Master of Science / Department of Diagnostic Medicine/Pathobiology / Natalia Cernicchiaro / Japanese encephalitis virus (JEV) is a virus of the Flavivirus genus that may result in encephalitis in vertebrate hosts. This vector-borne zoonosis occurs in Eastern and Southeastern Asia and an intentional or inadvertent introduction into the United States (US) would lead to important public health and economic consequences. The objective of this study was to gather, appraise, and synthesize primary research literature to identify and quantify vector and host competence for JEV, using a systematic review-metaanalysis (SR-MA) approach. After defining the research question, we performed a search in selected electronic databases. The title and abstract of the identified articles were screened for relevance using a defined set of exclusion and inclusion criteria, and relevant articles were subjected to a risk of bias assessment followed by data extraction. Random-effects subgroup meta-analysis models were fitted by species (mosquito or vertebrate host species) to estimate pooled summary measures as well as to compute the variance between studies. Meta-regression models were fitted to assess the association between different predictors and the outcomes of interest and to identify sources of heterogeneity among studies. Data were extracted from 171 peer-reviewed articles. Most studies were observational (59.06%) and reported vector competence (60.2%). The outcome measures reported pertained to transmission efficiency, host preference, and vector susceptibility to infection within vector competence; and susceptibility to infection within host competence. All outcome measures (JEV proportion of infection in vectors and hosts from observational studies; and JEV infection, dissemination, and transmission rates in vectors from experimental studies) had high heterogeneity. Mosquito species, diagnostic method, country, and capture method represented important sources of heterogeneity associated with the proportion of JEV infection in vectors; host species and region were considered sources of heterogeneity associated with the proportion of JEV infection in hosts; and diagnostic and mosquito capture methods were deemed important contributors of heterogeneity for the minimum infection rate (MIR) outcome. Mosquito species and administration route represented the main sources of heterogeneity associated with JEV infection rate in vectors. Quantitative estimates resulting from this SR-MA will be inputted into risk assessment models to evaluate risks associated with the introduction of JEV in the US.

No description available.

Tick-borne encephalitis risk assessment based on classification of vegetation from remote sensing data Abstract The main aim of this thesis has been to find out how to classify various categories of forest vegetation with a different risk of exposure to the tick-borne encephalitis based on the Landsat imagery. The legend used here is derived from the one used in the projects by Daniel, Kolář, Zeman (1995) and Daniel, Kolář, Beneš (1999) but has been reduced to only five classses with no overlaps in their definitions (I. coniferous stands, II. mixed stands, III. young deciduous stands and stand ecotones with a highly heterogeneous structure, IV. deciduous stands with a homogeneous structure, V. deciduous stands with a heterogeneous structure). The supervised classification with the Maximum Likelihood Classifier has been used on the Landsat imagery from various seasons. Difficulties concerned with the presence of clouds and varying Sun elevation across the imagery had to be adressed in the course of the work. The training sites and the control points have been defined by the field research and interpretation of the relevant orthophotomaps and Landsat imagery in 5-4-3 RGB composite. The mask of the forest has been created on the ZABAGED data basis. The time horizon of 2006 - 2010 has been the primary focus....

