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Hogan, Vanessa E. "The role of mitochondira in demyelinating disease." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493200.
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520 L $$aIn the CNS, myelination of axons is essential for the rapid conduction of impulses down the nerve. In demyelinated or failing axons however, conduction is less efficient and requires more energy. The principal function of mitochondria is to provide energy for the axon but in doing so they generate most of the intra-axonal reactive oxygen species (ROS). Therefore and increased energy requirement will promote an increased production of ROS which could lead to significant damage to essential DNA, proteins and lipids and could eventually damage the axon. This thesis investigates the mitochondrial involvement in axonal pathology in the CNS diseases, multiple sclerosis (MS), autosomal dominant optic atrophy (ADOA) and tosomal dominant optic atrophy with cataract (ADOAC).
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Matyszak, M. K. "Immune mediated inflammatory responses in the central nervous system." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334846.
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Kerstetter, Fogle Amber E. "ROLE OF CHEMOKINES IN REGULATING OLIGODENDROCYTE DEVELOPMENT, ASTROGLIOSIS, AND DEMYELINATING DISEASES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1258139447.
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Teixeira, Carlos Augusto Ciarlini. "CaracterÃsticas clÃnicas e epidemiolÃgicas de 146 pacientes com esclerose mÃltipla acompanhados na cidade de Fortaleza, CE, Brasil, entre os anos 1979 e 2010." Universidade Federal do CearÃ, 2011. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=7515.
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nÃo hÃPara analisar a histÃria natural da Esclerose MÃltipla (EM) no estado do CearÃ, Brasil, o autor estuda retrospectivamente 146 pacientes diagnosticados por critÃrios de Poser e / ou McDonald-2010. CasuÃstica e mÃtodos: dados biogrÃficos, clÃnicos e para-clÃnicos obtidos em visitas ambulatoriais e nos surtos. Considera como desfechos de incapacidade os marcos EDSS 4, 6 e 7. Com software estatÃstico R ( RKWard 0.5.3 ) faz anÃlise descritiva, teste exato de Fisher (p < 0,05) e curvas de anÃlise de tempo atà o evento ( Kaplan-Meier). Mais de 75 % dos pacientes sÃo acompanhados durante atà 15 anos. Resultados: EM predomina no sexo feminino (80,82 %); tem inÃcio antes dos 30 anos de idade em 47,9 % dos casos. Pacientes com educaÃÃo de nÃvel superior (33,5 %) representam mais do dobro do esperado na populaÃÃo em geral. Nas avaliaÃÃes inicial e evolutiva predominam os sintomas sensitivos, motores e esfincterianos. Pacientes mais jovens e com evoluÃÃo recorrente â remitente atingem EDSS 4 apÃs maior intervalo de tempo. A proporÃÃo de casos de EM benigna à de 4,7 %. A taxa anualizada de surtos à 0,6. Os dois primeiros surtos da maioria dos pacientes ocorreram nos primeiros 3 anos. O tempo entre 1 e 2 surtos tem relaÃÃo positiva com o tempo para atingir EDSS 4, 6 e 7. A duraÃÃo da doenÃa atà o Ãbito (8 casos, 5,4 %) foi em mÃdia de 14,4 anos. PrevalÃncia de EM no estado do Cearà à estimada em 2,9 / 100.000 habitantes. ConclusÃo: As caracterÃsticas clÃnicas e evolutivas da EM, no estado do Cearà (latitude sul entre 2o 46â e 7o 52â), sÃo semelhantes Ãs observadas mundialmente.
In order to study the natural history of Multiple Sclerosis (MS) in the state of CearÃ, Brazil, the author retrospectively analyzes 146 patients diagnosed according to Poser and/or McDonald-2010 criteria. Cases and methods: biographical, clinical and para-clinical data collected on outpatient visits and at relapses. EDSS scores 4, 6 and 7 used as disability outcomes. Statistical software R (RKWard 0.5.3) used to perform descriptive analysis, Fisher exact test (p< 0,05) and time-to-the-event curves (Kaplan-Meier). Results: over 75 % of the patients followed for as long as 15 years; disease onset before 30 years of age in 47,9 %, with female sex preponderance (80.82 %). Patients with university education (33,5 %) are in high proportion when compared to the general population. Sensory, motor and sphincter complaints are the most common, in both initial and final examinations. Younger patients with relapsing-remitting MS took a longer time to reach EDSS 4. The proportion of benign MS cases was 4, 7 %. Annualized relapse rate was 0,6 . For most patients, the first two relapses took place in the initial three years of illness.Time between 1st. and 2nd relapses bears a positive relationship with time to reach EDSS 4, 6 and 7. Disease duration until death (8 cases , 5,4 %) was an average of 14,4 years. The prevalence of MS in the state of CearÃ, Brazil, is estimated as 2,9 / 100.000 inhabitants. Conclusion: Clinical course of MS in the state of CearÃ, Brazil (south latitudes between 2o 46â and 7o 52â ) is similar to that observed worldwide.
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Belzycki, Sari E. "Measurement of brain atrophy in pediatric patients with clinically isolated demyelinating syndromes and multiple sclerosis." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112380.
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Brain atrophy has been used as a marker for disease progression in Multiple Sclerosis (MS). SIENA, an automated tool for measuring brain volume change, was tested to see whether MRI slice thickness and gap presence affect longitudinal atrophy measures. Isotropic global scan-rescan images were used to simulate 3 mm and 5 mm axial slice thicknesses with 1 and 2mm gaps, respectively. SIENA remained accurate and precise with increasing slice thickness and gap presence. Furthermore, symmetric pre-registration was crucial for scans with larger slice-thickness and gaps.SIENA was used to observe atrophy in children who have experienced a Clinically Isolated Syndrome (CIS) of the type leading to MS (CIS-MS). Brain atrophy was present within the first three months after a CIS event, and then subsided over the rest of the year. If the first acute episode was excluded, there was no significant difference in atrophy rates between the CIS-MS group and the CIS group, and no significant difference between those with T2-weighted brain lesions versus those who had none.
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Caruana, P. "Visual psychophysics and magnetic resonance imaging in demyelinating disease of the visual system." Thesis, Keele University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245886.
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Riley, Victoria Jane. "The effect of cytokines on neurological exacerbations in multiple sclerosis and experimental demyelinating disease." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621588.
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Vana, Adam C. "The oligodendrocyte progenitor response to demyelination /." Download the dissertation in PDF, 2006. http://www.lrc.usuhs.mil/dissertations/pdf/vana2006.pdf.
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Kornfeld, Samantha F. "MiR-145-5p: Its Roles in Oligodendrocyte Differentiation and Its Contributions to the Pathophysiology of Demyelinating Disease." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40617.
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Multiple sclerosis (MS) is a debilitating disease in which demyelinated lesions form in the central nervous system (CNS). A specific microRNA, miR-145-5p, is dysregulated both in blood samples from RRMS patients and in chronic lesions from progressive MS patients. In the context of remyelination, miR-145-5p regulation may be important as it exhibits strong differential regulation in oligodendrocytes (OLs), the myelinating cells of the CNS, and is also expressed in other CNS glial cell types. Dysregulation of miR-145-5p may therefore play into pathologies observed in both relapsing-remitting (RRMS) and progressive MS. Using pre-clinical rodent models, we aimed to determine how altering normal expression of miR-145-5p specifically affects OL maturation, and how the dysregulation observed in MS may affect various aspects of disease.
