role of th1 and th17 cd4+ t cell subsets in the pathogenesis of ...

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ACKNOWLEDGMENTS / AGRADECIMENTOS I start to thank my most direct collaborators in the development of this thesis. To my supervisor in Germany, Prof. Dr. Hartmut Wekerle, who welcomed me in his lab with complete open arms, encouraged and supported my projects and ideas. Thank you so much for the straightforward scientific thinking and also wonderful stories that always taught us something. To Dr. Gurumoorthy Krishnamoorthy, my “supervisor‐in‐the‐lab” so many thanks for your friendship and great leadership, for the beneficial scientific discussions, constant positive input and all the patience in the most stressing times. This healthy supervising synergy was so beneficial for my doctoral education that I will always be very grateful to both. Quero agradecer ao meu orientador em Portugal, o Doutor João Malva. Apesar de não ter estado muito tempo presente no seu laboratório, muito obrigada pelo seu incondicional apoio nestes quatro anos, pela sua colaboração, conselhos e um espírito sempre positivo. To all my lab colleagues in Munich: Bernadette Pollinger, Marsilius Mues, Kerstin Berer, Michail Koutrolos and Irene Arnold‐Ammer, for all the companionship, support and joyful environment. Additionally, I would also like to thank Vijay Kumar, Kristina Streyl and Hema Mohan, great colleagues in the department. Ao meu laboratório em Coimbra, quero agradecer em especial à Liliana Bernardino e à Raquel Ferreira pela vossa extrema dedicação e colaboração. I also would like to thank my external collaborators in this thesis: Professor Hans Lassmann from the Medical University of Vienna, for his collaboration with the histological data; and Hans Faber and Frank Weber, from the Max‐Planck Institute of Psychiatry in Munich, for performing the microarrays and the pathway analysis. Aos organizadores do Programa Doutoral em Biologia Experimental e Biomedicina do CNC, por me terem dado a oportunidade de realizar o meu doutoramento a um elevado nível científico. Em especial aos Doutores Miguel Castelo Branco e João Ramalho pelo apoio no primeiro ano. Ainda, um grande obrigada a todos os meus colegas durante os cursos graduados: Joana Lourenço, Mariana Bexiga, Catarina Pimentel, Ana Teles, Carina Santos, Ana Cristóvão, Lígia Gomes, Gisela Silva, Ricardo Soares, Eduardo iii
Page 1: Helena Sofia de Azevedo Domingues T
Page 5: Quero dedicar esta tese ao André e
Page 8 and 9: 2 1.6.1 Protective and detrimental
Page 10 and 11: 4 5.2 ‐ Results .................
Page 12 and 13: MBP - Myelin basic protein MCP‐1
Page 15: THESIS PLANNING The present thesis
Page 18 and 19: CNS. Finally, it was found that tra
Page 20 and 21: EAE não‐clássico, atáxico. Cur
Page 23: CHAPTER 1 INTRODUCTION
Page 26 and 27: By mechanisms that are still not cl
Page 28 and 29: The importance of the EAE model is
Page 30 and 31: the recruitment of the endogenous B
Page 32 and 33: studies between MS susceptibility a
Page 34 and 35: 28 1.3.4 B CELLS B cells belong to
Page 36 and 37: inflammatory cytokines and cellular
Page 38 and 39: Figure 1.2 - CD4 + helper T cell di
Page 40 and 41: Figure 1.3 ‐ Important events in
Page 42 and 43: a monoclonal antibody was found to
Page 44 and 45: experimental autoimmune uveitis (EA
Page 46 and 47: inflammation show increased levels
Page 48 and 49: in turn increases vulnerability of
Page 50 and 51: 44 1.7 ‐ STRATEGIC THERAPIES IN M
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that regulate diverse biological pr
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Rev‐Erbα plays an unequivocal ro
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CHAPTER 2 MATERIALS AND METHODS
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Antibody purification buffers Neutr
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56 2.1.3 GENE EXPRESSION ANALYSIS B
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58 Rev‐Erbα RORα RORC (human) R
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60 2.2 - METHODS 2.2.1 MICE All ani
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then pelleted. The pellet was re‐
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EAE scores were given as follows: s
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of 75% ethanol and finally dissolve
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68 2.2.17 FT7.1 CELL LINE CULTURE T
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Erbβ were obtained by PCR on the r
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72 2.2.24 STATISTICS Descriptive st
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CHAPTER 3 - IN VIVO ANALYSIS OF TH1
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We assessed whether chemokines and
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Figure 3.12 - Chemokines and chemok
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Figure 3.14 - Inflammatory genes ex
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production (McGeachy et al., 2007).
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come from the evidences demonstrate
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induces a classical EAE phenotype,
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102
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characterized the mechanisms of Th1
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Figure 4.2 - Th1 but not Th17 cells
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Figure 4.3 - Only pre‐activated T
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110
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Also, of interest is the observatio
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hours with FT7.1 cells in the prese
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granzymes A and B, FasL and perfori
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118
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120
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production. Additionally, there wer
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Gene expression analysis by real‐
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126 5.2.2 RELEVANCE OF REV‐ERBα
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Figure 5.5 - Effect of heme, Rev‐
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Figure 5.7 ‐ Evaluation Rev‐Erb
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suggests that their target genes ex
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134
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contact and that in a model where a
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FT7.1 cells Th17 cells demonstrated
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Bettelli E, Baeten D, Jager A, Sobe
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(2008) IL‐9‐ and mast cell‐me
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Kitze B, Pette M, Rohrbach E, Stadt
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Lopez‐Diego RS, Weiner HL (2008)
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Obermeier B, Mentele R, Malotka J,
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Stromnes IM, Cerretti LM, Liggitt D
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Yang XO, Pappu BP, Nurieva R, Akimz
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