3/10/14. Ultrastructural organization. Gram Stain. Infection leads to production of inducers of inflammation. Gram negative.

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1 Infection leads to production of inducers of inflammation or dendritic cell Inflammatory mediators: Complex and many, but include: Lipids and Proteins (cytokines/chemokines) TNF Others Ultrastructural organization Capsule Ribosomes DNA Cytoplasm Cell wall Plasma membrane Pili Flagellum Gram Stain Gram negative Gram positive 1

2 QuesEon What is the molecular difference between gram posieve and gram negaeve? Gram (+) cell envelope structure external milieu protein lipoteichoic acid teichoic acid cell wall periplasmic space peptidoglycan plasma membrane cytoplasm Gram (-) cell envelope structure outside cytoplasm 2

3 Infection leads to production of inducers of inflammation or dendritic cell Inflammatory mediators: Complex and many, but include: Lipids and Proteins (cytokines/chemokines) TNF Others Immunity to Infection Principle 1 Every clinical infection is a consequence of failure or subversion of innate immunity 3

4 Principle 2 The innate and adaptive immune systems evolved to protect against infections Innate only Innate + primieve adapeve Innate and adapeve Characteristics of Innate and Adaptive Immune Responses Innate Immunity Relatively nonspecific Not influenced by prior exposure to the same invading agent Develops rapidly, is transient Adaptive Immunity (Humoral & Cellular) Develops in response to antigenic exposure Highly specific Takes a moderate amount of time to develop, then persists for a long time Results in immunologic memory 4

5 Elements of Innate Immunity Important in Resistance to Bacteria Cells Monocytes/Macrophages NK/NKT cells Neutrophils Dendritic cells Platelets Soluble mediators Complement Defensins Cytokines What is complement? How is it acevated? QuesEon 5

6 Complement opsonizes bacteria Infection leads to production of inducers of inflammation or dendritic cell Inflammatory mediators: Complex and many, but include: Lipids and Proteins (cytokines/chemokines) TNF Others Significance of Differences: antimicrobial peptides hydrophobic cationic (+) defensin external leaflet cytoplasmic leaflet external leaflet cytoplasmic leaflet Zwitterionic phospholipid (+/-) Acidic phospholipid (+/-) 6

7 Infection leads to production of inducers of inflammation or dendritic cell Inflammatory mediators: Complex and many, but include: Lipids and Proteins (cytokines/chemokines) TNF Others What happens next? QuesEon PRRs, PAMPs & TLRs The innate immune system initiates the immune response through pattern recognition receptors (PRRs) that recognize microbial products called pathogen-associated molecular patterns (PAMPs) Toll-like receptors (TLRs) function as important PRRs 7

8 Pathogen pattern receptors Receptor Microbial activators Ligand TLR1 Bacteria (mycobacteria, N. meningitidis) Lipopeptides, soluble factors TLR2 Bacteria, Fungi LPS, lipoteichoic acid, peptidoglycan etc. TLR3 Viruses dsrna TLR4 Bacteria LPS TLR5 Bacteria Flagellin TLR6 Bacteria, Fungi Lipoteichoic acid, Lipopeptides, zymosan TLR7 Viruses ssrna, imidazoquinolines TLR8 Viruses ssrna, imidazoquinolines TLR9 Bacteria, Viruses Unmethylated DNA (CpG) NOD1 Bacteria Peptidoglycan NOD2 Bacteria Peptidoglycan Toll-like Receptors What happens next? QuesEon 8

9 Human Pattern Recognition Molecules Pathogen associated molecular pattern (pamp) Toll-like receptor (TRL-X) Nucleotide oligomerization domain (NOD) external milieu TNF-a, IL-1 NF-Κb cytoplasm nucleus NF-Κb Control of gene expression of immunologic mediators 9

10 3/10/14 Leukocyte recruitment to sites of inflammation or DC See Abbas and Lichtman Fig. 2-7 Note: molecular details of leukocyte extravasaeon will be covered in lecture Friday Pathogen Interfaces with the adaptive and innate immune system T " Peripheral tissues T Blood vessels T Draining lymph nodes T Inflammatory monocytes/macrophages T cell area Lymphocytes/NK cells Neutrophils Follicle B Dendritic cells 10

11 QuesEon Where do the neutrophils come from? 11

12 Principle 3 Pathogen location determines protective immune mechanisms CD8 + T cells CD4 + T cells Principle 4 Nonopportunistic pathogens subvert normal mechanisms of immunity Opportunistic pathogens exploit defects in immunity The source of pep,des for MHC 1 and II 36 12

13 An,gens must be processed in order to be recognised by T cells Soluble naeve Ag Cell surface naeve Ag Soluble pepedes of Ag T Y Cell surface pepedes of Ag Cell surface pepedes of Ag presented by cells that express MHC anegens ANTIGEN PROCESSING No T cell response No T cell response No T cell response No T cell response T cell response An,gen Presenta,on MHC II and CD4 T cells From Janeway, Immunobiology, 5th edieon 38 CD4+ T cells mature into functionally distinct subsets Downloaded from: StudentConsult (on 12 September :28 PM) 2005 Elsevier 13

14 MHC II bound pepede acevates CD4+ T helper cell CD4+ cell binds to B cell preseneng the SAME pepede:mhc II complex Structural features of antibodies FAb fragment Fc fragment 12. Effector functions IgG IgM IgA IgD 14

15 Antibodies Antibodies protect by binding and blocking Antibodies provide protection by opsonization 15

16 Antibodies protect by activating ( fixing ) complement Release of histamine, heparin, glycosaminoglycans, eosinophil chemotacec factor, etc. 14d. QuesEon? how does IgE bind to mast cells 16

17 15. (Eosinophilia is associated with infec,on by invasive worms) 16. Eosinophil 17

18 Eosinophil inclusion bodies contain: major basic protein, eosinophil ca,onic protein, phospholipase B ( Charcot- Leyden crystals), etc 17c. QuesEon How does IgE bind to Eosinphils? CD4 cells recognize antigen bind to MHC II MHCII = extracytoplasmic antigens CD8 cells recognize antigen bound to MHC I MHCI = Intracytoplasmic antigens CD4 + T cells CD8 + T cells 18

19 MHC I bound pepede acevates CD8+ T cell Effector func,ons of CD8 + cytotoxic T cells Primary func,on: kill infected cell (Frey) Green= tubulin Red= lyec granule Cytoplasm is reorganized: Golgi focuses towards target cell, MTOC moves to synapse,, lyec granules move to synapse Granules fuse to T cell plasma membrane and empty into close proximity of target cell Mechanisms of CTL-mediated lysis of target cells 19

20 Prokaryotic vs. Eukaryotic cells: Medical relevance of structural differences Vaccines Antibiotics Targets Intrinsic resistance Bacterial Pathogenesis Stages of infectious disease process Attachment, manipulation of host cells, toxin delivery, evasion of host defenses 20