BIOL 520 W2009 Overview Immunology.ppt
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BIOL 520 W2009 Overview Immunology.ppt BIOL 520 W2009 Overview Immunology.ppt Presentation Transcript

  • BIOL 520 Advanced Immunology W2009 Lecture 1 Overview Immunology
  • Immunology
    • Recognition of self and non-self
      • Antigens
    • Elimination of non-self
      • Exogenous targets
        • Microbes
        • Allergens
        • Foreign material
      • Endogenous targets
        • Tumors
  • Two Arms of Host Defense
    • Innate immunity
      • Natural immunity
      • Defense system functional at birth
      • Preformed or available within hours after infection
      • Pattern recognition
      • Widely present in nature
    • Adaptive immunity
      • Acquired
      • Available within days
      • Specificity
      • Memory
      • In higher vertebrates
    Innate Adaptive
  • Key Players in Immunology Complement Antimicrobial (Poly)Peptides Phagocytes Epithelial Cells NK Cells Innate Antibodies Defense Proteins Lymphocytes (B-Ly, T-Ly) Cells Adaptive
  • Most Immune Cells are Found in Blood Granulocytes Monocytes Lymphocytes Natural Killer Cells
  • Some Immune Cells are Found in the Tissue Mast cells Dendritic Cells
  • Hematopoiesis Pluripotent Stem Cell Lymphoid Progenitor GEMM Progenitor Lymphocytes NK-Cells Erythrocytes Megakaryocyte Monocyte Macrophage Neutrophil Basophil Eosinophil Platelets B-Ly T-Ly Plasma cell Activated T-cell Dendritic cell
  • Defense Cells Have Specific Tasks
    • Epithelial cells
      • Barrier (physical, chemical)
      • Communcate
    • Phagocytes
      • Ingest
      • Kill
      • Digest
    • NK-cells
      • Lyse infected cells or tumor cells
    • B-lymphocytes
      • Produce antibodies
    • T-helper lymphocytes
      • Strengthen defense cells to improve their function
      • Regulate immune responses
    • T-killer lymphocytes
      • Lyse with specificty infected cells or tumor cells
  • Epithelial Cell Defense TLR Microbial Products (LPS, PG, etc) Antimicrobial Peptides Cytokines
    • TLR: Toll-like receptor (pattern recognition)
    • LPS: lipopolysaccharide
    • PG: peptidoglycan
  • Opsonophagocytosis
    • Opsonization
    • Attachment
    • Engulfment
    • Phagosome formation
    • Phagolysosome formation
    • Killing and digestion
    1. 2./3. 4. 5. 6.
  • NK Cell Mediated Killing
    • Triggered by two mechanisms
      • Antibody dependent cytotoxicity
      • Recognition of altered surface molecules
    • Mediated by:
      • Perforin
        • Pore-forming toxin
        • Permeabilizes target cell membrane
      • Granzyme
        • Enzyme
        • Induces apoptosis (cell suicide)
      • TNF 
        • Apoptosis
    Packaged in Granules
  • Recognition of Foreign Material
    • Pattern Recognition
    • Toll Like receptors
      • TLR1-10
    • All involved in Immune defense
      • Intracellular region with homology to IL1 receptor
    • Activated directly by microbial products not normally found in host
    • Specific antigen recognition
    • Antigen Receptor
    • B cell receptor
      • antibody molecule
    • T cell receptor
      • TCR
  • TLRs and Their Ligands Intracellular Extracellular Cytoplasmic membrane Peptidoglycan TLR2
  • Effects of TLR Activation
    • Cytokine up-regulation and secretion
      • Pro-inflammatory cytokines
      • Chemokines
    • Reactive oxygen and nitrogen metabolites
    • Antimicrobial peptide production
      • HBD2
    • Up-regulation of surface molecules enhancing adaptive immune responses
      • Co-stimulatory signals
      • MHC-II
    • Apoptosis
    Innate Immunity Adaptive Immunity
  • Basic Structure of an Antibody Molecule
    • 2 light and 2 heavy chains
    • Disulfide bonds
    • Hinge region
    • N-terminus: variable, antigen binding
    • C-terminus: constant region, effector function
      • 5 isotypes
        • IgD, IgM, IgG, IgA, IgE