First using a miR-145 knockdown model in primary rat OLs, we found in vitro that miR-145-5p plays a role both in maintaining oligodendrocyte progenitor cells (OPCs) in their proliferative state and preventing premature differentiation to OLs and that knockdown of miR-145 in OLs enhanced their differentiation. These effects were due at least in part to miR-145-5p regulation of a critical myelin gene transcription factor. The effects of miR-145-5p were further assessed in a miR-145 knockout mouse model in vivo. Contrary to in vitro assays, enhanced myelination was not detectable during development in these animals, nor when remyelination was assessed using the cuprizone toxic model of acute demyelination. However, chronic cuprizone exposure resulted in striking remyelination and functional recovery in miR-145 deficient animals. Sparse remyelination in wild-type animals with chronic cuprizone exposure was concomitant with upregulation of miR-145-5p, which was not the case with acute exposure, identifying miR-145-5p dysregulation as a unique feature of chronic demyelination. Specific assessment of miR-145-5p overexpression in OLs in vitro resulted in severe differentiation deficits and eventual apoptosis, driven molecularly by altered expression of multiple pathways critical to successful OL differentiation and subsequent myelination.
Finally, we induced an inflammatory model of demyelination, experimental autoimmune encephalomyelitis (EAE), in our miR-145 knockout mouse to assess the role of miR-145-5p in autoimmune-mediated myelin damage. The clinical severity of EAE in miR-145 deficient animals was reduced, and this was accompanied by reduced loss of myelin and lessened immune cell infiltration in miR-145 knockout spinal cords. Alterations in both astrocytic and microglial activation were detected with loss of miR-145, suggesting that improved clinical outcomes in this model may be underpinned by changes in EAE-mediated neuroinflammation.
Collectively, these data suggest that miR-145-5p plays differing roles in both progressive and inflammatory MS, affecting multiple glial cell types in the CNS. Excitingly, loss of miR-145 expression in our mouse model of chronic demyelination allowed extensive remyelination and functional recovery following chronic demyelination, and in EAE improved clinical outcomes driven by underlying improvements in myelin retention and altered neuroinflammatory reactions. Thus, miR-145-5p merits further investigation as a potential therapeutic target to help overcome both remyelination failure in all forms of progressive MS and inflammation-driven demyelination in RRMS and early secondary progressive MS (SPMS).
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Kvarnström, Maria. "Mechanisms in inflammatory demyelinating diseases of the nervous system : immunological and methodological aspects /." Linköping : Linköpings universitet, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med892s.pdf.
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Danilov, Alexandre I. "Neurogenesis, neural stem cells and nitric oxide in neuroinflammation /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-484-8/.
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Thummala, Suneel K. "Axon Initial Segment Stability in Multiple Sclerosis." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4038.
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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by inflammation and demyelination. In addition to these hallmark features, MS also presents with axonal pathology, which is likely responsible for the signs and symptoms of the disease. Although prominent in MS, axonal pathology is frequently considered a consequence of demyelination and not a primary event. This conclusion is consistent with demyelination inducing the loss of specific axonal domains, known as the nodes of Ranvier that are responsible for the propagation of action potentials along the axon. In contrast, we propose that axonal pathology associated with MS is a primary pathological event, independent of demyelination, and not a product of it. In support of our hypothesis, we have analyzed a different axonal domain known as the axon initial segment. Whereas a single axon has numerous nodes of Ranvier uniformly distributed along the axon, each axon contains only a single axon initial segment that is positioned immediately distal to the neuronal cell body. The axon initial segment is responsible for action potential generation and modulation, and hence is essential for normal neuronal function. Background studies conducted by our lab, employing a murine model of demyelination/remyelination, revealed no correlation between axon initial segment stability and myelin integrity. Here we investigate the fate of the axon initial segment in human multiple sclerosis. While not statistically significant, we provide data demonstrating an apparent 40% reduction in AIS numbers in MS. We further provide qualitative evidence that AIS integrity in MS is not dependent on myelination suggestive that axonal pathology may be a primary event in MS, independent of demyelination. Our current findings are intriguing, but unfortunately this study is underpowered, and more samples will be required to determine whether this apparent reduction is statistically significant.
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Itani, Farah R. "Infection with neuroantigen-encoding Listeria: induction of CD8 T cell responses and suppression of demyelinating disease." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5780.
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Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) with characteristic multifocal lesions or ‘ plaques’ of demyelination mainly in the white matter of the brain ( involving cerebral cortex, cerebellar, brain stem and spinal cord). These MS plaques vary in size and shape, and are composed of infiltrates of lymphocytes and macrophages - which contain myelin debris. CD8 T cells are more prevalent in CNS lesions and display oligoclonal expansion. However, their role in disease remains unclear with studies showing both protective and pathogenic roles for myelin-specific CD8 T cells in the experimental autoimmune encephalomyelitis (EAE) model. Our studies have demonstrated a disease-suppressive function for CNS-specific CD8 T cells in a model where the antigen is exogenously administered in vivo and used for in vitro CD8 activation. My studies focus on probing the nature of the CD8 response elicited by endogenously presented myelin antigens in vivo utilizing a novel approach, infection with Listeria monocytogenes (LM) encoding for myelin proteolipid protein peptide PLP178-191 (LM-PLP).
I show that LM-PLP infection preferentially induces PLP-specific CD8, but not CD4, T cell responses. Despite this, infection does not result in autoimmunity. In fact, routinely induced EAE is significantly ameliorated in LM-PLP-infected mice, compared to controls. Disease suppression is dependent on the presence of CD8 T cells, and the effector molecules IFN-g and perforin. CNS T cell infiltration and inflammatory responses are reduced in LM-PLP-protected mice, and CD4 T cells from LM-PLP-protected mice are less inflammatory than those from controls. Importantly, infection with LM-PLP ameliorates already established disease. My studies indicate that myelin-specific CD8 T cells induced by endogenous presentation of antigen attenuate CNS autoimmunity in multiple mouse models of EAE, implicating the potential of this approach as a novel immunotherapeutic strategy.
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Gardner, Christopher James. "Grey matter demyelination and neurodegeneration in multiple sclerosis : a new animal model for studying disease mechanisms." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/9228.
