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BACKGROUND: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. DESIGN / METHODS: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. RESULTS: KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. CONCLUSION: Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.
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Doenças Autoimunes do Sistema Nervoso , Autoimunidade , Encefalite , Doença de Hashimoto , Animais , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos Retrospectivos , Autoanticorpos , Convulsões , Mamíferos , Canal de Potássio Kv1.2RESUMO
Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Predisposição Genética para Doença/genética , Proteoma/genética , Antígenos de Histocompatibilidade Classe II , Antígenos HLA , Haplótipos , Alelos , Autoanticorpos , Cadeias HLA-DRB1/genéticaRESUMO
OBJECTIVE: This study was undertaken to quantify epilepsy-related costs of illness (COI) in Germany and identify cost-driving factors. METHODS: COI were calculated among adults with epilepsy of different etiologies and severities. Multiple regression analysis was applied to determine any epilepsy-related and sociodemographic factors that serve as cost-driving factors. RESULTS: In total, 486 patients were included, with a mean age of 40.5 ± 15.5 years (range = 18-83 years, 58.2% women). Mean 3-month COI were estimated at 4911, 2782, and 2598 for focal, genetic generalized, and unclassified epilepsy, respectively. The mean COI for patients with drug-refractory epilepsy (DRE; 7850) were higher than those for patients with non-DRE (4720), patients with occasional seizures (3596), or patients with seizures in remission for >1 year (2409). Identified cost-driving factors for total COI included relevant disability (unstandardized regression coefficient b = 2218), poorer education (b = 2114), living alone (b = 2612), DRE (b = 1831), and frequent seizures (b = 2385). Younger age groups of 18-24 years (b = -2945) and 25-34 years (b = -1418) were found to have lower overall expenditures. A relevant disability (b = 441), DRE (b = 1253), frequent seizures (b = 735), and the need for specialized daycare (b = 749) were associated with higher direct COI, and poorer education (b = 1969), living alone (b = 2612), the presence of a relevant disability (b = 1809), DRE (b = 1831), and frequent seizures (b = 2385) were associated with higher indirect COI. SIGNIFICANCE: This analysis provides up-to-date COI data for use in further health economics analyses, highlighting the high economic impacts associated with disease severity, disability, and disease-related loss of productivity among adult patients with epilepsy. The identified cost drivers could be used as therapeutic and socioeconomic targets for future cost-containment strategies.
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Epilepsia Resistente a Medicamentos , Epilepsia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Psicossociais da Doença , Estudos Transversais , Epilepsia/tratamento farmacológico , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/tratamento farmacológico , Adulto JovemRESUMO
OBJECTIVE: Patients with temporal lobe epilepsy caused by autoimmune limbic encephalitis (AI-TLE) clinically resemble patients with temporal lobe epilepsy with non-autoimmune etiologies (NAI-TLE) but have a different prognosis and require specific adjusted therapies. The objective of this study was to investigate whether patients with these forms of TLE can be discerned by means of neuropsychological assessment. METHODS: Data from 103 patients with TLE (nâ¯=â¯39 with AI-TLE and nâ¯=â¯64 with NAI-TLE, including nâ¯=â¯39 with hippocampal sclerosis [HS] and nâ¯=â¯25 with low-grade epilepsy-associated tumors [LEAT]) and 25 healthy controls who underwent comprehensive neuropsychological assessments were analyzed retrospectively. The neuropsychological characteristics (mean z-scores) were compared between groups using one-way ANOVA, independent-samples t-tests, and discriminant function analysis (DFA). RESULTS: The groups of patients with TLE showed significantly lower performance in attentional, visuospatial, verbal memory, and nonverbal memory functions compared to the healthy controls. Solely in the domain of executive functions, patients with AI-TLE showed significantly lower performance compared to patients with NAI-TLE regarding cognitive flexibility (pâ¯=â¯0.002) and verbal fluency (pâ¯=â¯0.018). Moreover, the DFA identified cognitive flexibility to be most appropriate to differentiate between patients with AI-TLE and patients with HS. Group membership was correctly predicted through neuropsychological assessment alone in 66.7% of the patients using cross-validation. SIGNIFICANCE: We were able to identify specific neuropsychological features in our sample of patients with AI-TLE. While all groups of patients with TLE showed the expected TLE-typical memory impairments, significant differences between patients with AI-TLE and NAI-TLE were present only in the cognitive domain of executive functions. This finding facilitates the choice of suitable psychometric tests in clinical routine and, thus, the clinical differential diagnosis between these entities.