  • Basic Functions and Distribution of Antibodies + monomer +++ - +/- Diffusion into extravascular sites - - +++ -- - Transport across placenta - +++ - - + Transport across epithelium IgE IgA IgG IgD IgM Distribution - + +++ - +++ Complement activation +++ - + - - Sensitization of mast cells - - ++ - - Sensitization for killling by NK cells - + +++ - + Opsonization - ++ ++ - + Neutralization IgE IgA IgG IgD IgM Functional Activity
  • T Cell Receptor
    • 2 chains
      • Connected by disulfide bond
      • Variable region
      • Constant region
      • Short cytoplasmic tail
    • Mostly  and  chain
    • Some specialized T-cells have  and  chain (  T cells)
  • T-Cell Antigens
    • Short contiguous amino acid (aa) sequence
    • Processed antigens
      • Antigen must have been unfolded and degraded
      • Primary aa structure
    • Only when bound to a specialized antigen presenting molecule (MHC)
    APC MHC T-Ly
  • TCR Recognizes Antigen Presented by MHC Molecules
    • MHC: major histocompatibility complex
    • First identified in transplantation immunology
    • T cells recognize antigen bound to an MHC molecule
    • Two types of MHC molecules
      • MHC I: presents endogenous peptides
        • Virus encoded
        • Produced by intracellularly replicating microorganisms
        • Tumor antigens
      • MHC II: presents exogenous peptides
        • Uptake through phagocytosis and degradation in phagolysosome
    MHC I MHC II CTL TH
  • CTL and MHC I TH and MHC II Apoptosis of Target Cell Immune modulation of target cell TH1, TH2: Activation TH3: Inhibition
  • Immune Cells Interact via Cytokines and Surface Molecules Complement Antimicrobial (Poly)Peptides Phagocytes Epithelial Cells NK Cells Innate Antibodies Defense Proteins Lymphocytes (B-Ly, T-Ly) Cells Adaptive
  • Cytokines
    • Soluble glycoproteins
    • ~ 25 kD
    • Cell to Cell communication
      • Autocrine, paracrine,endocrine
    • Act by binding to specific receptors
      • Receptor expression varies
      • Receptors can be shared by different cells
      • Different cells can respond differently
    Interleukins Chemokines Growth Factors Cytokines
  • Antimicrobial Peptides
    • Natural peptide antibiotics
    • Amphiphilic
      • Cationic
      • Hydrophobic
    • Microbial killing through membrane permeabilization
    + + + + + + + + +
  • Complement
    • System of plasma proteins
    • Activates a cascade of proteolytic reactions and subsequent protein aggregation on the microbial surface but not on host cell surface
    • Coat microbes with a substance that is bound by phagocytes (opsonization)
    • Form pores on microbial surfaces triggering killing
    • Release small peptides that contribute to inflammation
  • Lymphatic Tissue
    • Central
      • Bone marrow
      • Thymus
    • Secondary
      • Spleen
      • Lymph nodes
      • GALT (gut associated lymphatic tissue)
        • Tonsils
        • Peyer’s patches
        • Appendix
    Production Interaction with Ag Maturation
  • Thymus Immature T-Cells Mature naive T-Cells Hassall’s corpuscule (Cell destruction?) Bone marrow precursor Blood stream
  • Lymph Node
  • The Spleen
  • Organization of the Spleen
    • White pulpa
      • Leukocytes arranged around the blood vessels and sinuses
    • Red pulpa:
      • Blood vessels and sinuses
    • Marginal Zone
      • Border between white and red pulpa
  • Peyer’s Patches
  • Time Course of the Immune Response
  • Infection Triggers an Innate Inflammatory Response
  • Dendritic Cells Initiate Adaptive Immune Responses
  • Adaptive Immune Responses Augment Innate Immune Responses
  • References
    • Janeway’s Immunobiology, 7th edition, 2008
    • Textbook of Hematology, McKenzie, 2 nd edition, 1996
    • Microbiology: An Introduction; Tortora et al, 8 th edition, 2004
    • http://www-medlib.med.utah.edu/WebPath/HEMEHTML/HEMEIDX.html
    • http://www.siumed.edu/%7Edking2/erg/smallint.htm
    • Primary literature: available per request