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Multiple sclerosis is the commonest neurological disease affecting young adults. Whilst the initial relapsing-remitting disease phase is associated with inflammatory demyelination and is treatable with immunomodulatory drugs, the secondary progressive phase (SP-MS) is associated with ongoing axonal loss and cortical atrophy and is currently untreatable. Studies of SP-MS have revealed the presence of extensive subpial demyelinated lesions within the cerebral cortex. This pathology is associated with a high level of meningeal inflammation, a gradient of cell loss from the cortical surface and high levels of microglia activation. To test the hypothesis that pro-inflammatory cytokines diffusing from the cerebral meninges could be responsible, we have established an animal model mimicking cortical grey matter pathology. Female DA rats were immunised with 5μg recombinant myelin oligodendrocyte glycoprotein (rmMOG) in incomplete Freunds adjuvant (IFA). This dose was insufficient to initiate encephalomyelitis, but did initiate an anti-MOG humoral immune response in the periphery. Twenty days post-immunisation animals received an injection of tumour necrosis factor (TNF) and interferon gamma (IFNγ) into the subarachnoid space at the sagittal sulcus. Immunohistochemistry revealed areas of subpial demyelination extending through cortical layers I–III. Lesions were maximal after 7 days and had resolved by remyelination at 14 days. A gradient of microglia/macrophage activation was present from the cortical surface. The extent of demyelination correlated with activation of microglia in the cortex and macrophages within the meninges. Activated microglia were observed contacting myelin, oligodendrocytes and neurons. In the demyelinated cortex, expression of the TNF receptors TNFR1A and TNFR1B was upregulated on oligodendrocytes and perivascular macrophages respectively. CD8+ T cells were observed in the meninges, corpus callosum and scattered throughout the grey matter, whereas CD4+ T cells and CD79a+ B cells were restricted to the meninges. Oligodendrocyte numbers were reduced in the upper cortical layers prior to demyelination (days 1 and 3 post-injection), but were still present in demyelinated lesions at day 7. Numbers of neurons and astrocytes were not changed. Control animals immunised with IFA and injected with cytokines had increased presence of inflammatory cells within the meninges but no demyelination. Animals immunised with rmMOG and injected with PBS had no demyelination or immune response within the meninges or cortex. Thus, acute subpial demyelination was dependent on a pre-existing immune response against myelin protein, coupled with generalised pro-inflammatory signalling within the meninges. These findings support our hypothesis of a role for meningeal inflammation in the cortical pathology of MS and describe for the first time an animal model that can be used to study the molecular mechanisms involved. Future research will aim to maintain meningeal inflammation and produce a model of chronic demyelination.
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Marino, Meghan J. "Monogenic Diseases Masquerading as Multiple Sclerosis: A Systematic Review." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1296249495.
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Henriksson, Freddie. "Economic aspects of chronic diseases : multiple sclerosis and diabetes mellitus /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-5023-7/.
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Wei, Terence. "The role of the neuroendocrine axis in multiple sclerosis." Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389374.
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Santos, Stella de Aparecida Ederli Pinto dos. "Diagnóstico diferencial das lesões tumefativas desmielizantes do sistema nervoso central na infância e adolescência: revisão sistemática da literatura." Instituto Fernandes Figueira, 2013. https://www.arca.fiocruz.br/handle/icict/10988.
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Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil.
As lesões tumefativas desmielinizantes (LTD) do SNC apresentam extrema dificuldade diagnóstica em virtude da similaridade clínica e radiológica com outras entidades nosológicas, incluindo doenças neoplásicas, inflamatórias e infecciosas. Frequentemente, o caráter indefinido das lesões aponta para a necessidade de biópsia cerebral com alto risco de morbidade. Portanto, o reconhecimento das características neurorradiológicas da LTD é fundamental para evitar a utilização de procedimentos invasivos. Na prática clínica, os exemplos das formas tumefativas não tumorais são os seguintes: esclerose múltipla (EM), neuromielite óptica (NMO), doença de Schilder e encefalomielite agudadisseminada (ADEM).Objetivo e Métodos: Analisar, através de revisão sistemática da literatura, quais ferramentas diagnósticas clínicas, radiológicas e laboratoriais são utilizadas pelos autores na investigação da etiologia das LTDs do SNC na infância.Resultados: As doenças desmielinizantes encontradas foram as seguintes: EM em 36% dos casos; LTD, sem classificação específica, em 27%; ADEM 17%;doença de Schilder 13 % e NMO 7%. De todos os casos estudados, em 45% houve recorrência de eventos desmielinizantes. Não há protocolo definido em relação aos tipos de exame solicitados nem a sequência apropriada ou oportunidade de indicá-los. Os exames mais realizados pelos autores foram os seguintes: RM de crânio, exame histopatológico, pesquisa de bandas oligoclonais e índice de IgG no líquor, RM de coluna e pesquisa de anticorpo antiaquaporina 4. Conclusão: A análise da literatura mostra que os dados mais relevantes para se definir o diagnóstico das LTDs são obtidos através da história e evolução clínica dos pacientes, e exames de neuroimagem; é fundamental que pacientes portadores de LTD sejam acompanhados a médio/longo prazo na tentativa de aumentar as possibilidades diagnósticas; não existe protocolo universal de abordagem das LTDs; há necessidade incondicional de implementação de fluxo de procedimentos capazes de orientar o diagnóstico das LTDs na infância e adolescência.
Introduction: The tumefactive demyelinating lesions (TDL) of the CNS have extremely difficult diagnosis due to the clinical and radiological similarity with other nosological entities, including neoplastic, inflammatory and infectious diseases. Commonly, the undefined character of the lesions points to the need of brain biopsy with high risk of morbidity. Thus, the recognition of neuroradiological characteristics of the TDL is critical to avoid the use of invasive procedures. In the clinical practice, the examples of the non tumorous forms of tumefactive lesions are the following: multiple sclerosis (MS), optic neuromyelitis (ONM), Schilder`s disease and acute disseminated encephalomyelitis (ADEM). Objective and Methods: Analysis, through the systematic review of the literature, which clinic, radiological and laboratorial diagnostic tools are used by the authors in the investigation of the etiology of the TDL`s of the CNS in the childhood. Results: The following demyelinating diseases have been found: MS in 36% of the cases; TDL without a specific classification in 27%; ADEM 17%;Schilder`s disease 13 % and ONM 7%. Considering all the cases studied, in 45% had recurrence of demyelinating events. There is no defined protocol with respect to the types with medical exams requested neither the appropriate sequence or the opportunity of indicate them. The medical exams more conducted by the authors were the following: MRI of skull,histopathological exam, research of oligoclonal bands and IgGindex in the liquor, MRI of spine and research of anti-aquaporin-4 antibody. Conclusion: The analysis of the literature shows that the most relevant data to define the diagnosis of the TDLs are obtained through the history and clinical evolution of the patients and neuroimaging tests.It is critical that the patients with TDL be accompanied over the medium/long term in an attempt of increase the diagnostic possibilities; there is not an universal protocol of approach of the TDL; there is unconditional necessity of implementation of flow of procedures able to guide the diagnosis of the TDLs in the childhood and adolescence.
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Chalk, Holly McCartney. "Coping with Multiple Sclerosis: coping strategies, personality, and cognitive appraisals as predictors of adjustment among multiple sclerosis patients." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1178213739.
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Phillips, Mark W. "Spiritual dimensions coping with chronic illness such as multiple sclerosis /." Theological Research Exchange Network (TREN), 2000. http://www.tren.com.
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Morandi, Elena. "The viral hypothesis in multiple sclerosis : role of Epstein-Barr virus and human endogenous retroviruses." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/45125/.