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INTRODUCTION: Patient education is a central component of quality care. Enhancing patient knowledge can improve patients' quality of life and facilitate successful self-management. We sought to identify patients' knowledge levels and knowledge gaps regarding epilepsy-related risks, morbidity, and mortality. METHODS: Adult patients with epilepsy presenting to the university hospitals in Frankfurt, Greifswald, and Marburg between February 2018 and May 2020 were asked to participate in this questionnaire-based study. RESULTS: A total of 238 patients (52% women), with a mean age of 39.2â¯years (range: 18-77â¯years), participated in this study. Spontaneously, the majority of patients (51.3%) named driving a car, and other traffic-related accidents as possible causes of morbidity and mortality, and 23.9% of patients reported various causes of premature death, such as suffocation, drowning, and respiratory or cardiac arrest due to seizures. Falls due to epilepsy (19.7%) and injuries in general (17.6%) were named as further causes of morbidity and mortality. The vast majority were aware that alcohol (87.4%), sleep deprivation (86.6%), and risky activities in daily life (80.3%) increased the risk of seizure occurrence or increased morbidity and mortality. Regarding overall mortality, 52.1% thought that people with epilepsy were at greater risk of premature death, whereas 46.2% denied this fact to be true. Only 29.4% were aware of status epilepticus, and 27.3% were aware of sudden unexpected death in epilepsy (SUDEP). Driving ability, working ability, and seizure risk were named as major or moderate concerns among patients, but the risk of premature mortality was not a major concern. One-quarter of all patients (26.9%) indicated that they were not counseled about any risk factors or causes of morbidity or mortality by their physicians. CONCLUSIONS: A lack of knowledge concerning premature mortality, SUDEP, and status epilepticus exists among adult patients with epilepsy. A substantial number of patients indicated that these issues were not discussed adequately by their physicians.
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INTRODUCTION: When the SARS-CoV-2 pandemic reached Europe in 2020, a German governmental order forced clinics to immediately suspend elective care, causing a problem for patients with chronic illnesses such as epilepsy. Here, we report the experience of one clinic that converted its outpatient care from personal appointments to telemedicine services. METHODS: Documentations of telephone contacts and telemedicine consultations at the Epilepsy Center Frankfurt Rhine-Main were recorded in detail between March and May 2020 and analyzed for acceptance, feasibility, and satisfaction of the conversion from personal to telemedicine appointments from both patients' and medical professionals' perspectives. RESULTS: Telephone contacts for 272 patients (mean age: 38.7â¯years, range: 17-79â¯years, 55.5% female) were analyzed. Patient-rated medical needs were either very urgent (6.6%, nâ¯=â¯18), urgent (23.5%, nâ¯=â¯64), less urgent (29.8%, nâ¯=â¯81), or nonurgent (39.3%, nâ¯=â¯107). Outpatient service cancelations resulted in a lack of understanding (9.6%, nâ¯=â¯26) or anger and aggression (2.9%, nâ¯=â¯8) in a minority of patients, while 88.6% (nâ¯=â¯241) reacted with understanding, or relief (3.3%, nâ¯=â¯9). Telemedicine consultations rather than a postponed face-to-face visit were requested by 109 patients (40.1%), and these requests were significantly associated with subjective threat by SARS-CoV-2 (pâ¯=â¯0.004), urgent or very urgent medical needs (pâ¯=â¯0.004), and female gender (pâ¯=â¯0.024). Telemedicine satisfaction by patients and physicians was high. Overall, 9.2% (nâ¯=â¯10) of patients reported general supply problems due to SARS-CoV-2, and 28.4% (nâ¯=â¯31) reported epilepsy-specific problems, most frequently related to prescriptions, or supply problems for antiseizure drugs (ASDs; 22.9%, nâ¯=â¯25). CONCLUSION: Understanding and acceptance of elective ambulatory visit cancelations and the conversion to telemedicine consultations was high during the coronavirus disease 2019 (COVID-19) lockdown. Patients who engaged in telemedicine consultations were highly satisfied, supporting the feasibility and potential of telemedicine during the COVID-19 pandemic and beyond.
