1. BIOL 520 Advanced Immunology W2009 Lecture 1 Overview Immunology 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 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 InnateAdaptive

4. Key Players in Immunology InnateAdaptive Cells Phagocytes Epithelial Cells NK Cells Lymphocytes (B-Ly, T-Ly) Defense Proteins Complement Antimicrobial (Poly)Peptides Antibodies

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

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

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. 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

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

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

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) –TNF  Apoptosis Packaged in Granules

12. 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

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

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 Functional ActivityIgMIgDIgGIgAIgE Neutralization +-++ - Opsonization +-++++- Sensitization for killling by NK cells --++-- Sensitization of mast cells --+-+++ Complement activation +++- +- DistributionIgMIgDIgGIgAIgE Transport across epithelium +--+++- Transport across placenta ---+++-- Diffusion into extravascular sites +/- - +++ + mon omer

17. 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)

18. 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

19. 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 CTL MHC II TH

20. CTL and MHC ITH and MHC II Apoptosis of Target CellImmune modulation of target cell TH1, TH2: Activation TH3: Inhibition

21. Immune Cells Interact via Cytokines and Surface Molecules InnateAdaptive Cells Phagocytes Epithelial Cells NK Cells Lymphocytes (B-Ly, T-Ly) Defense Proteins Complement Antimicrobial (Poly)Peptides Antibodies

22. 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

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 Immature T-Cells Mature naive T-Cells Hassall’s corpuscule (Cell destruction?) Bone marrow precursor 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, 2 nd edition, 1996 Microbiology: An Introduction; Tortora et al, 8 th edition, 2004 http://www- medlib.med.utah.edu/WebPath/HEMEHTML/HEMEIDX.htmlhttp://www- medlib.med.utah.edu/WebPath/HEMEHTML/HEMEIDX.html http://www.siumed.edu/%7Edking2/erg/smallint.htm Primary literature: available per request