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Epstein Barr Virus (EBV) is a major risk factor in Multiple Sclerosis (MS), via as yet unclear mechanisms. Several hypotheses have been proposed to explain how EBV infection could cause MS and the aim of this thesis was to better understand the mechanisms of action of EBV in the context of MS studying a) the role of EBV in myelin antigen presentation by B cells and b) the association of HERVs with MS. In a non-human primate experimental autoimmune encephalomyelitis (EAE) model, an EBV-related lymphocryptovirus enables B cells to protect a proteolysis-sensitive immunodominant myelin oligodendrocyte glycoprotein (MOG) peptide (residues 35- 55) against destructive processing. This facilitates its cross-presentation to autoaggressive cytotoxic MHC-E-restricted cytotoxic T cells. The present study extends these observations to human B cells and identifies a key role of autophagy. EBV infection upregulated antigen presentation-related markers on B cells and activated the cross-presentation machinery. Although human MOG protein was degraded less in EBV-immortalized B-lymphoblastoid cell lines (LCL) than in uninfected B cells, induction of cathepsin G activity by EBV led to total degradation of the immunodominant peptides. Inhibition of cathepsin G or citrullination of the arginine residue within a LC3-interacting regions (LIR) motif of immunodominant MOG peptides abrogated their degradation. Internalized MOG co-localized with autophagosomes, which may protect it from destructive processing. Thus, EBV infection switched MOG processing in B cells from destructive to productive possibly facilitating cross-presentation of disease-relevant epitopes to CD8+ T cells. This mechanism could facilitate presentation of myelin autoantigens that may be involved in MS induction and progression. The first part of this thesis shows a possible EBV-mediated mechanism involved in MS pathogenesis, but it is likely that different mechanisms act alternatively or cumulatively in different individuals based on environmental and genetic differences. A further mode of action of EBV is through the activation of Human Endogenous Retroviruses (HERVs). In normal conditions HERVs are silenced or expressed at low levels, but in some pathological cases, like MS, their expression is higher than in the healthy population. We performed a systematic review and meta-analysis of the literature on the association between HERVs and MS. The systematic review suggested a strong association between HERV expression and MS, in particular with the HERV-W family. The meta-analysis showed odds ratios of 22, 44, and 6 for the expression of MSRVpol in serum/plasma, MSRVenv in PBMC and MSRVpol in CSF respectively. Furthermore, we confirmed the association experimentally. An increased expression of MSRV/HERV-Wenv and TLR4 RNA was detected in blood of MS patients compared with control groups and the viral protein Env was expressed mainly by B cells and monocytes, but not by T cells. Our finding that EBV infection can induce the expression of MSRV/HERV-Wenv is consistent with previous reports in the literature. We also established that such increased expression was not due to a repression of retroviral restriction factors in LCL. A further connection between HERVs and MS is supported by the observation that people infected by HIV may have a lower risk of developing MS than the HIV non- infected, healthy population. We found that the expression of MSRV/HERV-Wenv RNA in HIV-infected people was lower than in MS patients and similar to healthy controls. Nevertheless, there was no difference in MSRV/HERV-Wenv expression between antiretroviral drug -treated and -untreated HIV patients. The expression of MSRV/HERV-Wenv was also detected in vitro in LCL treated with different classes of antiretroviral treatments (ART) and only Efavirenz (NNRI) reduced MSRV/HERV- Wenv expression. In conclusion, taking in consideration the multifactorial aetiology of MS, it is likely that EBV infection and increased expression of MSRV/HERV-W are significant contributing factors in genetically predisposed individuals. This thesis helps to better understand the mechanisms of action of EBV and HERVs in the context of MS.
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Simpson, Julie. "The role of chemokines in the pathology of multiple sclerosis and other neuroinflammatory diseases." Thesis, Sheffield Hallam University, 1999. http://shura.shu.ac.uk/7108/.
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The recruitment of circulating leukocytes and resident glial cells to sites of CNS inflammation is dependent on the chemokine gradients they encounter and the chemokine receptors they express. Multiple sclerosis (MS), subacute sclerosing panencephalitis (SSPE) and coeliac disease (CD), with associated neurological complications, are neuroinflammatory diseases with different aetiologies, but which share common CNS neuropathological features including large perivascular inflammatory cell infiltrates, microglial hyperplasia and reactive astrocytosis. The results of this study suggest that in SSPE CNS the interferon -y-inducible a chemokines IP-10 and Mig, predominantly expressed by astrocytes and microglia, play a role in lesion formation. In contrast, the ßchemokine MEP-la, expressed both by perivascular macrophages and resident microglia, plays a role in the recruitment of inflammatory cells into CD cerebellar tissue. The highest levels of a- and ß-chemokine expression were detected in actively demyelinating MS lesions with high levels of inflammation and widespread demyelination. In these lesions, RANTES was predominantly expressed by the endothelium, MCP- l, IP-10 and Mig by reactive astrocytes, and MIP-lß by microglia. These findings suggest not all neuroinflammatory diseases with common pathological features share a common chemokine profile. The highest level of chemokine receptor expression was also associated with chronic active MS lesions: infiltrating T-lymphocytes predominantly expressing CXCR3 and CCR5, and foamy macrophages within the lesion predominantly expressing CCR3, CCR5 and CCR8. In vitro studies confirmed the production of chemokines and the expression of chemokine receptors by isolated rat astrocytes and microglia following cytokine stimulation. The results of this study suggest chemokines play a critical role in the recruitment of cells to sites of inflammation in the CNS.
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Cavar, Marko. "Mutational Analysis of CD127 and Its Role in Immunological Diseases." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34404.
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Interleukin (IL) -7 is an essential non-redundant cytokine that influences T-cell differentiation, proliferation, homeostasis and T-cell functions. In T-cells, IL-7 signals are transduced via IL-7's heterodimeric receptor composed of a common, γ chain (CD132) and an IL-7 specific, α chain (CD127). In light of the many roles that IL-7 plays in T-cell biology, it is no surprise that CD127 expression is tightly regulated in T-cells.
In this study, I explore the effects that disease specific mutations in CD127 have on CD127 expression, regulation and signal transduction using an in vitro T-cell model. Here I specifically examined four disease associated mutations of CD127: P132S associated with severe combined immunodeficiency; L242_L243insNPC associated with T-cell acute lymphoblastic leukemia; I356V & T244I associated with autoimmune diseases like multiple sclerosis, rheumatoid arthritis and type 1 diabetes. In developing my model, I decided to use Jurkat cells because they expressed high endogenous surface levels of CD132, low endogenous surface levels of CD127 and endogenous STAT5. Jurkat cells were transduced with lentiviruses that induced expression of either WT or one of the four mutant CD127.
I found that transduced Jurkat cells produced the WT and all four mutant CD127 proteins. I also found that wild type CD127, I356V, L242_L243insNPC and T244I mutant CD127 proteins were all expressed at the same level on the cell surface. However, I could not detect P132S mutated CD127 protein in its native state on the surface or intracellularly. I also found no differences between the mutant CD127 and wild type CD127 with regards to the level of soluble CD127 transcripts. I found that cell lines expressing L242_L243insNPC, I356V and T244I mutant CD127 protein, down-regulated surface CD127 at high IL-7 doses (25ng/mL) to the same extent as in the cell line expressing wild type CD127 protein. Interestingly, at the low IL-7 dose (1ng/mL) these mutant CD127 cell lines down-regulated surface CD127 to a lesser degree the wild type CD127 cell line.