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Instituições de Assistência Ambulatorial/organização & administração , Assistência Ambulatorial/organização & administração , Infecções por Coronavirus/prevenção & controle , Epilepsia/terapia , Controle de Infecções/organização & administração , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Telemedicina/organização & administração , Adolescente , Adulto , Idoso , Assistência Ambulatorial/métodos , Agendamento de Consultas , Betacoronavirus , COVID-19 , Infecções por Coronavirus/epidemiologia , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/epidemiologia , Encaminhamento e Consulta , SARS-CoV-2 , Telefone , Adulto JovemRESUMO
In an aging society, epilepsy in old age will become a more and more relevant disease. The diagnosis is often difficult because of the frequent occurrence of focal seizures in old age, which are easily overlooked. The diagnosis is often delayed, particularly in older patients who, for example also suffer from dementia. The causes of the epilepsy can be manifold in the aging brain. Another challenge for neurologists is the medicinal treatment of geriatric epilepsy, as many anticonvulsive drugs can be associated with serious side effects and interactions. The evidence for the effectiveness and tolerability of anticonvulsive drugs in old age is insufficient, so that the choice of drugs must be made on an individual basis. Status epilepticus is a neurological emergency, which occurs not only more frequently in older than in younger persons but is also associated with a higher mortality, so that immediate diagnosis and adequate treatment is necessary.
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Anticonvulsivantes , Epilepsia , Idoso , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Encéfalo/patologia , Demência/complicações , Epilepsia/complicações , Epilepsia/tratamento farmacológico , HumanosRESUMO
Autoantibodies against contactin-associated protein 2 (Caspr2) not only induce limbic autoimmune encephalitis but are also associated with pain conditions. Here, we analyzed clinical data on pain in a large cohort of patients included into the German Network for Research in Autoimmune Encephalitis. Out of 102 patients in our cohort, pain was a frequent symptom (36% of all patients), often severe (63.6% of the patients with pain) and/or even the major symptom (55.6% of the patients with pain). Pain phenotypes differed between patients. Cluster analysis revealed two major phenotypes including mostly distal-symmetric burning pain and widespread pain with myalgia and cramps. Almost all patients had IgG4 autoantibodies and some additional IgG1, 2, and/or 3 autoantibodies, but IgG subclasses, titers, and presence or absence of intrathecal synthesis were not associated with the occurrence of pain. However, certain pre-existing risk factors for chronic pain like diabetes mellitus, peripheral neuropathy, or preexisting chronic back pain tended to occur more frequently in patients with anti-Caspr2 autoantibodies and pain. Our data show that pain is a relevant symptom in patients with anti-Caspr2 autoantibodies and support the idea of decreased algesic thresholds leading to pain. Testing for anti-Caspr2 autoantibodies needs to be considered in patients with various pain phenotypes.
