BIOL 520 Advanced Immunology W2009 Lecture 1 Overview Immunology
Immunology <ul><li>Recognition of self and non-self </li></ul><ul><ul><li>Antigens </li></ul></ul><ul><li>Elimination of n...
Two Arms of Host Defense <ul><li>Innate immunity </li></ul><ul><ul><li>Natural immunity </li></ul></ul><ul><ul><li>Defense...
Key Players in Immunology Complement Antimicrobial (Poly)Peptides Phagocytes Epithelial Cells NK Cells Innate Antibodies D...
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 Mo...
Defense Cells Have Specific Tasks <ul><li>Epithelial cells </li></ul><ul><ul><li>Barrier (physical, chemical) </li></ul></...
Epithelial Cell Defense TLR Microbial Products (LPS, PG, etc) Antimicrobial Peptides Cytokines <ul><li>TLR: Toll-like rece...
Opsonophagocytosis <ul><li>Opsonization </li></ul><ul><li>Attachment </li></ul><ul><li>Engulfment </li></ul><ul><li>Phagos...
NK Cell Mediated Killing  <ul><li>Triggered by two mechanisms </li></ul><ul><ul><li>Antibody dependent cytotoxicity </li><...
Recognition of Foreign Material <ul><li>Pattern Recognition </li></ul><ul><li>Toll Like receptors </li></ul><ul><ul><li>TL...
TLRs and Their Ligands Intracellular Extracellular Cytoplasmic membrane Peptidoglycan TLR2
Effects of TLR Activation <ul><li>Cytokine up-regulation and secretion </li></ul><ul><ul><li>Pro-inflammatory cytokines </...
Basic Structure of an Antibody Molecule <ul><li>2 light and 2 heavy chains </li></ul><ul><li>Disulfide bonds </li></ul><ul...
Basic Functions and Distribution of Antibodies + monomer +++ - +/- Diffusion into extravascular sites - - +++ -- - Transpo...
T Cell Receptor <ul><li>2 chains </li></ul><ul><ul><li>Connected by disulfide bond </li></ul></ul><ul><ul><li>Variable reg...
T-Cell Antigens <ul><li>Short contiguous amino acid (aa) sequence </li></ul><ul><li>Processed antigens </li></ul><ul><ul><...
TCR Recognizes Antigen Presented by MHC Molecules  <ul><li>MHC: major histocompatibility complex </li></ul><ul><li>First i...
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 Ce...
Cytokines <ul><li>Soluble glycoproteins </li></ul><ul><li>~ 25 kD </li></ul><ul><li>Cell to Cell communication </li></ul><...
Antimicrobial Peptides <ul><li>Natural peptide antibiotics </li></ul><ul><li>Amphiphilic </li></ul><ul><ul><li>Cationic </...
Complement <ul><li>System of plasma proteins </li></ul><ul><li>Activates a cascade of proteolytic reactions and subsequent...
Lymphatic Tissue <ul><li>Central </li></ul><ul><ul><li>Bone marrow  </li></ul></ul><ul><ul><li>Thymus </li></ul></ul><ul><...
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 <ul><li>White pulpa </li></ul><ul><ul><li>Leukocytes arranged around the blood vessels and sinu...
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 <ul><li>Janeway’s Immunobiology, 7th edition, 2008 </li></ul><ul><li>Textbook of Hematology, McKenzie, 2 nd  ed...
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BIOL 520 W2009 Overview Immunology.ppt

  1. 1. BIOL 520 Advanced Immunology W2009 Lecture 1 Overview Immunology
  2. 2. Immunology <ul><li>Recognition of self and non-self </li></ul><ul><ul><li>Antigens </li></ul></ul><ul><li>Elimination of non-self </li></ul><ul><ul><li>Exogenous targets </li></ul></ul><ul><ul><ul><li>Microbes </li></ul></ul></ul><ul><ul><ul><li>Allergens </li></ul></ul></ul><ul><ul><ul><li>Foreign material </li></ul></ul></ul><ul><ul><li>Endogenous targets </li></ul></ul><ul><ul><ul><li>Tumors </li></ul></ul></ul>
  3. 3. Two Arms of Host Defense <ul><li>Innate immunity </li></ul><ul><ul><li>Natural immunity </li></ul></ul><ul><ul><li>Defense system functional at birth </li></ul></ul><ul><ul><li>Preformed or available within hours after infection </li></ul></ul><ul><ul><li>Pattern recognition </li></ul></ul><ul><ul><li>Widely present in nature </li></ul></ul><ul><li>Adaptive immunity </li></ul><ul><ul><li>Acquired </li></ul></ul><ul><ul><li>Available within days </li></ul></ul><ul><ul><li>Specificity </li></ul></ul><ul><ul><li>Memory </li></ul></ul><ul><ul><li>In higher vertebrates </li></ul></ul>Innate Adaptive
  4. 4. Key Players in Immunology Complement Antimicrobial (Poly)Peptides Phagocytes Epithelial Cells NK Cells Innate Antibodies Defense Proteins Lymphocytes (B-Ly, T-Ly) Cells Adaptive