Further studies are required to elucidate whether P132S mutated CD127 is expressed on the surface and if T224I and I356V mutations in CD127 enhance signaling. By understanding CD127 dysregulation and dysfunction in disease states, we can potentially develop therapeutics that can return the function of CD127 to normalcy.
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Manrique, Hoyos Natalia [Verfasser], Mikael [Akademischer Betreuer] Simons, Wolfgang [Akademischer Betreuer] Brück, and Till [Akademischer Betreuer] Marquardt. "Neurodegeneration in toxin-mediated demyelinating animal models of Multiple Sclerosis / Natalia Manrique Hoyos. Gutachter: Mikael Simons ; Wolfgang Brück ; Till Marquardt. Betreuer: Mikael Simons." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2012. http://d-nb.info/1044306084/34.
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Grouios, Angela. "Public reactions and perceptions associated with three neuro-degenerative diseases : Parkinson's, Alzheimer's and Multiple Sclerosis /." Swinburne Research Bank, 2006. http://hdl.handle.net/1959.3/4481.
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Thesis (BA(Hons) (Psychology)) - Faculty of Life and Social Sciences, Swinburne University of Technology, 2006."October 2006". A thesis is submitted in fulfillment of the requirements for the degree Bachelor of Arts (Honours), [Faculty of Life and Social Sciences], Swinburne University of Technology - 2006. Typescript.
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Zeman, Adam. "The cerebrospinal fluid and serum in multiple sclerosis and other neurological disorders : the significance of oligoclonal bands." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386770.
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Reid, Phillip. "Functional Neutralizing Monoclonal Antibodies F-2-1 Against gp42 Ameliorates Disease Progression in Experimental Autoimmune Encephalomyelitis." Scholarship @ Claremont, 2018. http://scholarship.claremont.edu/cmc_theses/1822.
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Multiple Sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), occurring in isolated attacks or progressive forms. Many observations implicate Epstein-Barr virus (EBV) in the pathogenesis of MS. With the relentless accumulation of evidence for a significant pathogenic role of EBV in MS, I believe it may be possible to prevent and cure MS by effectively controlling EBV infection. Currently, monoclonal antibodies (MAb) are used as therapeutics for a molecular targeted approach to slowing disease progression in MS. However, to my knowledge, there have been no antibodies targeted against EBV infection in any model of MS. The objective of this study is to determine whether or not a MAb against EBV could be a therapeutic target for EAE. In this study, I will propose an experiment that will examine the effects of intraperitoneal injection of MAb F-2-1 in 2-month-old new humanized BALB/c Rag2-/- ll2rg-/- (BRG) adult EBV/EAE male mice. My expected results suggest that mice with EBV/EAE + MAb F-2-1 may have an attenuated clinical disease course. Through immunohistochemical studies, I will also propose that MAb F-2-1 may decrease inflammation, demyelination and axonal loss in the CNS of mice with EAE. I believe that this novel treatments success would depend on MAb F-2-1’s ability to inhibit clonal expansion of EBV-infected autoreactive B cell in the CNS. Ultimately, my proposed experiment suggests that inhibition of virus-cell fusion of EBV to the B cell membrane might attenuate neuropathology in EAE. I hope that my prospective study highlights the importance of controlling EBV in patients with MS and provides grounds for optimism on how to successfully treat MS by controlling EBV infection. In conclusion, by proposing an alternative therapeutic approach, I hope that this hypothetical experiment will aid in future investigations that could further our knowledge on treatment and prevention of multiple sclerosis
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Kobelt, Gisela. "Health economic assessment of medical technology in chronic progressive diseases : multiple sclerosis and rheumatoid arthritis /." Stockholm, 2003.
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van, den Heuvel Ananda. "The utility of group narrative therapy to facilitate psychological adjustment in multiple sclerosis." Thesis, Canterbury Christ Church University, 2011. http://create.canterbury.ac.uk/10195/.
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Section A reviews and critically evaluates the empirical literature on psychosocial interventions for multiple sclerosis (MS), the determinants of adjustment to MS, and the theoretical frameworks to account for these. Further, a conceptual and empirical review of the literature on narrative therapy is provided and an argument advanced for the utility of narrative therapy in facilitating adjustment to MS. Possible areas for further research are outlined. Section B describes a feasibility study which aimed to begin to test a theoretical argument for the application of group narrative therapy to facilitate psychosocial adjustment to MS, and to ascertain the feasibility of a larger scale randomised controlled trial. Fourteen MS patients received 8 weekly sessions of group narrative therapy delivered at two sites in England. Quality of life, coping processes, and illness representations were assessed at two time points prior to the intervention and immediately after the intervention, and analysed using Wilcoxon Matched-Pairs tests. Additional qualitative measures were taken and analysed using content analysis. The feasibility of a larger scale study was, in part, assessed by means of semi-structured interviews with health professionals involved in the study, and analysed using thematic analysis. Although none of the findings reached statistical significance upon correcting for multiple comparisons, positive trends were revealed for the mental health component of quality of life, confrontive coping, and the consequences component of illness representations. With respect to the feasibility of this study, several issues pertaining to recruitment and data collection emerged from the data that can inform future research. Taken together, the results of this pilot study are promising and warrant further investigation using a sufficiently large sample. Section C provides a reflection on the skills and abilities developed and learning needs identified whilst undertaking the research. It further offers a critical reflection on the study‟s methodology and the potential implications for clinical practice. Further potential lines of enquiry are outlined.
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Sefia, Eseberuo. "Mechanism of immune tolerance induction in antigen-specific human autoimmune disease." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8982.
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Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system and is considered to be a T-cell mediated autoimmune disease. The “ideal” method in treating MS would be an antigen-specific therapy that does not require generalized immunosuppression. To date there are no definitive treatments for MS but there are several licensed therapies such as -interferon. Unfortunately the effect of interferon (IFN) is reduced by the development of neutralizing antibodies (NAbs) in up to 35% of MS patients within two years of starting treatment. An immunization schedule was developed in the BALB/c mice by subcutaneous administration of recombinant human IFN, and this resulted in development of high incidence of NAbs to the protein in the BALB/c model termed “NAbs model”. The mechanism of NAbs formation in this model is believed to be similar to that observed in IFN-treated MS patients with NAbs, which is as a result of an immune response to the protein. We elected to study NAbs in the context of IFN rather than MS directly to investigate the effects of antigen-specific tolerization strategies on the outcome of NAbs and indirectly on the outcome of IFN treatment in MS disease. The depletion of the immune cells triggers a reconstitution program that leads to renewal of the immune cell repertoire. Tolerance can be induced by intravenous administration of a protein. Within this window of reconstitution following depletion, it is hoped that the immune system can be manipulated to tolerate an otherwise foreign protein (human recombinant IFN). The tolerance strategy employed in this project was immune cell depletion using antibodies and mitoxantrone, followed by intravenous re-introduction of rhIFN. Tolerance was successfully induced in the NAbs model by intravenous administration of rhIFN, and further enhanced by immune cell depletion prior to intravenous administration of rhIFN. The BALB/c “NAbs model” offers a suitable model for use in investigating induction of tolerance to rhIFN following the formation of NAbs to the protein. The antigen of interest is known and the time to NAbs formation is also known. Tolerance induction can be monitored and investigated in this model.