Neben dem bekannten Tropismus des Masernvirus für CD150-positive aktivierte Zellen des Immunsystems, spielt der Endothelzelltropismus für die akute Masernviruserkrankung einschließlich ihren nachfolgenden Komplikationen eine wichtige pathogene Rolle. Die Infektion der Endothelzellen steht in Zusammenhang mit dem Auftreten des MV-Exanthems. Es ist auch möglich, dass die „Akute Enzephalitits“ und der Viruseintritt ins zentrale Nervensystem wie im Falle der subakuten sklerosierenden Panenzephalitis (SSPE) durch Endothelzellinfektion vermittelt wird. Ziel der Arbeit war herauszufinden, wie und ob das MV Endothelzellbarrieren überwinden kann mittels Transport infizierter Leukozyten oder durch Infektion von EZs mit basolateraler Virusfreisetzung. Es wurde untersucht, ob die Fähigkeit von primären humanen T- Zellen durch polarisierte Zellschichten von „human brain microvascular endothelial cells“ (HBMECs) zu wandern durch die Infektion beeinflusst wird. Die Fähigkeit von infizierten Lymphozyten durch die Poren der Filter zu wandern war teilweise beeinträchtigt, jedoch war das Ergebnis statistisch nicht signifikant. Im Gegensatz dazu war die Fähigkeit der Zellen durch Endothelzellbarrieren zu wandern drastisch reduziert. Nach Infektion adhärierten die Leukozyten stärker auf den Endothelzellen. Bei dieser Adhäsion von PBMCs an Endothelzellen kam es trotz Infektion zur Ausbildung von sogenannten „transmigratory cups“ oder docking- Strukturen. Dieser enge Zell-Zell-Kontakt hatte zur Folge, dass die MV-Infektion vom Lymphozyten auf die Endothelzelle übertragen wurde. Die MV-Hüllproteine wurden auf der apikalen und basolateralen Seite infizierter Endothelzellen exprimiert wie anhand von Aufnahmen mit dem konfokalen Mikroskop am Beispiel des H-Proteins gezeigt werden konnte. Titrationen ergaben, dass das Virus auf beiden Seiten der Zellen freigesetzt wurde. Desweiteren wurde bestätigt, dass auch für polarisierte Endothelzellen die auf Tyrosin basierenden Transportsignale verantwortlich sind für die basolaterale Virusfreisetzung. Die Daten unterstützen die Hypothese, dass das Virus mit Hilfe der Infektion und der bipolaren Virusfreisetzung über Endothelzellbarrieren / In addition to the known tropism of measles virus (MV) for CD150-positive activated cells of the immune system, its endothelial cell tropism plays an important pathogenic role during acute measles and the following complications. The infection of endothelial cells is associated with the rash. It is also possible that endothelial infection mediates the acute encephalitis and viral entry in the central nervous system in cases of subacute sclerosing panencephalitis (SSPE). The aim of this investigation was to find out, how and if at all MV is able to overcome endothelial barriers via transport of infected leukocytes or infection of endothelial cells with basolateral virus release. We analysed if the capacity of primary human T cells to transmigrate through “human brain microvascular endothelial cells” (HBMECs) is influenced by the infection. The capacity of infected lymphocytes to migrated through filter pores was partially reduced but the results were statistacally not significant. In contrast the capacity to migrate through endothelial barriers was drastically reduced. The attachment of PBMCs to the endothelial monolayer was increased once the cells were infected. During this attachment normal so called “transmigratory cups” or docking-structures were formed, although the leukocytes were infected. As a consequence of this close cell-cell-contact the MV-infection was transferred to the endothelial cells. The MV envelope proteins were expressed on the apical and basolateral side as could be shown on pictures taken with the confocal microscope. Titrations showed that the virus was released on both sides of the cells. Moreover it could be demonstrated, that tyrosine-based sorting signals were responsible for basolateral virus release from polarized endothelial cells. These data support the hypothesis, that the virus can cross endothelial barriers by infection of the endothelium and by bipolar virus release.

Pela grande produção de equinos no Brasil, perdas econômicas causadas por mortalidade ou perdas reprodutivas neste plantel simbolizam grandes prejuízos, tanto na produção para o mercado interno quanto para a exportação. Necessário se faz o acompanhamento de enfermidades que afetam o sistema nervoso desta espécie. Agentes virais e bacterianos causando problemas neurológicos e reprodutivos, nesta espécie, são amplamente estudados no Brasil. Pouco se conhece sobre o papel dos protozoários da família Sarcocystidae em determinar sinais clínicos neurológicos e reprodutivos. O objetivo deste estudo é identificar protozoários formadores de cistos, com potencial para causar doença neurológica e reprodutiva, em amostras de tecido encefálico de equinos com diagnóstico clínico de encefalopatias e de fetos abortados. Foram analisadas 165 amostras de SNC e 21 amostras de feto abortado de equinos, enviados ao Instituto Biológico para realização de exames laboratoriais. As amostras foram submetidas à nested PCR-ITS1 com primers direcionados às regiões conservadas do lócus ribossômico de protozoários da família Sarcocystidae. Após confirmação do resultado, os produtos de amplificação foram sequenciados para a determinação das sequências ITS1, discriminatórias entre as diversas espécies de protozoários da família Sarcocystidae. Das 15 amostras positivas (duas de feto abortado e 13 de SNC de equino com sintomatologia neurológica) em 14 o protozoário