  5. 5. Most Immune Cells are Found in Blood Granulocytes Monocytes Lymphocytes Natural Killer Cells
  6. 6. Some Immune Cells are Found in the Tissue Mast cells Dendritic Cells
  7. 7. 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
  8. 8. Defense Cells Have Specific Tasks <ul><li>Epithelial cells </li></ul><ul><ul><li>Barrier (physical, chemical) </li></ul></ul><ul><ul><li>Communcate </li></ul></ul><ul><li>Phagocytes </li></ul><ul><ul><li>Ingest </li></ul></ul><ul><ul><li>Kill </li></ul></ul><ul><ul><li>Digest </li></ul></ul><ul><li>NK-cells </li></ul><ul><ul><li>Lyse infected cells or tumor cells </li></ul></ul><ul><li>B-lymphocytes </li></ul><ul><ul><li>Produce antibodies </li></ul></ul><ul><li>T-helper lymphocytes </li></ul><ul><ul><li>Strengthen defense cells to improve their function </li></ul></ul><ul><ul><li>Regulate immune responses </li></ul></ul><ul><li>T-killer lymphocytes </li></ul><ul><ul><li>Lyse with specificty infected cells or tumor cells </li></ul></ul>
  9. 9. Epithelial Cell Defense TLR Microbial Products (LPS, PG, etc) Antimicrobial Peptides Cytokines <ul><li>TLR: Toll-like receptor (pattern recognition) </li></ul><ul><li>LPS: lipopolysaccharide </li></ul><ul><li>PG: peptidoglycan </li></ul>
  10. 10. Opsonophagocytosis <ul><li>Opsonization </li></ul><ul><li>Attachment </li></ul><ul><li>Engulfment </li></ul><ul><li>Phagosome formation </li></ul><ul><li>Phagolysosome formation </li></ul><ul><li>Killing and digestion </li></ul>1. 2./3. 4. 5. 6.
  11. 11. NK Cell Mediated Killing <ul><li>Triggered by two mechanisms </li></ul><ul><ul><li>Antibody dependent cytotoxicity </li></ul></ul><ul><ul><li>Recognition of altered surface molecules </li></ul></ul><ul><li>Mediated by: </li></ul><ul><ul><li>Perforin </li></ul></ul><ul><ul><ul><li>Pore-forming toxin </li></ul></ul></ul><ul><ul><ul><li>Permeabilizes target cell membrane </li></ul></ul></ul><ul><ul><li>Granzyme </li></ul></ul><ul><ul><ul><li>Enzyme </li></ul></ul></ul><ul><ul><ul><li>Induces apoptosis (cell suicide) </li></ul></ul></ul><ul><ul><li>TNF  </li></ul></ul><ul><ul><ul><li>Apoptosis </li></ul></ul></ul>Packaged in Granules
  12. 12. Recognition of Foreign Material <ul><li>Pattern Recognition </li></ul><ul><li>Toll Like receptors </li></ul><ul><ul><li>TLR1-10 </li></ul></ul><ul><li>All involved in Immune defense </li></ul><ul><ul><li>Intracellular region with homology to IL1 receptor </li></ul></ul><ul><li>Activated directly by microbial products not normally found in host </li></ul><ul><li>Specific antigen recognition </li></ul><ul><li>Antigen Receptor </li></ul><ul><li>B cell receptor </li></ul><ul><ul><li>antibody molecule </li></ul></ul><ul><li>T cell receptor </li></ul><ul><ul><li>TCR </li></ul></ul>
  13. 13. TLRs and Their Ligands Intracellular Extracellular Cytoplasmic membrane Peptidoglycan TLR2
  14. 14. Effects of TLR Activation <ul><li>Cytokine up-regulation and secretion </li></ul><ul><ul><li>Pro-inflammatory cytokines </li></ul></ul><ul><ul><li>Chemokines </li></ul></ul><ul><li>Reactive oxygen and nitrogen metabolites </li></ul><ul><li>Antimicrobial peptide production </li></ul><ul><ul><li>HBD2 </li></ul></ul><ul><li>Up-regulation of surface molecules enhancing adaptive immune responses </li></ul><ul><ul><li>Co-stimulatory signals </li></ul></ul><ul><ul><li>MHC-II </li></ul></ul><ul><li>Apoptosis </li></ul>Innate Immunity Adaptive Immunity
  15. 15. Basic Structure of an Antibody Molecule <ul><li>2 light and 2 heavy chains </li></ul><ul><li>Disulfide bonds </li></ul><ul><li>Hinge region </li></ul><ul><li>N-terminus: variable, antigen binding </li></ul><ul><li>C-terminus: constant region, effector function </li></ul><ul><ul><li>5 isotypes </li></ul></ul><ul><ul><ul><li>IgD, IgM, IgG, IgA, IgE </li></ul></ul></ul>
  16. 16. 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
  17. 17. T Cell Receptor <ul><li>2 chains </li></ul><ul><ul><li>Connected by disulfide bond </li></ul></ul><ul><ul><li>Variable region </li></ul></ul><ul><ul><li>Constant region </li></ul></ul><ul><ul><li>Short cytoplasmic tail </li></ul></ul><ul><li>Mostly  and  chain </li></ul><ul><li>Some specialized T-cells have  and  chain (  T cells) </li></ul>