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Kanthamneni, Naveen. "Development of Immunosupressant and Peptide Loaded Microparticles as Tolerogenic Vaccines for Treatment of Autoimmune Diseases." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331050212.
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Dahlman, Ingrid. "Genetic dissection of experimental autoimmune neuroinflammatory diseases in rats /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3768-0/.
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Fani, Maleki Adham. "Modulation of the innate immune system as a potential therapeutic strategy for Alzheimer's and Multiple Sclerosis Diseases." Doctoral thesis, Université Laval, 2021. http://hdl.handle.net/20.500.11794/69033.
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Leoni, Valerio. "On the possible use of oxysterols for the diagnosis and evaluation of patients with neurological and neurodegenerative diseases /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-255-1/.
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Callander, Margarita. "Epidemiological and genetic studies of multiple sclerosis with focus on the Swedish county of Värmland /." Linköping : Linköpings universitet, 2006. http://www.bibl.liu.se/liupubl/disp/disp2006/med949s.pdf.
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Jun, SangMu. "Vaccine platform for infection or autoimmune diseases using an ETEC fimbrial scaffold." Diss., Montana State University, 2009. http://etd.lib.montana.edu/etd/2009/jun/JunS0509.pdf.
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Moutsianas, Loukas. "Imputation aided analysis of the association between autoimmune diseases and the MHC." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:aa570447-9e25-42de-b10d-9f445c0a094e.
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The Major Histocompatibility Complex (MHC) is a genomic region in chromosome 6 which has been consistently found to be associated with the risk of developing virtually all common autoimmune diseases. Although its importance in disease pathogenesis has been known for decades, efforts to disentangle the roles of the classical human leukocyte antigens (HLA) and other variants responsible for the susceptibility to disease have often met with limited success, owing to the complex structure and extreme heterogeneity of the region. In this thesis, I interrogate the MHC for association with three common autoimmune diseases, ankylosing spondylitis, psoriasis and multiple sclerosis, with the aim of confirming the previously-reported associations and of identifying novel ones. To do so, I employ a systematic, joint analysis of single nucleotide polymorphism (SNP) and HLA allele data, in a logistic regression framework, using a recently developed algorithm to predict the HLA alleles for samples where such information is unavailable. To ensure the reliability of the analysis, I apply stringent quality control procedures and integrate over the uncertainty of the HLA allele predictions. Moreover, I resolve the haplotype phase of individuals from the HapMap project to create reliable reference panels, used in both HLA prediction and in quality control procedures. By directly testing HLA subtypes for association with the disease, the power to detect such associations is increased. I present the results of the analysis on the three disease phenotypes and discuss the evidence for important novel findings amongst both SNPs and HLA alleles in two of the diseases. In the final part of this thesis, I introduce a novel, model-based approach to detect inconsistencies in the data and show how it can be used to flag problematic SNPs which conventional quality control procedures may fail to identify.
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MARRIE, RUTH ANN. "THE INFLUENCE OF COMORBID DISEASES AND HEALTH BEHAVIORS ON CLINICAL CHARACTERISTICS, DISABILITY AT DIAGNOSIS, AND DISABILITY PROGRESSION IN MULTIPLE SCLEROSIS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1182528613.
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Terrill, Eileen F. "Women’s Experiences of Managing Relapsing-Remitting Multiple Sclerosis with Disease Modifying Drugs: A Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsn_diss/4.
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Purpose: To describe the experience of managing relapsing-remitting multiple sclerosis among adult women users of injectable disease modifying drugs, including day-to-day management, medication beliefs, and health care provider influence.
Rationale/Significance of the study:Approximately 85% of the 400,000 Americans with multiple sclerosis have relapsing-remitting multiple sclerosis (RRMS), characterized by unpredictable relapses and partial or full remissions of neurological symptoms. Untreated, RRMS may progress to permanent, irreversible disability and decreased quality of life. Current guidelines recommend immediate and sustained treatment with injectable disease modifying drugs (DMDs). However, despite pronounced modest benefits, approximately 30%-62% of patients are not undergoing DMD therapy. A small number of quantitative studies have identified factors that predict adherence to injectable DMDs. However, little is known about injectable DMDs from patients’ perspectives. It is important to develop an understanding of the experience of managing RRMS among adult users of injectable DMDs in order for health care providers to provide ongoing education, counseling, and support.
Organizing Framework:The framework, Beliefs About Medicines, was used to guide the study.
Design: Qualitative descriptive design.
Setting: Data were collected from adult women with RRMS who received care from an MS clinic, a neurology practice, and through snowball sampling.
Sample: Purposive and theoretical sampling was used to recruit 32 women with RRMS. Maximum variation sampling ensured the appropriate breadth and depth of experiences. Women currently undergoing injectable DMD therapy (n = 25), as well as women who either discontinued (n = 6), or never used (n = 1) injectable DMDs were interviewed.
Methods: A qualitative descriptive design was utilized. Verification occurred through trustworthiness of data, including rich, thick description from qualitative interviews; field notes and memoing; and member checks. Simultaneous data collection, analysis, and interpretation facilitated interview revision in order to elicit or expand emerging themes. Content analysis inductively derived themes and patterns within and across categories. Participant quotes substantiated particular themes. Confirmability of the data analysis process was undertaken in consultation with the research advisor.
Implications: Findings elucidated adult women’s subjective experiences concerning management of RRMS among users of DMDs, including day-to-day management, medication beliefs, and health care provider influence. Results from this study can be used to educate, counsel, and support women in the management of RRMS.
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Hayashi, Celina. "Vitamin D and Retinal Nerve Fiber Layer Thickness in Patients with Multiple Sclerosis." Scholarship @ Claremont, 2014. http://scholarship.claremont.edu/scripps_theses/325.
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Multiple Sclerosis (MS) is a neurological autoimmune disease characterized by demyelination of central nervous system tissue and one way this is presented is in the demyelination of the retinal nerve, causing vision disturbance and loss (Munger et al., 2006). The thinning of the retinal nerve fiber layer (RNFL) can be measured and visualized using a noninvasive technique called Optical Coherence Tomography (OCT), which is also used to measure relative MS severity (Petzold et al., 2010). One environmental factor that has been found to have a relationship with MS is vitamin D; research findings suggest that sufficient levels of vitamin D may reduce the risk of developing MS, decrease MS severity, and may slow its progression (Ascherio et al., 2010; Munger et al., 2006; Muris et al., 2013). The mechanism by which vitamin D affects certain symptoms requires deeper investigation.
