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the recruitment of the endogenous B cell repertoire that cooperates with the auto‐ reactive T cell population to promote EAE pathogenesis (Pollinger et al., 2009). 24 1.3 ‐ THE IMMUNE PLAYERS IN MS AND EAE Early studies in MS identified the immune component of this disease correlating the cellular composition of brain lesions and CSF infiltrating cells with data from EAE models. These studies have substantiated the contribution of the CD4 + T cells (McFarland and Martin, 2007;Compston and Coles, 2002). For a long time, MS was considered a CD4 + T helper type 1 (Th1) cells‐mediated disease and the involvement of these cells is consistent with the HLA association to genetic susceptibility. But today we know that the pathogenic mechanisms are by far more complex and almost all immune cell types have at least some contribution, both from the acquired and innate immune system. Figure 1.1 – Myelin‐specific CD4 + T cells activation in the periphery and CNS [adapted from (Goverman, 2009)].
CHAPTER 1 ‐ INTRODUCTION Role of Th1 and Th17 CD4 + T cell subsets in the pathogenesis of EAE After breakage of immune cell tolerance, the immune system attack to the CNS can be divided into several stages. First, in order to be able to migrate to the CNS, the auto‐ reactive T lymphocytes must be activated in peripheral lymphoid organs, such as lymph nodes and the spleen, by antigen‐presenting cells (APCs) which include B cells, macrophages and dendritic cells (DCs). Then, these activated cells cross the blood brain barrier (BBB) and infiltrate the CNS perivascular space and parenchyma. Within the CNS, it is believed that the effector T helper cells subsets are re‐activated both by CNS antigen presenting resident cells, such as astrocytes and microglia, and infiltrating macrophages and DCs, where they release inflammatory cytokines and attract further cells from the immune system (Dittel, 2008) (Figure 1.1). A second invasion wave follows, which seems to be independent of antigen recognition or activation status, and inflammation develops contributing to myelin loss and, consequently, axonal degeneration and neuronal death. 1.3.1 CD4 + HELPER T CELLS Several data clearly demonstrate the importance of CD4 + T cells in EAE (Linington et al., 1984;Schluesener and Wekerle, 1985). The discovery that CNS antigen‐specific T cells cultured and activated in vitro could induce EAE after transfer to naïve recipients (Ben‐ Nun et al., 1981) also proved the need for T cell activation, a requirement for migration across the BBB to reach the CNS (Flugel et al., 2001). In fact, one pioneering study showed that mice transgenic in their TCR specific for MBP, found to be pathogenic in EAE experiments, developed spontaneous EAE if kept in conventional, not specific pathogen‐free (SPF) conditions (Goverman et al., 1993). This showed that the mere presence of CNS antigen‐specific T cells in the immune system is not sufficient to trigger disease but that cells need to be activated first. Though it is difficult to translate CD4 + T cell‐mediated EAE to all MS clinical aspects, CD4 + T cells are generally believed to be central in pathogenesis (Kitze et al., 1988;Pette et al., 1990b;Pette et al., 1990a), and this view is supported by the genetic association 25
Page 1: Helena Sofia de Azevedo Domingues T
Page 4 and 5: Ferreira e Ricardo Marques pela mot
Page 7 and 8: TABLE OF CONTENTS Acknowledgments /
Page 9 and 10: 2.2.13 Quantitative real‐time PCR
Page 11 and 12: ABBREVIATIONS aa - Amino acid ADCC
Page 13: PUBLICATIONS During the development
Page 17 and 18: SUMMARY Multiple sclerosis (MS) is
Page 19 and 20: RESUMO A Esclerose Múltipla (EM)
Page 21: OBJECTIVES The main aim of this the
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Our experiments make several points
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Additionally, IL‐4 and IL‐5 wer
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3.4a, b). In addition, we consisten
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The CNS infiltrating mononuclear ce
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Histology and immunohistochemistry
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and brain stem and cerebellum more
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CHAPTER 3 - IN VIVO ANALYSIS OF TH1
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CHAPTER 4 EVALUATION OF CYTOTOXIC P
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4.1 - SUMMARY CHAPTER 4 - EVALUATIO
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CHAPTER 4 - EVALUATION OF CYTOTOXIC
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CHAPTER 5 MICROARRAY ANALYSIS OF T
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5.1 ‐ SUMMARY CHAPTER 5 -MICROARR
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CHAPTER 5 -MICROARRAY ANALYSIS OF T
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CHAPTER 6 GENERAL DISCUSSION AND MA
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CHAPTER 6 - GENERAL DISCUSSION AND
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CHAPTER 6 - GENERAL DISCUSSION AND
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REFERENCE LIST Abromson‐Leeman S,
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REFERENCE LIST Role of Th1 and Th17
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NOTES
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NOTES Role of Th1 and Th17 CD4 + T
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NOTES Role of Th1 and Th17 CD4 + T
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