envolvido foi Toxoplasma gondii e em uma delas Sarcocystis neurona. Para Neospora spp não foi encontrada nenhuma amostra positiva. Nas amostras de SNC também foi realizado o exame histopatológico para análise das alterações histopatológicas. Todos os materiais positivos para S. neurona ou T. gondii apresentaram algum tipo de alteração (infiltrado inflamatório meníngeo/neurópilo), congestão/edema, hemorragia, necrose, malácia, indicando a ação de patógeno neurotrópico. A frequência de amostras positivas pela nested PCR-ITS1, para a presença de protozoários foi 7,9% (13/165) e de abortamento por protozário (T. gondii) foi de 9,5% (2/21). Sarcocystis neurona foi encontrado em apenas uma amostra de SNC. Pelos resultados é possível inferir que a ocorrência de mieloencefalite e abortamentos causados pelos protozoários Sarcocistideos em equinos pode revelar-se maior do que se considera atualmente, caso o estudo do SNC nesta espécie seja executado rotineiramente para a conclusão de casos clínicos. / Regarding the importance of equine husbandry in Brazil, economic losses due to mortality or reproductive failures within these herds could mean significant problems for national and international trade market. Therefore, it is necessary to research for diseases affecting the central nervous system (CNS). In Brazil, a broad amount of studies has been made concerning viral and bacterial neurvous and/or reproductive diseases. Although, little is stablished about the rule of protozoan from Sarcocystidae family leading to that kind of symptomatology. This study aimed to identify cystic protozoa which are potentially pathogenic for reproductive and neural tracts using samples from equine encephalic tissue of animals diagnosed with clinical encephalopathy and aborted fetuses. 165 samples of equine CNS and 21 aborted fetuses of this same species were analyzed in the Instituto Biológico facilities. They were submitted to nested PCR-ITS1 using primer to conserved regions from ribosomal locus of Sarcocystidae family protozoa. After confirmatory results, amplified samples were submitted to sequencing for determination of ITS-1 sequences, which are discriminatory concerning the several species of protozoan from Sarcocystidae family. Among the 15 positive identified samples (2 from aborted fetuses and 13 from adult equine CNS), in 14 were detected Toxoplasma gondii as the protozoa involved with the symptoms and in one of them Sarcocystis neurona was detected. None was found positive for Neospora spp. All samples collected were examined using histopathological techniques looking for disease findings. Positive samples for S. neurona or T. gondii showed varied types of alteration (neutrophilic/meningeal inflammatory infiltrate), congestion/edema, hemorrhage, necrosis and malacia, indicating that they were affected by a neurotropic pathogen. The frequency of parasitic equine encephalitis using nested PCR-ITS1 was 7,9% (13/165) and abortion by protozoa (T. gondii was 9,5% (2/21). The incidence of these diseases may be higher than registered nowadays if equine CNS could be analyzed during clinical diagnosis routine for case conclusion.

As junções comunicantes são estruturas celulares que permitem o trânsito de moléculas entre as células, desempenhando funções de sinalização e transporte intercelular. São formadas por proteínas denominadas conexinas e representam estruturas-chave no funcionamento de tecidos altamente complexos e integrados, como o sistema nervoso central (SNC). O presente estudo avalia os efeitos da deleção da conexina 32 (Cx32) na inflamação e regeneração/cicatrização do SNC após 1, 3, 7, 10 e 20 dias pós-injeção intracerebral de brometo de etídio em camundongos deletados para Cx32 e camundongos normais. Para tanto, quantificou-se a expressão dos genes para fator de necrose tumoral alfa (TNFα), fator de crescimento transformador beta 1 (TGFβ), metaloproteinase 3 (MMP3), metaloproteinase 9 (MMP9) e inibidor tecidual de metaloproteinases 1 (TIMP1), através de PCR em tempo real. Os resultados indicam variáveis diferenças no padrão de expressão, incluindo variação na expressão de todos os genes pesquisados no período de 3 dias pós-injeção, ápice dos mecanismos de inflamação aguda. Estes resultados sugerem que a conexina 32 pode desempenhar funções importantes na sinalização molecular do processo inflamatório e regenerativo/cicatricial do sistema nervoso central. / Gap junctions are cellular structures that allow transit of molecules between cells, performing intercellular signaling and transportation. They are formed by proteins denominated connexins and represent key structures in highly complex and integrated tissues, such as the central nervous system (CNS). The present study evaluates the effects of connexin 32 (Cx32) deletion upon CNS inflammation and egeneration/cicatrization after 1, 3, 7, 10 and 20 days after intracerebral injection of ethidium bromide in Cx32 Knock Out and normal mice. To accomplish so, Real Time PCR gene expression quantification was performed uppon tumour necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFβ), metalloproteinase 3 (MMP3), metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinases 1(TIMP1) genes. Results indicate variable differences in the expression pattern, including difference in expression of all evaluated genes in the 3 days after injection period, apex of the acute inflammation mechanisms. These results suggest that Cx32 may perform important functions on molecular inflammatory and regenerative/cicatrization signalling in the CNS.