This research examines the relationship between serum concentrations of 25-hydroxyvitamin D and retinal nerve fiber layer thicknesses in patients with MS. It was hypothesized that patients with sufficient vitamin D levels would have less demyelination of the retinal nerve caused by MS, and therefore would have a thicker RNFL in both eyes based on the proposed immunomodulatory role of vitamin D found in other studies. Blood samples were assayed to measure the concentration of 25-hydroxyvitamin D and OCT was used to measure RNFL thicknesses in patients with MS at the Harbor-UCLA Medical Center Neurology Clinic. Patients with sufficient levels of 25-hydroxyvitamin D had a greater mean global RNFL thickness in both eyes than in patients with insufficient levels of 25-hydroxyvitamin D; however the differences were not significant. Further research is necessary in order to determine whether or not there is a correlation between vitamin D and RNFL thickness and what role vitamin D plays in MS presentation.
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Haynes, Eric E. "Identifying Common Genes from Rheumatoid Arthritis, Systemic Lupus, Multiple Sclerosis and Sjogrens Syndrome by Pooling Existing Microarray Data." University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1374011043.
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Viar, Kenneth E. II. "Role of SARM1 in Chronic Immune-Mediated Central Nervous System Inflammation." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5819.
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SARM1 is an injury-induced nicotinamide adenine dinucleotide nucleosidase (NADase) that was previously shown to promote axonal degeneration in response to traumatic, toxic, and excitotoxic stressors. This raises the question of whether a SARM1-dependent program of axonal degeneration is central to a common pathway contributing to disease burden in neurological disorders. The degree to and mechanism by which SARM1 inactivation decreases the pathophysiology of such disorders is of interest to establish the rationale to pursue SARM1 as a therapeutic target. In this study, we compare the course and pathology of experimental autoimmune encephalomyelitis (EAE) in Sarm1-knockout (KO) mice and wild-type littermates to test the contribution of SARM1-dependent axonal degeneration specifically in the context of chronic, immune-mediated central nervous system (CNS) inflammation. The question of whether SARM1 loss in Sarm1-KO mice would inhibit, promote, or have a negligible impact on EAE-induced axonal degeneration and more broadly CNS inflammation was explored using a variety of analyses: quantification of clinical score in a chronic EAE model, CNS immune infiltrate profile, axon initial segment morphology in layer V cortical neurons, axonal transport disruption and transection in the lumbar spinal cord. Additionally, we have proposed a method for detecting SARM1 activation in situusing a novel SARM1-mCitrine bimolecular fluorescence complementation (BiFC) technique. Successful implementation of such a molecular tool would allow for a detailed, mechanistic approach to enhance our understanding of upstream intracellular signals that trigger SARM1 activation.
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Li, Jinan. "Multifunctional roles of plasmin in inflammation : Studies of animal models on rheumatoid arthritis, multiple sclerosis, wound healing and infection." Doctoral thesis, Umeå : Dept. of medical biochemistry and biophysics, Univ, 2005. http://www.diva-portal.org/umu/theses/abstract.xsql?dbid=422.
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Fontoura, Paulo Pacheco da. "Terapêuticas antigénio-especificas no tratamento das doenças desmielinizantes: estudos sobre a vacinação com ADN e a descoberta de um novo alvo antigénico." Doctoral thesis, Faculdade de Ciências Médicas. Universidade Nova de Lisboa, 2008. http://hdl.handle.net/10362/5202.
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RESUMO
A Esclerose Múltipla (EM) é uma doença desmielinizante crónica do Sistema
Nervoso Central (SNC), provocada, em grande parte, por um ataque imuno-mediado contra
diversos elementos da bainha de mielina. Dentro dos alvos antigénicos desta resposta
autoimune, vários componentes proteicos e lipídicos da mielina têm vindo a ser
identificados ao longo dos anos, entre os quais se destacam a proteína básica de mielina(MBP), glicoproteína ligodendrocitária da mielina (MOG), proteína proteolipídica (PLP) e glicoproteína associada à mielina (MAG). Com o desenvolvimento do modelo animal de
Encefalomielite Autoimune Experimental (EAE), diversas terapias antigénio-específicas foram desenhadas, baseadas na modificação benéfica da resposta autoimune contra a mielina, tais como a administração de mielina ou seus componentes, os copolímeros terapêuticos, os ligandos peptídeos alterados e, recentemente, a vacinação com ácido desoxirribonucleico (ADN) codificador de proteínas de mielina, integrado em plasmídeos e purificado para administração parentérica.
Neste trabalho, apresentamos os resultados de um extenso conjunto de experiências, subordinadas a dois temas fundamentais: 1) avaliação do potencial terapêutico, e dos mecanismos de acção, da vacinação tolerizadora com ADN codificador de
proteínas de mielina (MBP, MOG, PLP, MAG) na EAE, e da associação desta vacinação com
a administração de ADN de citocinas Th2, ou de oligonucleótidos imunomoduladores; 2)
identificação e caracterização da resposta imune contra um novo componente da mielina
com potencial antigénico, a proteína inibidora do recrescimento axonal, Nogo-A.
No que respeita à vacinação com ADN, os nossos resultados comprovam a eficácia
desta terapêutica antigénio-específica na prevenção e tratamento da EAE. Os seus
mecanismos de acção incluem, entre outros, a supressão anérgica da proliferação antigénioespecífica dos linfócitos T anti-mielina (no modo de prevenção da doença), o enviesamento Th2 da resposta imune (quando co-administrada com a vacina de ADN codificadora da citocina IL-4, funcionando como terapia génica local), e a redução da diversificação de epítopos da resposta humoral anti-mielina, avaliada através de myelin spotted arrays. A
associação das vacinas de ADN com oligonucleótidos imunomoduladores GpG,
desenvolvidos para contrariar as sequências CpG imunoestimuladoras presentes no vector
de vacinação, levou à melhoria da sua eficácia terapêutica, devida, provavelmente, ao efeito estimulador preferencial dos oligonucleótidos GpG sobre linfócitos Th2 e sobre células reguladoras NK-T. Com base nestes resultados a vacinação com ADN foi desenvolvida para o tratamento da EM em humanos, com ensaios clínicos a decorrerem neste momento.
Em relação à proteína Nogo-A, estudos de estrutura primária e de previsão de
antigenicidade identificaram a região Nogo-66 como alvo antigénico potencial para a EAE.
Nas estirpes de ratinho SJL/J e C57BL/6, fomos capazes de induzir sinais clínicos e
histológicos de EAE após imunização com os epítopos encefalitogénicos Nogo1-22, Nogo23-
44 e Nogo45-66, utilizando protocolos de quebra de tolerância imune. Ao mesmo tempo,
identificámos e caracterizámos uma resposta linfocitária T específica contra os antigénios contidos na região Nogo-66, e uma resposta linfocitária B com diversificação intra e intermolecular a vários determinantes presentes noutras proteínas da mielina. A transferência adoptiva de linhas celulares Th2 anti-Nogo45-66, levou à melhoria clínica e histológica da EAE em animais recipientes induzidos com outros antigénios de mielina, após migração destas células para o SNC. Estes dados comprovam a importância da Nogo-66 como antigénio na EAE, e a eficácia de terapias antigénio-específicas nela baseadas.
