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Multiple Sclerosis (MS) is a neurodegenerative autoimmune disease that affects millions of people worldwide. Although the exact cause of MS is unknown, it is clear that CD4+ T helper cells play a significant role, namely T helper 1 (Th1) and T helper 17 (Th17) cells. The Notch family of proteins plays a role in the development and differentiation of T helper cells. Previous data has shown that inhibition of Notch impairs the ability of T helper cell differentiation. Additionally specific inhibition of certain Notch members inhibits specific T helper cell differentiation, for example the inhibition of Notch 1 inhibits Th1 and iTreg polarization [Samon et al., 2008]. However, the effects of the other Notch family members on CD4+ T cells are not fully studied. We propose that Notch 3 plays an extensive role in the regulation of Th1, Th2, Th17, and iTreg polarizations. In addition, we propose that Notch 3 regulates function of T helper cell function in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Data in this thesis show that Notch 3 plays a significant role in the polarization of Th1, Th17 and iTreg polarization [Karlsson et al., 2011]. We present evidence that the heterozygous and homozygous Notch 3 knockout exhibits a significant decrease in polarization toward Th1, Th17 and iTreg cell fates. Exopolysaccharide (EPS) is a compound that has been previously shown to play a protective role in other inflammatory diseases. EPS has been shown to produce anti-inflammatory macrophages. We propose that a similar anti-inflammatory effect might be possible in EAE. We found that EPS had a significant effect on EAE induction, decreasing the onset and peak disease score. EPS also reduced the concentration of IFN-γ, IL17A, and GM-CSF in the supernatants of the splenocytes after restimulation with MOG. Further experimental data is needed to prove the effects of EPS on EAE and the method by which EPS function. These data indicate that Notch 3 could be crucial in regards to EAE due to the effects on Th1 and Th17 which are instrumental in EAE induction [Raphael et al., 2015].

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-06-27T18:12:44Z No. of bitstreams: 1 alyriateixeiradias.pdf: 10088679 bytes, checksum: 54e2cba2e92e9707b5c8813c456ca1cb (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-06-28T12:50:27Z (GMT) No. of bitstreams: 1 alyriateixeiradias.pdf: 10088679 bytes, checksum: 54e2cba2e92e9707b5c8813c456ca1cb (MD5) / Made available in DSpace on 2016-06-28T12:50:27Z (GMT). No. of bitstreams: 1 alyriateixeiradias.pdf: 10088679 bytes, checksum: 54e2cba2e92e9707b5c8813c456ca1cb (MD5) Previous issue date: 2012-03-01 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A esclerose múltipla (EM) é uma doença autoimune que acomete o sistema nervoso central (SNC) promovendo inflamação, desmielinização e subsequente comprometimento neurológico. A encefalomielite autoimune experimental (EAE) é o modelo animal mais amplamente utilizado para o estudo da EM, podendo ser induzida por uma grande diversidade de protocolos. Porém, o resultado da doença pode ser diferente em cada modelo, dependendo das características genéticas dos animais utilizados, da fonte e concentração do material antigênico e do modo de aplicação do antígeno, refletindo, em parte, a heterogeneidade encontrada nas diversas formas clínicas da EM. Portanto, devido à diversidade de modelos de indução de EAE, vários fatores relacionados à resposta imunológica, permanecem pouco conhecidos. O presente trabalho buscou avaliar a diferença entre duas concentrações antigênicas, utilizadas na indução, sobre o desenvolvimento clínico da EAE e em diversos parâmetros da resposta imunológica. Para isto, a EAE foi induzida em camundongos da linhagem C57BL/6, utilizando-se a glicoproteína mielínica de oligodendrócitos (MOG35-55), em duas concentrações diferentes (100 ou 300 μg do peptídeo MOG35-55) e mantendo-se as concentrações de Mycobacterium tuberculosis (4 mg/mL) e toxina pertussis (300 ng) constantes. Foi então acompanhado o curso clínico da doença, nos dois protocolos utilizados, durante um período de 58 dias. Além disso, parâmetros da resposta imunológica, como avaliação do infiltrado celular no cérebro e dosagem de citocinas e quimiocinas no SNC e linfonodos inguinais foram acompanhados no 7°, 10°, 14°, 21° e 58° dias após a indução. Observou-se que embora não tenha ocorrido diferença significativa entre os grupos de animais imunizados em relação à pontuação do escore clínico, ocorreram diferenças importantes entre estes dois protocolos no que diz respeito ao perfil de citocinas, quimiocinas e infiltrado celular no cérebro. O aumento das citocinas pró-inflamatórias e quimiocinas no SNC ocorreu de forma precoce no grupo imunizado com 100 μg do peptídeo MOG35-55, que também exibiu infiltrado celular precoce e mais intenso do que o grupo imunizado com 300 μg do peptídeo MOG35- 55. Além disso, o nível das quimiocinas CCL5 e CCL20 e das citocinas de perfil Th1 e Th17 foram, de forma geral, mais elevados no grupo imunizado com 100 μg do peptídeo MOG35-55. Os resultados sugerem que somente a variação na concentração antigênica do MOG35-55, no momento da indução, não é capaz de induzir diferentes cursos clínicos de EAE e que a concentração mais elevada do antígeno (300 μg do peptídeo MOG35-55) parece promover algum mecanismo regulador ou de tolerância, que deve ser melhor estudado. / Multiple sclerosis (MS) is an inflammatory autoimmune disease of central nervous system (CNS) that causes demyelination and neurological deficit. The experimental autoimmune encephalomyelitis (EAE) is the most common model for study this disease. The EAE can be induced by different protocols and the score of the disease is related to the genetic background of the animals, the concentration of antigen and the way of induction, reproducing the heterogeneity of the MS. Thus, due to the diversity of EAE induction, different factors related to immune response are still unclear. The aim of this study was evaluate the difference between two antigen concentrations in the development of EAE and the parameters of immune response. The EAE was induced in C57BL/6 female mice with the myelin oligodendrocyte glycoprotein (MOG35-55) in two different concentrations (100 or 300μg of MOG35-55), but keeping the same concentrations of Mycobacterium tuberculosis (4 mg/mL) and pertussis toxin (300 ng). The disease clinical signs were followed until the 58th day after induction in both protocols, and the immunological parameters, such as cellular infiltrate at brain and levels of cytokines and chemokines at CNS and lymph nodes, were evaluated at 7th, 10th, 14th, 21st and 58th days post induction. In relation to the clinical score, were not observed significant differences between the different protocols, however the cytokines, chemokines and cellular infiltrate profile at brain showed interesting results. The release of Th1 and Th17 cytokines and the CCL5 and CCL20 chemokines at CNS occurred early and more intense at 100μg MOG35-55 group, in accordance with the earlier and intense cellular infiltrate than 300μg MOG35- 55 group. In conclusion, the results suggest that only the differences in the MOG35-55 concentration at induction, is not capable of induce different clinical signs of EAE and that the 300 μg of MOG35-55 seems to promote a regulatory or tolerance mechanism that deserves further studies.

