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BIOL 520 Advanced Immunology W2009

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. Adaptive immunity Acquired

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BIOL 520 Advanced Immunology W2009

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  1. BIOL 520 Advanced Immunology W2009 Lecture 1 Overview Immunology

  2. Immunology • Recognition of self and non-self • Antigens • Elimination of non-self • Exogenous targets • Microbes • Allergens • Foreign material • Endogenous targets • Tumors

  3. Two Arms of Host Defense • Adaptive immunity • Acquired • Available within days • Specificity • Memory • In higher vertebrates • Innate immunity • Natural immunity • Defense system functional at birth • Preformed or available within hours after infection • Pattern recognition • Widely present in nature Innate Adaptive

  4. Key Players in Immunology

  5. Most Immune Cells are Found in Blood Granulocytes Lymphocytes Monocytes Natural Killer Cells

  6. Some Immune Cells are Found in the Tissue Mast cells Dendritic Cells

  7. Hematopoiesis Pluripotent Stem Cell Megakaryocyte GEMM Progenitor Lymphoid Progenitor Platelets Erythrocytes Lymphocytes Monocyte Neutrophil Basophil Eosinophil T-Ly NK-Cells B-Ly Activated T-cell Dendritic cell Macrophage Plasma cell

  8. 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 Defense Cells Have Specific Tasks

  9. Epithelial Cell Defense Microbial Products (LPS, PG, etc) TLR Antimicrobial Peptides • TLR: Toll-like receptor (pattern recognition) • LPS: lipopolysaccharide • PG: peptidoglycan Cytokines

  10. Opsonophagocytosis • Opsonization • Attachment • Engulfment • Phagosome formation • Phagolysosome formation • Killing and digestion 5. 6. 4. 2./3. 1.

  11. 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) • TNFa • Apoptosis Packaged in Granules

  12. 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 Recognition of Foreign Material

  13. TLRs and Their Ligands Extracellular Peptidoglycan TLR2 Cytoplasmic membrane Intracellular

  14. 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

  15. 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

  16. Basic Functions and Distribution of Antibodies

  17. 2 chains Connected by disulfide bond Variable region Constant region Short cytoplasmic tail Mostly a and b chain Some specialized T-cells have g and d chain (gd T cells) T Cell Receptor

  18. T-Ly 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) MHC APC

  19. TH CTL 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 endogenouspeptides • 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

  20. CTL and MHC I TH and MHC II Apoptosis of Target Cell Immune modulation of target cell TH1, TH2: Activation TH3: Inhibition

  21. Immune Cells Interact via Cytokines and Surface Molecules

  22. Cytokines Growth Factors Interleukins Chemokines 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

  23. + + + Antimicrobial Peptides + + + • Natural peptide antibiotics • Amphiphilic • Cationic • Hydrophobic • Microbial killing through membrane permeabilization + + +

  24. 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

  25. 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

  26. Thymus Bone marrow precursor Immature T-Cells Mature naive T-Cells Hassall’s corpuscule (Cell destruction?) Blood stream

  27. Lymph Node

  28. The Spleen

  29. 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

  30. Peyer’s Patches

  31. Time Course of the Immune Response

  32. Infection Triggers an Innate Inflammatory Response

  33. Dendritic Cells Initiate Adaptive Immune Responses

  34. Adaptive Immune Responses Augment Innate Immune Responses

  35. References • Janeway’s Immunobiology, 7th edition, 2008 • Textbook of Hematology, McKenzie, 2nd edition, 1996 • Microbiology: An Introduction; Tortora et al, 8th 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

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