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10 ulatory (Treg) cells. Treg cells devoted to control immune responses to self-antigens were defined as “natural Treg cells” including natural killer T (NKT) and CD4 + CD25 + Foxp3 + T cells. NKT cells represent a distinct population of T cells showing properties of NK cells, but expressing α/β TCR, which specifically recognize glycolipids often expressed by pathogens and tumour cells (Bendelac 1997). NKT secrete large amounts of IL-4, IL-10, IFN-γ and transforming growth factor-β (TGF-β). It is generally accepted that Foxp3 is a master control gene for the development and function of natural CD4 + CD25 + Tregs, and there is no doubt that CD4 + CD25 + Foxp3 + T cells originate from the thymus as a distinct T cell subset (Sakaguchi 2000, Holm 2004), mainly devoted to control self-reactive T cells escaped to negative selection, thus ensuring peripheral tolerance to autoantigens and protecting from autoimmunity. However, the mechanism by which natural Tregs exert their suppressive activity is still elusive. Mechanisms of T-cell polarization Differentiation of naive Th cells into Th1, Th2 or Th17 effector cells occurs upon direct contact with APCs. A number of factors are involved in determining the nature of the effector phenotype that will develop, including the nature and affinity of the antigen, the type of TCR signaling, the nature of the coreceptor signals, and, more importantly, the predominant cytokine environment. Th cells respond to the products of many signaling cascades from a wide range of membrane-bound receptors, including cytokine receptors, and undergo four steps of development: (i) activation of particular cytokine genes; (ii) commitment to a certain effector phenotype (Th1, Th2, or Th17); (iii) inhibition of the opposing cytokine genes, and (iv) stabilization and potentiation of the phenotype (Grogan 2001). The developmental stages of effector T cells are mediated by different mechanisms, including control of gene expression by intracellular signaling cascades from cellsurface receptors and chromatin remodelling. APCs initiate the first step in the development of adaptive immunity and tune the T-cell response according to the nature of the invading pathogens. Pathogen-associated molecular patterns (PAMPs) of APCs through ligation of pattern recognition receptors (PRRs) start APC activation, in particular of DCs (Janeway 2002, Kapsenberg 2003). The most common receptors involved are the Toll-like receptors (TLRs), members of the IL-1R superfamily (Akira 2001), which discriminate between different types of pathogens. Receptors on DCs bind inflammation-associated tissue-specific factors, which are characteristic for the type of tissue and the pathogen-specific response pattern of that tissue. The binding of tissue factors also activates DCs and constitutes an indirect method of pathogeninduced maturation.Tissue factors include cytokines, chemokines, eicosanoids, heat-shock proteins and necrotic cell lipids (Beg 2002). Bone marrow DCs migrate as immature cells to sites of pathogen invasion, G. Del Prete - The complexity of the CD4 T-cell response where pathogens activate their maturation into immunostimulatory effector cells. Mature DCs migrate into lymphoid organs and provide naive T cells with antigen that stimulates specific TCRs, costimulatory molecules that prevent tolerance, and polarizing factors that determine which phenotype of effector T-cell will be produced. DC maturation results in the production of functionally different effector DC subsets that release polarizing signals (the most important are cytokines), which selectively promote the development of Th1, Th2, or Th17 cells (Reis e Sousa 2001). Mature effector DCs, which are referred to as DC1, DC2 and regulatory DC, selectively express cytokines, coreceptors and other polarizing signals that promote the development of Th1, Th2 or regulatory T cells, respectively. The majority of TLRs mediate the development of Th1promoting DCs (DC1), whereas most of the PRRs that mediate Th2-cell-inducing DCs (DC2) remain undefined. However, it has recently been shown that the synthetic TLR2 ligand Pam3Cys can elicit a Th2-inducing phenotype in DCs (Redecke 2004). Therefore, according to the nature of the foreign antigen, DCs determine the intensity and the functional phenotype of the immune response generated. The next step in the development of a Th1 or a Th2 immune response is the physical interaction between the different activated DCs and the naive Th cell. An immunological synapse is formed between T cells and APCs with a dynamic process occurring when a T-cell comes into physical contact with the DC (Boes 2002). The activated naive Th cell then matures into a cell able to perform Th1 or Th2 functions (Table 1). Whether a Th1 or a Th2 response is induced is determined when TCRs recognize the specific antigen peptide and induce intracellular signals, such as protein kinase C (PKC), calcium ions, nuclear factor-κB, that help generate the appropriate immune response (Constant 1997, Rogers 1999 , Noble 2000). Other signals are required for the activation of Th cells and these are dependent on cell interactions involving coreceptor molecules on the DC and the T-cell. For example, CD40, CD80, CD86, the programmed death- 1 ligand (PD-L1), programmed death-2 ligand (PD-L2) and