5 Anglický abstrakt Experimental autoimmune encephalomyelitis (EAE) is widely accepted as a murine model of human multiple sclerosis autoimmune disease. Murine EAE is usually actively induced by immunization with a suitable myelin antigen. Following immunization, CD4+ T helper lymphocytes Th1 and Th17 accumulate in the nervous tissue and via the production of cytokines, they mediate an inflammatory reaction and the subsequent destruction of myelin. The main goal of this study was the induction of EAE with clinically observable symptoms and the observation of changes in the counts and phenotypes of cells, mainly NK and T cells. NK cells express a wide range of inhibitory and activation receptors from the C-lectin-like receptor superfamily. The specific ligand of the activating NKR-P1C isoform is still unknown and thus this receptor's involvement in EAE was also observed. Another goal was the use of medication with regard to the disease progress improvement. For the purposes of this study, two inbred murine strains with distinct NKR-P1 surface expression were used - the SJL/J strain (expressing inhibitory NKR-P1B) and C57BL/6 (expression activating NKR-P1C). SJL mice elicited a relapse-remitting of EAE, while C57BL/6 had chronic EAE. Both mouse strains exerted changes in the counts of NK...

Tese de mestrado integrado. Engenharia Informática e Computação. Faculdade de Engenharia. Universidade do Porto. 2012

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Methyl-CpG-binding protein 2 (MeCP2 is) is an epigenetic regulator that binds to methylated DNA. Initially identified as transcriptional repressor, MeCP2 also binds to different proteins functioning as gene activator. Importantly, MecCP2 gene mutations and changes in MeCP2 levels are associated to several forms of mental retardation and autism-related disorders; including Rett, a neurodevelopmental disorder affecting primarily girls. While brain MeCP2 was considered to be exclusively neuronal, this regulator is also present in glia. We found that oligodendrocytes, the myelinating cells of the central nervous system (CNS), express particularly high MeCP2 levels at a developmental stage that precedes their final maturation. Moreover, downregulation of MeCP2 levels by treatment of immature oligodendrocytes with small interference RNA (siRNA), reduced the expression of 14 kDa myelin basic protein (MBP) and MOG, two markers of mature oligodendrocytes. These observations raise the possibility that oligodendrocytes have a direct participation in Rett syndrome and other autism-related disorders.

This work deals with three different constructions of the extended binary Golay code G24. The first construction is based on a projective plane of order four. In terms of it Steiner system (5, 8, 24) is built. Linear span of its blocks forms a linear binary [24, 12, 8] code C. Every binary [24, 12, 8] code is isomorphic to C which is known as extended binary Golay code G24. The second construction uses so-called Miracle Octad Generator (MOG). All MOG-words of weight eight form Steiner system (5, 8, 24). The third construction uses impartial combinatorial game Mogul. In terms of its P-positions one can create a linear binary [24, 12, 8] code. The fact that is is also a lexikographic code is useful for parametres estimate. 1

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