Pela grande produção de equinos no Brasil, perdas econômicas causadas por mortalidade ou perdas reprodutivas neste plantel simbolizam grandes prejuízos, tanto na produção para o mercado interno quanto para a exportação. Necessário se faz o acompanhamento de enfermidades que afetam o sistema nervoso desta espécie. Agentes virais e bacterianos causando problemas neurológicos e reprodutivos, nesta espécie, são amplamente estudados no Brasil. Pouco se conhece sobre o papel dos protozoários da família Sarcocystidae em determinar sinais clínicos neurológicos e reprodutivos. O objetivo deste estudo é identificar protozoários formadores de cistos, com potencial para causar doença neurológica e reprodutiva, em amostras de tecido encefálico de equinos com diagnóstico clínico de encefalopatias e de fetos abortados. Foram analisadas 165 amostras de SNC e 21 amostras de feto abortado de equinos, enviados ao Instituto Biológico para realização de exames laboratoriais. As amostras foram submetidas à nested PCR-ITS1 com primers direcionados às regiões conservadas do lócus ribossômico de protozoários da família Sarcocystidae. Após confirmação do resultado, os produtos de amplificação foram sequenciados para a determinação das sequências ITS1, discriminatórias entre as diversas espécies de protozoários da família Sarcocystidae. Das 15 amostras positivas (duas de feto abortado e 13 de SNC de equino com sintomatologia neurológica) em 14 o protozoário envolvido foi Toxoplasma gondii e em uma delas Sarcocystis neurona. Para Neospora spp não foi encontrada nenhuma amostra positiva. Nas amostras de SNC também foi realizado o exame histopatológico para análise das alterações histopatológicas. Todos os materiais positivos para S. neurona ou T. gondii apresentaram algum tipo de alteração (infiltrado inflamatório meníngeo/neurópilo), congestão/edema, hemorragia, necrose, malácia, indicando a ação de patógeno neurotrópico. A frequência de amostras positivas pela nested PCR-ITS1, para a presença de protozoários foi 7,9% (13/165) e de abortamento por protozário (T. gondii) foi de 9,5% (2/21). Sarcocystis neurona foi encontrado em apenas uma amostra de SNC. Pelos resultados é possível inferir que a ocorrência de mieloencefalite e abortamentos causados pelos protozoários Sarcocistideos em equinos pode revelar-se maior do que se considera atualmente, caso o estudo do SNC nesta espécie seja executado rotineiramente para a conclusão de casos clínicos. / Regarding the importance of equine husbandry in Brazil, economic losses due to mortality or reproductive failures within these herds could mean significant problems for national and international trade market. Therefore, it is necessary to research for diseases affecting the central nervous system (CNS). In Brazil, a broad amount of studies has been made concerning viral and bacterial neurvous and/or reproductive diseases. Although, little is stablished about the rule of protozoan from Sarcocystidae family leading to that kind of symptomatology. This study aimed to identify cystic protozoa which are potentially pathogenic for reproductive and neural tracts using samples from equine encephalic tissue of animals diagnosed with clinical encephalopathy and aborted fetuses. 165 samples of equine CNS and 21 aborted fetuses of this same species were analyzed in the Instituto Biológico facilities. They were submitted to nested PCR-ITS1 using primer to conserved regions from ribosomal locus of Sarcocystidae family protozoa. After confirmatory results, amplified samples were submitted to sequencing for determination of ITS-1 sequences, which are discriminatory concerning the several species of protozoan from Sarcocystidae family. Among the 15 positive identified samples (2 from aborted fetuses and 13 from adult equine CNS), in 14 were detected Toxoplasma gondii as the protozoa involved with the symptoms and in one of them Sarcocystis neurona was detected. None was found positive for Neospora spp. All samples collected were examined using histopathological techniques looking for disease findings. Positive samples for S. neurona or T. gondii showed varied types of alteration (neutrophilic/meningeal inflammatory infiltrate), congestion/edema, hemorrhage, necrosis and malacia, indicating that they were affected by a neurotropic pathogen. The frequency of parasitic equine encephalitis using nested PCR-ITS1 was 7,9% (13/165) and abortion by protozoa (T. gondii was 9,5% (2/21). The incidence of these diseases may be higher than registered nowadays if equine CNS could be analyzed during clinical diagnosis routine for case conclusion.