  18. 18. T-Cell Antigens <ul><li>Short contiguous amino acid (aa) sequence </li></ul><ul><li>Processed antigens </li></ul><ul><ul><li>Antigen must have been unfolded and degraded </li></ul></ul><ul><ul><li>Primary aa structure </li></ul></ul><ul><li>Only when bound to a specialized antigen presenting molecule (MHC) </li></ul>APC MHC T-Ly
  19. 19. TCR Recognizes Antigen Presented by MHC Molecules <ul><li>MHC: major histocompatibility complex </li></ul><ul><li>First identified in transplantation immunology </li></ul><ul><li>T cells recognize antigen bound to an MHC molecule </li></ul><ul><li>Two types of MHC molecules </li></ul><ul><ul><li>MHC I: presents endogenous peptides </li></ul></ul><ul><ul><ul><li>Virus encoded </li></ul></ul></ul><ul><ul><ul><li>Produced by intracellularly replicating microorganisms </li></ul></ul></ul><ul><ul><ul><li>Tumor antigens </li></ul></ul></ul><ul><ul><li>MHC II: presents exogenous peptides </li></ul></ul><ul><ul><ul><li>Uptake through phagocytosis and degradation in phagolysosome </li></ul></ul></ul>MHC I MHC II CTL TH
  20. 20. CTL and MHC I TH and MHC II Apoptosis of Target Cell Immune modulation of target cell TH1, TH2: Activation TH3: Inhibition
  21. 21. 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
  22. 22. Cytokines <ul><li>Soluble glycoproteins </li></ul><ul><li>~ 25 kD </li></ul><ul><li>Cell to Cell communication </li></ul><ul><ul><li>Autocrine, paracrine,endocrine </li></ul></ul><ul><li>Act by binding to specific receptors </li></ul><ul><ul><li>Receptor expression varies </li></ul></ul><ul><ul><li>Receptors can be shared by different cells </li></ul></ul><ul><ul><li>Different cells can respond differently </li></ul></ul>Interleukins Chemokines Growth Factors Cytokines
  23. 23. Antimicrobial Peptides <ul><li>Natural peptide antibiotics </li></ul><ul><li>Amphiphilic </li></ul><ul><ul><li>Cationic </li></ul></ul><ul><ul><li>Hydrophobic </li></ul></ul><ul><li>Microbial killing through membrane permeabilization </li></ul>+ + + + + + + + +
  24. 24. Complement <ul><li>System of plasma proteins </li></ul><ul><li>Activates a cascade of proteolytic reactions and subsequent protein aggregation on the microbial surface but not on host cell surface </li></ul><ul><li>Coat microbes with a substance that is bound by phagocytes (opsonization) </li></ul><ul><li>Form pores on microbial surfaces triggering killing </li></ul><ul><li>Release small peptides that contribute to inflammation </li></ul>
  25. 25. Lymphatic Tissue <ul><li>Central </li></ul><ul><ul><li>Bone marrow </li></ul></ul><ul><ul><li>Thymus </li></ul></ul><ul><li>Secondary </li></ul><ul><ul><li>Spleen </li></ul></ul><ul><ul><li>Lymph nodes </li></ul></ul><ul><ul><li>GALT (gut associated lymphatic tissue) </li></ul></ul><ul><ul><ul><li>Tonsils </li></ul></ul></ul><ul><ul><ul><li>Peyer’s patches </li></ul></ul></ul><ul><ul><ul><li>Appendix </li></ul></ul></ul>Production Interaction with Ag Maturation
  26. 26. Thymus Immature T-Cells Mature naive T-Cells Hassall’s corpuscule (Cell destruction?) Bone marrow precursor Blood stream
  27. 27. Lymph Node
  28. 28. The Spleen
  29. 29. Organization of the Spleen <ul><li>White pulpa </li></ul><ul><ul><li>Leukocytes arranged around the blood vessels and sinuses </li></ul></ul><ul><li>Red pulpa: </li></ul><ul><ul><li>Blood vessels and sinuses </li></ul></ul><ul><li>Marginal Zone </li></ul><ul><ul><li>Border between white and red pulpa </li></ul></ul>
  30. 30. Peyer’s Patches
  31. 31. Time Course of the Immune Response
  32. 32. Infection Triggers an Innate Inflammatory Response
  33. 33. Dendritic Cells Initiate Adaptive Immune Responses
  34. 34. Adaptive Immune Responses Augment Innate Immune Responses
  35. 35. References <ul><li>Janeway’s Immunobiology, 7th edition, 2008 </li></ul><ul><li>Textbook of Hematology, McKenzie, 2 nd edition, 1996 </li></ul><ul><li>Microbiology: An Introduction; Tortora et al, 8 th edition, 2004 </li></ul><ul><li>http://www-medlib.med.utah.edu/WebPath/HEMEHTML/HEMEIDX.html </li></ul><ul><li>http://www.siumed.edu/%7Edking2/erg/smallint.htm </li></ul><ul><li>Primary literature: available per request </li></ul>
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