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Autoanticorpos , Proteínas de Membrana , Proteínas do Tecido Nervoso , Fenótipo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Coortes , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Dor/imunologia , Dor/etiologia , Dor/sangueRESUMO
BACKGROUND: Assessment of quality of life (QoL) has become an important indicator for chronic neurological diseases. While these conditions often limit personal independence and autonomy, they are also associated with treatment-related problems and reduced life expectancy. Epilepsy has a tremendous impact on the QoL of patients and their families, which is often underestimated by practitioners. The aim of this work was to identify relevant factors affecting QoL in adults with epilepsy. METHODS: This cross-sectional, multicenter study was conducted at four specialized epilepsy centers in Germany. Patients diagnosed with epilepsy completed a standardized questionnaire focusing on QoL and aspects of healthcare in epilepsy. Univariate regression analyses and pairwise comparisons were performed to identify variables of decreased QoL represented by the overall Quality of Life in Epilepsy Inventory (QOLIE-31) score. The variables were then considered in a multivariate regression analysis after multicollinearity analysis. RESULTS: Complete datasets for the QOLIE-31 were available for 476 patients (279 [58.6%] female, 197 [41.4%] male, mean age 40.3 years [range 18-83 years]). Multivariate regression analysis revealed significant associations between low QoL and a high score on the Liverpool Adverse Events Profile (LAEP; beta=-0.28, p < 0.001), Hospital Anxiety and Depression Scale - depression subscale (HADS-D; beta=-0.27, p < 0.001), Neurological Disorders Depression Inventory in Epilepsy (NDDI-E; beta=-0.19, p < 0.001), revised Epilepsy Stigma Scale (beta=-0.09, p = 0.027), or Seizure Worry Scale (beta=-0.18, p < 0.001) and high seizure frequency (beta = 0.14, p < 0.001). CONCLUSION: Epilepsy patients had reduced QoL, with a variety of associated factors. In addition to disease severity, as measured by seizure frequency, the patient's tolerability of anti-seizure medications and the presence of depression, stigma, and worry about new seizures were strongly associated with poor QoL. Diagnosed comorbid depression was underrepresented in the cohort; therefore, therapeutic decisions should always consider individual psychobehavioral and disease-specific aspects. Signs of drug-related adverse events, depression, fear, or stigmatization should be actively sought to ensure that patients receive personalized and optimized treatment. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00022024; Universal Trial Number: U1111-1252-5331).
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Predicting survival in patients with post-hypoxic encephalopathy (HE) after cardiopulmonary resuscitation is a challenging aspect of modern neurocritical care. Here, continuous electroencephalography (cEEG) has been established as the gold standard for neurophysiological outcome prediction. Unfortunately, cEEG is not comprehensively available, especially in rural regions and developing countries. The objective of this monocentric study was to investigate the predictive properties of repetitive EEGs (rEEGs) with respect to 12-month survival based on data for 199 adult patients with HE, using log-rank and multivariate Cox regression analysis (MCRA). A total number of 59 patients (29.6%) received more than one EEG during the first 14 days of acute neurocritical care. These patients were analyzed for the presence of and changes in specific EEG patterns that have been shown to be associated with favorable or poor outcomes in HE. Based on MCRA, an initially normal amplitude with secondary low-voltage EEG remained as the only significant predictor for an unfavorable outcome, whereas all other relevant parameters identified by univariate analysis remained non-significant in the model. In conclusion, rEEG during early neurocritical care may help to assess the prognosis of HE patients if cEEG is not available.
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BACKGROUND: Inflammation, particularly cytokine release, contributes to epileptogenesis by influencing the cerebral tissue remodeling and neuronal excitability that occurs after a precipitating epileptogenic insult. While several cytokines have been explored in this process, release kinetics are less well investigated. Determining the time course of cytokine release in the epileptogenic zone is necessary for precisely timed preventive or therapeutic anti-inflammatory interventions. METHODS: Hippocampal extracellular levels of six cytokines and chemokines (IL-1ß, IL-6, IL-10, CCL2, CCL3, and CCL5) were quantified at various time points during epileptogenesis in a rat model of mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) using microdialysis (MD). RESULTS: The analysis of microdialysates demonstrated consistent elevation at all time points during epileptogenesis for IL-1ß and IL-10. IL-10 release was maximal on day 1, IL-1ß release peaked at day 8. No correlation between local hippocampal IL-1ß concentrations and IL-1ß blood levels was found. CONCLUSION: The release kinetics of IL-1ß are consistent with its established pro-epileptogenic properties, while the kinetics of IL-10 suggest a counter-regulatory effect. This proof-of-concept study demonstrates the feasibility of intraindividual longitudinal monitoring of hippocampal molecular inflammatory processes via repetitive MD over several weeks and sheds light on the kinetics of hippocampal cytokine release during epileptogenesis.