As junções comunicantes são estruturas celulares que permitem o trânsito de moléculas entre as células, desempenhando funções de sinalização e transporte intercelular. São formadas por proteínas denominadas conexinas e representam estruturas-chave no funcionamento de tecidos altamente complexos e integrados, como o sistema nervoso central (SNC). O presente estudo avalia os efeitos da deleção da conexina 32 (Cx32) na inflamação e regeneração/cicatrização do SNC após 1, 3, 7, 10 e 20 dias pós-injeção intracerebral de brometo de etídio em camundongos deletados para Cx32 e camundongos normais. Para tanto, quantificou-se a expressão dos genes para fator de necrose tumoral alfa (TNFα), fator de crescimento transformador beta 1 (TGFβ), metaloproteinase 3 (MMP3), metaloproteinase 9 (MMP9) e inibidor tecidual de metaloproteinases 1 (TIMP1), através de PCR em tempo real. Os resultados indicam variáveis diferenças no padrão de expressão, incluindo variação na expressão de todos os genes pesquisados no período de 3 dias pós-injeção, ápice dos mecanismos de inflamação aguda. Estes resultados sugerem que a conexina 32 pode desempenhar funções importantes na sinalização molecular do processo inflamatório e regenerativo/cicatricial do sistema nervoso central. / Gap junctions are cellular structures that allow transit of molecules between cells, performing intercellular signaling and transportation. They are formed by proteins denominated connexins and represent key structures in highly complex and integrated tissues, such as the central nervous system (CNS). The present study evaluates the effects of connexin 32 (Cx32) deletion upon CNS inflammation and egeneration/cicatrization after 1, 3, 7, 10 and 20 days after intracerebral injection of ethidium bromide in Cx32 Knock Out and normal mice. To accomplish so, Real Time PCR gene expression quantification was performed uppon tumour necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFβ), metalloproteinase 3 (MMP3), metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinases 1(TIMP1) genes. Results indicate variable differences in the expression pattern, including difference in expression of all evaluated genes in the 3 days after injection period, apex of the acute inflammation mechanisms. These results suggest that Cx32 may perform important functions on molecular inflammatory and regenerative/cicatrization signalling in the CNS.

Infections in the central nervous system pose a considerable challenge to the host. On one hand, a quick and rapid immune response is important to control the infection, while on the other hand, too robust a response can damage the CNS, which has poor regenerative properties. Therefore, nowhere else in the body is such a balance between pro- and anti-inflammatory mediators as important. Mice infected with the coronavirus, mouse hepatitis virus strain J2.2-V-1, are a useful model for understanding the two sides of the immune system. In this neurotropic viral infection, demyelination occurs secondary to the immune response's control of the viral infection. Thus, J2.2-V-1 infection also functions as an infectious animal model for multiple sclerosis (MS). Many arms of the pro-inflammatory immune system have been studied during J2.2-V-1 infection but the anti-inflammatory immune response has not been thoroughly investigated prior to this study. The data demonstrated here represent an in-depth look into the role of regulatory T cells and IL-10 during J2.2-V-1 infection. Specifically, by adoptive transfer of Tregs, I show that there is a relative paucity of Tregs during J2.2-V-1 infection in C57BL/6 mice and their addition decreases clinical scores, demyelination and the T cell response during infection without affecting viral clearance. A RAG1-/- adoptive transfer model demonstrates clinical results consistent with results obtained in B6 mice, while further demonstrating that Tregs function in the draining cervical lymph node by dampening dendritic cell activation and pro-inflammatory chemokine and cytokine release. There is also a relative decrease in T cell proliferation. Thus, Tregs are protective in J2.2-V-1-induced encephalomyelitis and their enhancement is a potential therapy for MS. Additionally, IL-10 is an important anti-inflammatory component of the immune response, as its absence causes increased immunopathology with increased demyelination in J2.2-V-1-infected B6 mice. Through the