Th17 cell-mediated immune response in a subpopulation of dogs with idiopathic epilepsy.

BACKGROUND: Canine idiopathic epilepsy (IE) is a common neurological disease with severe impact on the owner´s and the dog's quality of life. A subpopulation of dogs with IE does not respond to antiseizure drugs (non-responder). Th17 cells (T helper cells) and their proinflammatory Interleukin-17 (IL-17) are part of the immune system and previous studies showed their involvement in the pathogenesis of several autoimmune diseases. Non-responder might have an abnormal immune response against structures of the central nervous system. To discover a new aetiology of canine IE and thereby optimising the therapy of intractable IE, this prospective study aimed to investigate Th17 cells and IL-17 in dogs with IE. The underlying hypothesis was that in some dogs with IE a Th17 cell-mediated immune response could be detectable. METHODS: 57 dogs with IE and 10 healthy dogs (control group, C) were enrolled in the study. EDTA blood was taken to measure Th17 cells by flow cytometry. IL-17 was measured in 35 cerebrospinal fluid (CSF) and 33 serum samples using an enzyme-linked immunosorbent assay (ELISA). It was investigated whether there was a significant increase of stimulated Th17 cells in blood samples or of IL-17 in serum and CSF samples of dogs with IE in comparison to C. Correlations between the amount of Th17 cells/µL or IL-17 and different clinical parameters e.g. seizure frequency, seizure type, seizure severity or treatment response were evaluated. Additionally, Th17 cells/µL were randomly controlled of 17 dogs with IE and were examined for changes over time and in relation to treatment response. RESULTS: Ten dogs with IE had strongly elevated stimulated Th17 cells/µL within the blood (>100 Th17 cells/µL). A slight positive correlation between stimulated Th17 cells/µL and seizure severity (p = 0.046; rSpear = 0.27) was proven in these dogs. In addition, 4/10 dogs with elevated Th17 levels experienced cluster seizures and status epilepticus in comparison to 9% of the dogs with non-elevated Th17 levels (<100 Th17 cells/µL). Dogs with IE had significantly higher IL-17 values in CSF and serum samples compared to C (p<0.001; p<0.002; respectively). CONCLUSION: In single dogs with IE, strongly increased amounts of Th17 cells were detectable and dogs with elevated Th17 cells seemed to have a greater risk for experiencing a combination of cluster seizures and status epilepticus. Therefore, an underlying Th17-cell mediated immune response was suspected and hence anti-inflammatory drugs could be indicated in these single cases with intractable epilepsy.

Immunogenetic protective factors in Genetic Generalized Epilepsy.

BACKGROUND: Genetic Generalized Epilepsies (GGEs) are a heterogeneous group of syndromes characterized by generalized seizure activity that affects both hemispheres, with mainly genetic causes. Neuroinflammation has been established as an important mechanism in epileptogenesis. The ability to develop an appropriated immune response is strongly determined by immunogenetic factors. In this setting, our aim was to evaluate potential associations between GGEs and immunogenetic factors. METHODS: The rs16944 (IL-1ß -511 T > C) polymorphism and the HLA-DRB1 locus were genotyped in a Portuguese GGE population. Association with two clinicopathological features, photosensitivity and refractoriness, was investigated. This case-control study included 323 GGE patients (187 F, 136 M, 34.0 ± 13.9 years of age), 145 of which with JME diagnosis (88 F, 57 M, 34.1 ± 14.0 years), and 282 healthy controls (174 F, 108 M, 37.7 ± 11.6 years). RESULTS: Decreased frequencies of the HLA-DRB1*09 and DRB1*13 alleles were observed in the GGE population. HLA-DRB1*07 frequency was increased in JME. Rs16944 allelic frequencies were similar between patients and controls. CONCLUSIONS: These results, not entirely consistent with previous reports, suggest that HLA molecules may have a complex role in epileptogenesis.

Generalized epilepsies: immunologic and inflammatory mechanisms.

This article focuses on the inflammatory processes in patients with generalized epilepsies. We specifically review the data regarding West, Lennox-Gastaut, and Landau-Kleffner syndromes as they have generalized clinical or electroencephalogram features. There is substantial evidence for a pathogenic implication of immune mechanisms in these epilepsies. Animal models and abnormalities in both cellular and humoral immunity support this hypothesis. They also appear to be particularly responsive to immunomodulatory therapies, which has raised the speculation that an unbalanced immune system may play an important role in the pathophysiology of these epileptic syndromes. In this article, we discuss clinical and experimental data that support the potential implication of immune mediated inflammation and immune response in the mechanism of these entities.

