1%), and antibiotics. Cell suspensions were cultured at 37°C, in 5% CO2 atmosphere, overnight with the vaccine at a predetermined optimal dilution (10%) or left unstimulated. Cytokines were measured blindly in the supernatants by a multiplexed‐cytokine assay using the 17‐Plex human kit (Bio‐Rad, Laboratories Inc., Marne‐La‐coquette, France) as described previously.11 Supernatants from the 2 culture conditions were analyzed for each child. Sufficient amounts of PBMCs were available to isolate monocytes in 5 DS patients and their respective controls. PBMCs (2 × 106) from each individual were distributed into culture medium (1 mL) supplemented with 10% fetal calf serum, and monocytes were allowed to adhere to plastic by incubation of the cell suspension in flat‐bottom culture walls for 2 hours at 37°C. After careful removal of nonadherent cells, culture medium was added (1 mL) to monocytes and cultures were processed as described earlier for PBMCs.

Data were analyzed using the Prism 5 software (GraphPad, San Diego, CA, USA). Cytokine/chemokine releases are expressed as median and range in Table 1. Vaccine‐specific cytokine/chemokine releases are expressed as mean ± standard error of the mean (SEM) in Figure 1. Statistical analysis was performed using Mann‐Whitney test. P values are considered statistically significant when P < .05.

Table 1. Cytokine/chemokine releases (median (range)) by peripheral blood mononuclear cells (PBMCs) and separated monocytes from healthy children and patients with Dravet syndrome (pg/mL)
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