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BACKGROUND: Cytotoxic T lymphocytes take on a leading role in many immune-related diseases. They function as key effector immune cells fighting cancer cells, but they are also considerably involved in autoimmune diseases. Common to both situations, CD8+ T cells need to adapt their metabolism and effector function to the harsh and nutrient-deprived conditions of the disease-associated microenvironment. METHODS: We used an in vitro starvation as well as rapamycin treatment protocol mimicking nutrient deprivation to generate CD8Low versus CD8High T cells and performed FACS-Sorting followed by transcriptomic profiling of the cytotoxic T cell subsets. Prominent markers identified in the CD8Low versus the CD8High T cells were then used to investigate the presence of these cell subsets in immune-related human diseases. Employing cancer tissue microarrays and PhenOptics multispectral imaging as well as flow cytometry, we studied these CD8+ T cell subsets in cancer and relapsing-remitting multiple sclerosis patients. RESULTS: Starvation induced a decreased expression of CD8, yielding a CD8Low T cell subpopulation with an altered transcriptomic signature and reduced effector function. CD8Low T cell showed enhanced ST2L and IL6ST (CD130) expression compared to CD8High T cells which expressed elevated KLRD1 (CD94) and granzyme B levels within the tumour microenvironment (TME). Spatial analysis revealed the presence of CD8High T cells in close proximity to tumour cells, while the CD8Low T cells resided at the tumour boundaries. Importantly, the number of tumour-infiltrating CD8Low T lymphocytes correlated with a poor prognosis as well as with enhanced cancer progression in human mammary carcinoma. We also found a reduced frequency of CD8Low T lymphocytes in a cohort of relapse (disease active) multiple sclerosis patients compared to healthy subjects during immune cell starvation in vitro. CONCLUSIONS: In summary, our data show that functionally distinct cytotoxic T lymphocytes can be identified based on their expression of CD8. Indicating a more general role in CD8 T cell immunity, these cells may play opposing roles in the TME, and also in the pathophysiology of autoimmune diseases such as multiple sclerosis.
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Doenças Autoimunes , Esclerose Múltipla , Humanos , Linfócitos T Citotóxicos , Esclerose Múltipla/genética , Linfócitos T CD8-Positivos , Recidiva Local de Neoplasia , Microambiente Tumoral/genéticaRESUMO
Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA)A receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs-such as intranasal administration-have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE.
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Benzodiazepinas , Estado Epiléptico , Anticonvulsivantes/efeitos adversos , Benzodiazepinas/efeitos adversos , Clonazepam/uso terapêutico , Diazepam/uso terapêutico , Humanos , Lorazepam/uso terapêutico , Midazolam , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
G-protein-coupled receptors (GPCRs), especially chemokine receptors, play a central role in the regulation of T cell migration. Various GPCRs are upregulated in activated CD4 T cells, including P2Y10, a putative lysophospholipid receptor that is officially still considered an orphan GPCR, i.e., a receptor with unknown endogenous ligand. Here we show that in mice lacking P2Y10 in the CD4 T cell compartment, the severity of experimental autoimmune encephalomyelitis and cutaneous contact hypersensitivity is reduced. P2Y10-deficient CD4 T cells show normal activation, proliferation and differentiation, but reduced chemokine-induced migration, polarization, and RhoA activation upon in vitro stimulation. Mechanistically, CD4 T cells release the putative P2Y10 ligands lysophosphatidylserine and ATP upon chemokine exposure, and these mediators induce P2Y10-dependent RhoA activation in an autocrine/paracrine fashion. ATP degradation impairs RhoA activation and migration in control CD4 T cells, but not in P2Y10-deficient CD4 T cells. Importantly, the P2Y10 pathway appears to be conserved in human T cells. Taken together, P2Y10 mediates RhoA activation in CD4 T cells in response to auto-/paracrine-acting mediators such as LysoPS and ATP, thereby facilitating chemokine-induced migration and, consecutively, T cell-mediated diseases.
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Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Receptores Purinérgicos P2Y/metabolismo , Receptores Purinérgicos P2/metabolismo , Trifosfato de Adenosina/metabolismo , Adulto , Idoso , Animais , Comunicação Autócrina/imunologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Quimiocinas/metabolismo , Quimiotaxia de Leucócito/imunologia , Encefalomielite Autoimune Experimental/sangue , Feminino , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Humanos , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Comunicação Parácrina/imunologia , Cultura Primária de Células , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2Y/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis. METHODS: We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes. RESULTS: We identified 2 independent risk loci harboring genome-wide significant variants (p < 5 × 10-8, OR ≥ 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes. DISCUSSION: This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.