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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Type 1 diabetes,No cure;therapy is insulin for life;physiologic glycaemic control never achieved,Incidence increasing by 5%every 5 years;costs,1 billion of UK NHS,budget,Excess morbidity and mortality,Anti-insulin:health,Anti-insulin:disease,Peakman,http:/www.uchsc.edu/misc/diabetes/eisenbook.html,Type 1 diabetes No cure;thera,1,CD8,T-cell,HLA I,Infiltrating CD4+,CD8+T cells,Anti-T cell therapies are effective,Islet cell autoantibodies,disease,CD4,T-cell,HLA II,TCR,Epitope,CD4,Treg,Type 1 diabetes is T cell mediated,Islet,autoantigen,APC,Peakman,CD8 HLA IInfiltrating CD4+,CD,2,The Immune System,Innate,Rapid Microbial Defense,Adaptive Immune System Activation,Acquired(Adaptive),Long-lived Microbial Defense,Neoplasm surveillance,Autoimmunity,Transplantation Rejection&Atopy,BDC,The Immune SystemInnateAcquire,3,The Innate Immune System,Antimicrobial Peptides(e.g.,Defensins,Cathelicidins),Phagocytes(Macrophages,Neutrophils,Monocytes,Dendritic Cells),Pattern Recognition Receptors,Alternative Complement System,NK Cells,B1B Cells,*,*,Aspects of both the innate and adaptive immune system,BDC,The Innate Immune SystemBDC,4,Selected Pattern Recognition Receptors:Toll-like Receptors,TLR:,Selected Ligands:,Role in Immunity:,Localization:,TLR1,PGN,Zymosan,Lipoproteins,Antifungal&Antibacterial,Dendritic Cells,Macrophages,T Cells,B Cells,Epithelium,TLR2,TLR6,TLR4,LPS,Antibacterial,TLR5,Flagellin,TLR11,?,TLR9,CpG,Antibacterial&Antiviral,TLR3,dsRNA,Antiviral,TLR7,ssRNA,TLR8,ssRNA,TLR10,?,?,Selected Pattern Recognition R,5,Selected Pattern Recognition Receptors:Other Families,Selected Pattern Recognition R,6,The Adaptive Immune System,Cell-mediated Immunity(Cytotoxicity),T cells,CD4+(Th1&Th2),CD8+(Tc1&Tc2),Humoral Immunity(Antibody production),B Cells,BDC,The Adaptive Immune SystemBDC,7,Th1 and Th2 CD4+T Cells,Th1,IL-12 induces differentiation,Cytokine Production:Interferon-,Interleukin-2,Intracellular Pathogens,Macrophage Activation,Delayed Type Hypersensitivity,Th2,IL-4 induces differentiation,Cytokine Production:Interleukin-4Interleukin-5Interleukin-13,Extracellular Pathogens,B Cell activation&IgE,Eosinophil responses,Immediate Type Hypersensitivity,BDC,Th1 and Th2 CD4+T CellsTh1Th2,8,H,uman,L,eukocyte,A,ntigen,human MHC,cell-surface proteins,important in self vs.nonself distinction,present peptide antigens to T cells,CLASS I:A,B,C,CLASS II:DR,DQ,DP,HLA,J.Noble,Human Leukocyte AntigenCLASS I,9,The Human Leukocyte Antigen Complex (6p21.31),DP DQ DR B C A,Class II,(1.1 Mb),Class III,Class I,(2.2Mb),Complement,and Cytokines,Class I-like genes,and pseudogenes,Frequent,Recombination,Recombination,is Rare,Telomere,Centromere,Recombination,is Rare,(0.7Mb),BDC,The Human Leukocyte Antigen Co,10,a3,b2,a1,a2,a1,a2,b1,b2,Binds 8-10mers,Expressed on most,Nucleated cells,Presents Cytosolic,Proteins to CD8+T cells,Binds 13-25mers,Expressed on APCs,Macs,B cells,activated,T cells,Presents Vesicular,Proteins to CD4+T cells,Class IClass II,HLA Class I and II Molecules Have a Distinct Structure and Function,BDC,a3b2a1a2a1a2b1b2Binds 8-10mers,11,Antigen,APC,Endocytosis,T Cell Receptor,Peptide,MHC II,CD4,+,T cell,T cell Recognition of Antigen on an APC,AntigenAPCEndocytosisT Cell Re,12,CD4,+,T cell,T Cell Receptor,Peptide,LPS,TLR4,Antigen Presenting Cell(APC),MHC II,“,Signal 1”,“,Signal 2”,“,Signal 3”,IL-1,IL-6,IL-12,CD28,B7,IL-12 Receptor,Signal 1:Specificity,Signal 2:Activation,Signal 3:Differentiation,T cell Activation by an Activated APC,CD4+T Cell ReceptorPeptideLPS,13,Absence of Signal 2,Activation,Clonal Anergy or Deletion,TCR,MHC,APC,Tolerance,T Cell,TCR,MHC,APC,Signal 1+Signal 2,B7,T Cell,cytokines,CD28,The 2-Signal Model of Lymphocyte Activation,BDC,Absence of Signal 2ActivationC,14,Immunological tolerance,Definition:,specific immune unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen(tolerogen vs immunogen),Significance:,All individuals should be tolerant of their own,antigens(self-tolerance);breakdown-autoimmunity,The induction of tolerance could be exploited to treat autoimmune diseases,Mechanisms of tolerance must first be understood,Fathman,Immunological toleranceDefinit,15,Mechanisms of unresponsiveness to self antigens,Central tolerance,Immature self-reactive T lymphocytes that recognize self antigens in the thymus undergo negative selection(deletion),Peripheral tolerance,Mature self-reactive T lymphocytes that escape central tolerance and recognize self antigens in peripheral tissues can be inactivated(,anergy,),killed(deletion)or regulated(suppressed),“Clonal ignorance”,Mature self-reactive lymphocytes do not respond to self antigens,in non-i
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