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

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28 1.3.4 B CELLS B cells belong to the adaptive immune system through the presence of unique antigen‐ specific B cell receptors (BCR), membrane‐bound immunoglobulins. When B cells are activated, they can differentiate into memory B cells or plasma B cells and the latter produce and release large amounts of antigen‐specific antibodies, as well as a panel of cytokines depending on the inflammatory milieu. Another role of B cells concerns antigen presentation as they also express the MHC class II molecule on their surface. This is of particular importance in the B and T cell crosstalk which, as mentioned above, can contribute to the EAE pathogenesis. EAE studies showed that injection of MOG‐ specific autoantibodies amplified T cell attack by increasing the severity and duration of clinical signs and inducing large scale demyelination (Linington et al., 1988). The presence of elevated amounts of immunoglobulins (Igs) in the CSF of MS patients was demonstrated many years ago (Kabat et al., 1950) and since then, association between the presence of CSF Igs and the MS clinical worsening suggested a role of B cells in the pathogenesis. Clonally expanded memory B cells have also been found in MS CSF and lesions. The increased Igs discovered in the CSF but not in the serum of MS patients suggested antibody production by local B cells. In fact, a recent report compared the transcriptomes and proteomes from CSF of MS patients. The data obtained demonstrated a strong overlap, indicating that CSF B cells produce the oligoclonal Ig bands (Obermeier et al., 2008). B cells are not able to cross intact BBB but, once disrupted B cells along with antibodies and complement molecules enter the CNS. The auto‐reactive antibodies can cause demyelination by opsonization of myelin for phagocytosis, or via complement activation leading to antibody dependent complement cytolysis (ADCC), which can be found in MS lesions and EAE CNS (Sospedra and Martin, 2005). 1.3.5 INNATE IMMUNE CELLS Innate immune responses comprise variable functions that range from non‐specific recognition of non‐self molecular structures by Toll‐like receptors (TLRs) and release of molecules such as nitric oxide, cytokines and chemokines, to the activation of antigen‐ specific adaptive immune responses. The innate immune cells include DCs,
CHAPTER 1 ‐ INTRODUCTION Role of Th1 and Th17 CD4 + T cell subsets in the pathogenesis of EAE macrophages, mast cells, NK cells and humoral factors like complement. In the CNS resides an innate immune‐derived population, the microglia. Although the main role of innate immune cells is to distinguish self from non‐self, activate specific adaptive immune responses and maintain homeostasis, they can also contribute to destructive autoimmunity. Innate immune cells as APCs are extremely important in the activation of CD4 + T cells, both in periphery and in the CNS. Macrophages, DCs and microglia express constitutively MHC class II molecules and thus are able to present antigen both to naïve and effector T cells and contribute, therefore, to antigenic spread. For example, DCs were demonstrated to bias effector T cell to Th17 differentiation in the CNS from a relapsing EAE model (Bailey et al., 2007). Macrophages, on their side, are also activated in EAE, release inflammatory cytokines and promote T helper responses, further contributing to pathogenesis (Tran et al., 1998;Martiney et al., 1998). However, type II macrophages, recognized as anti‐inflammatory cells, were very recently described as suppressors of EAE (Tierney et al., 2009). Macrophages also act as professional phagocytic cells, a key feature in the immune response against pathogens but probably also important in the removal of myelin debris in CNS damaged areas [though it is known that this process is more efficient in the peripheral nervous system (PNS) through optimal crosstalk with myelin‐producing Schwann cells]. Removal of myelin debris can enhance re‐myelination but also promote antigen presentation and re‐ activation of encephalitogenic T cells. A less explored field concerns the status of activation and maturation of the innate immune system during different phases of MS. For example, cytokines such as IL‐12, IL‐ 18 and TNFα are found in different levels in blood cell samples from relapsing‐remitting and chronic progressive MS patients and are mostly produced by dendritic cells (Weiner, 2008). This emphasizes the importance of innate immune cells in different phases of CNS inflammation, whose markers might help to predict the disease course. Microglial cells, on their side, reside in the CNS but are of hematopoietic origin. They respond to TLR ligands in pathogen infections, to neuronal dysfunction, pro‐ 29
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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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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