inducible costimulator ligand (ICOS-L) are expressed on APCs and their respective binding partners CD40L, CD28/cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-receptor 1 (PD-1), and ICOS are expressed on T cells. In order to achieve proper differentiation of the activated naive T cells, Tcell polarizing cytokines are required. For secretion of these factors to occur at the optimal time, i.e. when the DC comes into contact with the T-cell, the DC must be restimulated by the binding of CD40 to its ligand (CD40L) on the T-cell membrane (Cella 1996). Cytokines are the most influential factors that modulate the T-cell phenotype, and their action involves intracellular signals transmitted through cytokine receptors expressed on the T-cell surface. When cytokines bind to their receptors on naive Th cells, the
eceptor subunits move closer together and Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathways are activated and induce tyrosine phosphorylation of the cytokine receptor. The STAT proteins bind to the phosphorylated tyrosines on the receptor and also become phosphorylated. Phosphorylated STAT proteins translocate to the nucleus where they act as DNA transcription factors. The development of Th1 cells is regulated by transcription factors, such as STAT-4 and T-bet, which are different and antagonistic to those controlling the Th2 development, which are STAT-6, GATA-3 and c-maf (Szabo 2003). STAT-4 and T-bet are activated when IL- 12 is produced by DCs (Hsieh 1993), often in association with IFN-γ produced by NK cells, in response to the interaction of PAMPs with TLRs present on the surface of cells of the innate immunity (Iwasaki 2004). In contrast, Th2 transcription factors are activated when IL-4 production occurs (Le Gros 1990). The source of early IL-4 production remained unknown for many years. Two possibilities are now suggested: (a) IL-4 is produced by the naïve T cell following the interaction of its Notch receptors with the Jagged ligand on DCs (Amsen 2004); (b) at least in some parasitic infections, IL-4 is produced by a still-undefined cell type (non- T/non-B, c-kit + , FcεR1 - ) in response to stimulation by IL-25/IL-17E produced by macrophages or mast cells (Fallon 2006). Cytokine-induced Th1 polarizing signals Th1-cell development starts with the secretion of IL-12 and type 1 IFNs (IFN-α and IFN-β) released by macrophages and DCs upon activation by intracellular pathogens (Farrar 2002). IL-12 acts in an autocrine manner to generate a positive feedback loop, producing further IL-12. The IL-12 production induces NK cells to release IFN-γ, which also reinforces the macrophage and DC production of IL-12 in another amplifying positive feedback loop. While IFN-γ, IL-12 and type-1 G. Del Prete - The complexity of the CD4 T-cell response Table 1. Summary of the main activities of the different CD4 T-cell subsets T-cell subset Protection against Possible mechanisms Th1 a Intracellular bacteria and some viruses Macrophage activation, cytotoxic activity, increased cytoxity of NK and CD8 cells Th2 b Helminth parasites Activity of IL-4, IL-5 & IL-13, mediator release by activated mast cells and eosinophils Th17 c Extracellular bacteria, some fungi Granulocyte recruitment, chemokines Treg d Tolerance to self Control of excessive responses to non-self Inhibition of anti-self effector responses Th3, T1R, CD4+CD25+Foxp3+ through the release of IL-10 & TGF-β or other a Involved in organ-specific autoimmunity (Hashimoto’s thyroiditis, atrophic gastritis, Crohn’s disease, granulomatous disorders. b Responsible for allergic diseases, mucus hyper-secretion induced by IL-9. c Involved in chronic inflammatory and autoimmune diseases (animal models), inflammatory bowel disease, multiple sclerosis, rheumatoid and Lyme arthritis, chronic obstructive pulmonary disease, other? d Compliant to autoimmunity when deficient or inactive; compliant to cancer when they inhibit tumor-specific effector T cells; responsible for immunodeficiency when hyper-active. IFNs directly induce T cells to differentiate into Th1 cells, it is the IFN-γ from APCs and NK cells that also acts as an inhibitor of the Th2 pathway by preventing Th2 cell expansion (Murphy 2000). IFN-γ interaction with naive Th cells leads to the activation of STAT1, which then induces the expression of T-bet. T-bet production initiates the remodeling of the IFN-γ gene locus, the production of IFN-γ, the expression of the IL- 12R and the stabilization of its own expression through the autocrine activity of IFN-γ (Mullen 2001). Once the IL-12R is expressed, this cytokine further reinforces the Th1 differentiation. IL-12 signalling activates STAT3, STAT4 and NF-κB to promote the production of cytokines associated with the Th1 phenotype and chromatin remodelling. The IFN-γ secreted by Th1 cells as they develop stimulates surrounding naive Th cells to polarize into Th1 cells, in a self-renewing paracrine loop ( Kidd 2003). IL-12 also up-regulates IL-18R expression, and DC-derived IL-18 potentiates the functions of IL-12 at a later stage in the development of Th1 cells (Stoll 1998, Yoshimoto 1998). However, the role of IL-18 in promoting Th1 cell development is less crucial than that of IL-12 because partially redundant. Cytokine-induced Th2 polarizing signals The differentiation of Th2 effector cells primarily involves the action of IL-4, IL-6, IL-10 and IL-11. IL-4 induces the production of STAT6 in naive T cells, which in turn activates the expression of the zinc finger transcription factor GATA-3 ( Kaplan 1996, Ouyang 1998). GATA-3 and T-bet are mutually antagonistic. When IFN-γ, IL-12 and T-bet levels are high, GATA-3 production is inhibited, whereas when IL-4 and GATA- 3 levels increase, T-bet release is repressed. Both IL-4 and TCR signaling are required to up-regulate GATA-3 transcription, which induce remodeling of the Th2 cytokine gene cluster (Zheng 1997), resulting in the release of IL-3, IL-4, IL-5, IL-9, IL-10 and IL-13 and in the inhibition of the expression of the IL-12R and 11