No seu conjunto, os nossos resultados confirmam o potencial terapêutico das
vacinas de ADN codificadoras de proteínas de mielina, bem como a importância dos
encefalitogénios contidos na proteína Nogo-A para a fisiopatologia da EAE e da EM, com
eventual relevância para o desenvolvimento de novas terapias antigénio-específicas. O
aperfeiçoamento futuro destas terapias poderá levar, eventualmente, a uma capacidade de manipulação da resposta imune que permita o tratamento eficaz das doenças inflamatórias desmielinizantes, como a Esclerose Múltipla.
ABSTRACT
Multiple Sclerosis (MS) is a chronic demyelinating disease of the Central Nervous
System (CNS), caused, mainly, by an immune-mediated attack against several elements of
the myelin sheath. Among the antigenic targets for this autoimmune response, several
proteic and lipidic myelin components have been identified throughout the years, of which myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipidic protein (PLP), and myelin associated glycoprotein (MAG) are the best characterized. With the development of the animal model for MS, Experimental Autoimmune
Encephalomyelitis (EAE), several antigen-specific therapies have been designed, based on beneficial modifications of the autoimmune response against myelin. These have included myelin and myelin component administration, therapeutic copolymers, altered peptide ligands and, more recently, vaccination with myelin-protein encoding deoxyribonucleic acid (DNA), integrated into plasmids and purified for parenteral administration. In this work we present the results of an extensive series of experiments, subordinate to two fundamental areas: 1) evaluating the therapeutic potential, and mechanisms of action, of tolerizing myelin protein (MBP, MOG, PLP, MAG) DNA vaccination in EAE, alone and in association with Th2 cytokine DNA administration, or immunomodulatory oligonucleotides; 2) identifying and characterizing the immuneresponse against a new myelin component with antigenic potential, the axonal regrowth inhibitor Nogo-A. Regarding DNA vaccination, our results prove the efficacy of this antigen-specific therapy for the prevention and treatment of EAE. Its mechanisms of action include, among others, anergic suppression of antigen-specific T-cell proliferation against myelin (in prevention mode), Th2 biasing of the immune response (when co-administered with the IL- 4 codifying DNA vaccine, acting as local gene therapy), and reduction of epitope spreading of the anti-myelin antibody response, assessed by myelin spotted arrays. The combination
of myelin DNA vaccination with the administration of GpG immunomodulatory
oligonucleotides, designed to counteract immunostimulatory CpG motifs present in the
vaccination vector, led to an improvement in therapeutic efficacy, probably due to the
preferential stimulatory effect of GpG oligonucleotides on Th2 lymphocytes and on
regulatory NK-T cells. Based on these results, tolerizing DNA vaccination is being
developed for human use, with ongoing clinical trials.
As concerns the Nogo-A protein, based on studies of primary structure and
prediction of antigenicity, we identified the Nogo-66 region (responsible for the most of the inhibitory capacity of this protein) as a potential antigenic target for EAE. In the SJL/Jand C57BL/6 mouse strains, we were able to induce clinical and histological signs of EAE,after immunization with the encefalitogenic epitopes Nogo1-22, Nogo23-44 and Nogo45-66,using a tolerance breakdown protocol. Concomitantly, we identified and characterized a specific T cell response against these antigens, together with a B cell response which showed extensive intra and intermolecular epitope spread to several determinants present in other myelin proteins. Adoptive transfer of nti-Nogo45-66 Th2 cell lines resulted in clinical and histological improvement of EAE in recipient animals induced with other myelin antigens, after intraparenchymal CNS migration of anti-Nogo cells. These data confirm the relevance of Nogo-66 as an antigen in EAE, as well as the efficacy of antigenspecific
therapies based on the response against this protein.In conclusion, our results substantiate the therapeutic potential of myelin-encoding DNA vaccination, as well as the importance of encefalitogenic epitopes present in the Nogo-A protein for the pathophysiology of EAE and MS, with potential relevance for the creation
of new antigen specific-therapies. The future development of these therapies may
eventually lead to a degree of manipulation of the immune response that allows the
effective treatment of autoimmune, inflammatory, demyelinating diseases, such as Multiple Sclerosis.
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Papenfuss, Tracey L. "Hormones and dendritic cells influences on the initiation of the autoimmune disease experimental autoimmune encephalomyelitis /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1173196704.
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Clark, Kareem C. "Altered Axon Initial Segment Structure and Function In Inflammatory Disease." VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5115.
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Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal insults remain unclear. While most axonal pathologies characterized in MS are a direct consequence of myelin loss, we propose that axonal pathologies also occur independent of demyelination. In support of this idea, we recently reported that mice that develop experimental autoimmune encephalomyelitis (EAE), a model commonly used to mimic the pathogenesis of MS, exhibit a structural and functional disruption of the axon initial segment (AIS), a subdomain of the axon that acts as the trigger-zone for action potential generation. Importantly, this disruption is independent of myelin loss. Although the mechanism responsible for AIS disruption remains unclear, we observed an attenuation of the AIS insult following treatment with a known scavenger of oxygen free radicals. To further investigate the role of oxidative stress in modulating AIS stability, we employed an in vitro model in which neurons were exposed to a spontaneous reactive oxygen and nitrogen species generator. Through this approach, we demonstrated that oxidative stress is capable of AIS modulation acting through induction of cytosolic calcium (Ca2+) influx from both extracellular and intracellular sources, resulting in calpain protease activation. Furthermore, because rises in intracellular Ca2+ are central to these and other mechanisms of AIS disruption, we next investigated the cisternal organelle (CO), an AIS-localized Ca2+-regulating structure. Although this organelle could prove to be central to AIS modulation, very little is known about the mechanisms regulating its stability. Through this line of investigation, we provide the first evidence of pathological alteration to the CO in a disease state. This disruption precedes loss of AIS protein clustering and axo-axonic GABAergic input in both EAE and MS postmortem tissue. Overall, these studies reveal a primary axonal insult, independent of myelin loss, in a disease classically characterized as a white-matter pathology. Instead, this insult is most likely driven by oxidative stress through local Ca2+ dysregulation at the AIS, providing novel therapeutic targets for MS.
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McClain, Melanie A. "Pregnancy and the post-partum period regulate experimental autoimmune encephalomyelitis through immunoregulatory cytokine production." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1119898792.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xv, 95 p.; also includes graphics (some col.) Includes bibliographical references (p. 85-95). Available online via OhioLINK's ETD Center
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Suppiah, Vijayaprakash. "Genetics of autoimmune diseases : a study of immuno-regulatory genes : CTLA4, IL-4, IL-4RA, SOCS3, IFNG and IL-26 in multiple sclerosis, rheumatoid arthritis and juvenile idiopathic arthritis." Thesis, Queen's University Belfast, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437653.
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Bečanović, Kristina. "Genetic regulation of autoimmune neuroinflammation /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-726-6.
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Kristjansdottir, Gudlaug Thora. "Genetic Variation and Expression of the IRF5 Gene in Autoimmune Diseases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-99098.
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