development of a recombinant J2.2-V-1 virus that produces IL-10, I also demonstrate that increasing the level of IL-10 at the site of infection is protective early in the immune response. Antigen-specific IFN-γ+ CD4 and CD8 T cells produce IL-10 at the height of the inflammation. CD8 T cells require a high level of antigen stimulation and the most recently activated CD69+CD8 T cells express high levels of IL-10. Additionally, this IL-10 expression is transient in both CD4 and CD8 T cells, presumably only by the recently stimulated cells. Through microarray analysis, protein expression and cytolytic assay, I show that IL-10+CD8 T cells are more activated than IL-10-CD8 T cells. Nonetheless, the IL-10 produced is anti-inflammatory and its production in CD8 T cells is protective in J2.2-V-1-infected mice. Thus, the most activated and cytotoxic CD8 T cells self-regulate the immune response through the production of IL-10. Overall, these studies show that the anti-inflammatory component of the immune system is vital to protecting the host from the immunopathology that occurs during J2.2-V-1 virus clearance. Specifically, the addition of Tregs and IL-10 helps ameliorate clinical disease and demyelination. These studies suggest that increasing Tregs and/or increasing the cytokine IL-10 in patients with MS may have therapeutic potential.

Que se passe-t-il quand le système immunitaire attaque le cerveau ? Dans l'encéphalite à autoanticorps dirigés contre les récepteurs NMDA, le système immunitaire des patients dysfonctionne : au lieu de produire des anticorps pour combattre des organismes pathogènes, le système immunitaire produit des anticorps qui attaquent une protéine spécifique dans le cerveau des patients, les récepteurs NMDA. Ces récepteur sont indispensables à la mémoire et sont impliqués dans diverses maladies (schizophrénie, maladie d'Alzheimer). Les patients atteints d'encéphalite à autoanticorps dirigés contre les récepteurs NMDA souffrent de troubles neuropsychiatriques sévères (hallucinations, paranoïa, mouvements anormaux, épilepsie, amnésie, etc.) et la gravité de leur état de santé nécessite une prise en charge en réanimation. Malgré cette sévérité, 8 patients sur 10 récupèrent avec un traitement adapté. Les patients souffrant de cette maladie sont majoritairement des jeunes femmes porteuses d'une tumeur des ovaires. Le premier objectif de ma thèse est de comprendre le rôle de cette tumeur dans le dysfonctionnement du système immunitaire de ces patientes. Mon second objectif est de comprendre comment les autoanticorps attaquant les récepteurs NMDA vont perturber le fonctionnement du cerveau. Apporter des éléments de réponse à ces questions permettra à terme d'améliorer la prise en charge des patients / Anti-NMDA receptor (NMDAR) encephalitis is a rare but severe neuropsychiatric disorder initially described by J. Dalmau and colleagues in 2007. Anti-NMDAR encephalitis is defined by a clinical picture of encephalitis associated with the presence of IgG directed against the GluN1 subunit of NMDAR (NMDAR-Abs) in the cerebrospinal fluid (CSF) of patients. This disorder predominantly affects young women. Clinical presentation usually includes psychiatric symptoms and/or neurological symptoms often accompanied by decreased responsiveness and autonomic instabilities during the course of the disease . Despite the severity of the disease, 81% of patients recover fully or with mild sequels . 38% of patients had an underlying neoplasm, 94% of which were ovarian teratomas , indicating a role for this tumor in the immunopathogenesis of the disease. Studies in vitro and on animal models have demonstrated the pathogenicity of NMDAR-Abs but more studies are required to decipher the pathological role of anti-NMDAR antibodies. Two main research focuses have emerged in our group: understanding the events leading to the immune dysregulation in the ovary teratoma and identifying the pathological element(s) and how they act at the molecular and cellular levels to cause the broad neurological spectrum of symptoms observed in patients. My PhD was especially focused on 1) understanding the involvement of the underlying ovary teratoma in the triggering of the immune response during anti-NMDAR encephalitis and 2) studying the impact of prolonged exposure of the neuronal network to patients’ NMDAR-Abs and the potential involvement of microglial cells in the physiopathology of the disease