Spontaneous improvement of intractable epileptic seizures following acute viral infections.

In general, epileptic seizures become more serious following infections. However, transient and permanent improvement of epileptic seizures has been observed following acute viral infections, without a recent change in anti-epileptic therapy. Questionnaires were sent to 73 institutions, throughout Japan, where pediatric neurologists care for children with epilepsy to characterize this phenomenon through clinician survey. Completed surveys were received from 11 institutions, and 21 cases were selected for the study. The age of the patients were 6 months to 17 years. The West syndrome or epilepsy subsequent to West syndrome cases were 16 out of 21. Two cases of symptomatic generalized epilepsy and one case each of symptomatic partial epilepsy, continuous spike-waves of slow sleep and severe myoclonic epilepsy in infancy were also reported. These seizures disappeared within 2 weeks subsequent to viral infections such as, exanthema subitum, rotavirus colitis, measles and mumps. The disappearance of intractable epileptic seizures following acute viral infections might be related to the inflammatory processes or the increased levels of antibodies after viral infections.

Immunoreactivity of sera to a peptide derived from the serotonin 5-HT1A receptor in a group of children with developmental disorders: possible role in non-autistic epilepsy.

The presence of autoantibodies against the serotoninergic 5-HT1A receptor has been reported in serum from an autistic child using radioligand binding studies. It is now well established that, in cardiovascular diseases with an autoimmune component, patients present in their sera autoantibodies directed against the second extracellular loop of some G-protein coupled membrane receptors. We thus investigated by an enzyme-immunoassay method the presence of anti-5-HT1A receptor antibodies in sera of children with developmental disorders using synthetic peptides corresponding to the first and the second extracellular loops of this receptor. The population of children with developmental disorders was divided in autistic children with or without EEG abnormalities, and in non-autistic children with or without EEG abnormalities. We found that 6 out of 10 sera of non-autistic children with an abnormal EEG recognized the second extracellular loop of the 5-HT1A receptor. This is significantly higher than the other groups of children with developmental disorders or a healthy control group. These observations support the existence of an autoimmune component in epilepsy.

[Clinico-biochemical study in epilepsy]. / Kliniko-biokhimicheskoe issledovanie pri épilepsii.

Diagnostic opportunities of the test of paroxysmal activity (TPA) were examined in 253 epileptic patients of different age and duration of disease. It was established that the changes of autoantibodies (aAB) titers in the control group were about 64-110% (mean value 85%). Meanwhile in epileptic patients there was elevation of the same indices 2.1 times (182%). The correlation was observed between the levels of aAB titers and duration of the disease, frequency and character of paroxysmal disorders. The conclusion was made that TPA may be used quite successfully in diagnosis of epilepsy, especially in difficult cases. The level of accumulation of aABs in blood of patients with the fits may be used as new immunological index which may facilitate essentially objective of diagnosis of epilepsy.

Immune globulin treatment in intractable epilepsy of childhood.

Six children suffering from epilepsy refractory to conventional anti-convulsive therapy were treated with high-dose intravenous immune globulin (IVIG) (200 mg/kg three times per week, repeated after three weeks). In four children clinical and EEG findings markedly improved, while a partial response was noted in the other cases. These results suggest that high-dose intravenous immune globulin may have a beneficial effect in the treatment of intractable epilepsy.

[The immunopathology and immunogenetics of some forms of pediatric epilepsy]. / Immunopatologiia i immunogenetika nekotorykh form detskoi épilepsii.

52 patients with primary and 42 with secondary generalized epilepsy at the age of 2-16 years were examined. In all the patients blood content of T- and B-lymphocytes as well as of their subpopulations (T-helpers, T-suppressors) was estimated with the use of monoclonal antibodies. Immunogenetic studies of allogenic lymphocytes were also performed in mixed lymphocyte cultures for proband and mother. There was an increase of CD4/CD8 ratio (T-helper/T-suppressor) as well as elevation of B-lymphocytes level in patients with secondary generalized form of epilepsy. A positive reaction of allogenic lymphocytes from mother and child in mixed cultures was observed in 46 patients with primary generalized epilepsy (88.5%), in 16 cases with progredient disease. In secondary generalized form of epilepsy it occurred in 7 cases only (16.7%). In 28 cases of epilepsy with progredient course not only antiepileptic drugs but also immunomodulators were used with positive effect in 14 patients.