Page 1 and 2: PARASSITOLOGIA A publication of the
Page 3: P A R A SSIT O L O GIA Founded in 1
Page 6 and 7: The individual authors take respons
Page 9: Parassitologia 50, 2008 RICORDO DEL
Page 13: Parassitologia 50: 9-16, 2008 The c
Page 17 and 18: Chemokines have several functions a
Page 19 and 20: tion of the brain. Nature 421:744-8
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Page 23 and 24: adic or imported cases have been ob
Page 25 and 26: other EU countries, yet the impact
Page 27 and 28: Fasciola hepatica. II: La fasciolos
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Page 31 and 32: Ferry along the Potomac River. The
Page 33: for each of these chemical entities
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Page 40 and 41: 36 Many children with congenital to
Page 42 and 43: 38 Health promotion (Primary Preven
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Page 46 and 47: 42 References Ades AE, Gilbert R, T
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Page 51 and 52: C. Contini - management of toxoplas
Page 53 and 54: C. Contini - management of toxoplas
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Page 57: V. Meroni, F. Genco - Toxoplasmosis
Page 60 and 61: 56 A.W. Pfaff, E. Candolfi - Immuno
Page 62 and 63: 58 A.W. Pfaff, E. Candolfi - Immuno
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60 (Kijlstra et al., 2006). Regardi
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SIMPOSIO 2 IL PIANETA MALASSEZIA
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66 C. Cafarchia, D. Otranto - Malas
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Parassitologia 50: 69-71, 2008 Skin
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E. M. Difonzo, E. Faggi - Skin dise
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74 R. Galuppi, M.P. Tampieri - Mala
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76 R. Galuppi, M.P. Tampieri - Mala
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78 Table 1. Current composition of
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Parassitologia 50: 81-83, 2008 Diag
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tribution and population size of Ma
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86 A. Peano, M.G. Gallo - Treatment
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88 A. Peano, M.G. Gallo - Treatment
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90 (vii) Antimycotic properties, pr
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Parassitologia 50: 93-95, 2008 Unco
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SIMPOSIO 3 AEDES ALBOPICTUS IN ITAL
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98 test, whereas for the remaining
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100 pyriproxyfen is twice as biolog
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Parassitologia 50: 103-104, 2008 Bl
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Parassitologia 50: 105-107, 2008 De
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B. Cignini et al. - The ten-year ex
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110 cumstances of isolation of Bahi
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Parassitologia 50: 113-115, 2008 Im
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for what concern the time of biting
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118 during the past winter season w
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Parassitologia 50: 121-123, 2008 Ae
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fall recorded in the considered per
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126 Remarks Surprisingly, except fo
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128 Conclusion A. Tamburro - Admini
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SIMPOSIO 4 IL RUOLO DELLA RICERCA N
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134 approach and SAR studies. DDcl
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136 Program financed by ANTIMAL. S.
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138 A. della Torre et al. - Researc
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140 A. della Torre et al. - Researc
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Parassitologia 50: 143-145, 2008 He
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E. Schwarzer et al. - Hemozoin and
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148 geographic distribution in sub-
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150 K.E., Beldjord, C., Nagel, R.L.
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Parassitologia 50, 2008 Angelini P.
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