Innate immunity lecture


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  • Phagocytosis requires 1. Binding to particle / microbe 2. Actin-filament formation under particle. 3. Membrane extension and fusion behind particle 4. Fusion with lysosome (endocytic pathway).
  • Hallmarks of an Inflammatory Response Redness Heat Swelling Pain
  • Acute-phase proteins are produced by liver cells in response to cytokines released by macrophages in the presence of bacteria. They include serum amyloid protein (SAP) (in mice but not humans), C-reactive protein (CRP), fibrinogen, and mannan- binding lectin (MBL). SAP and CRP are homologous in structure; both are pentraxins, forming five-membered discs, as shown for SAP (photograph on the right). CRP binds phosphorylcholine on certain bacterial and fungal surfaces but does not recognize it in the form in which it is found in host cell membranes. It both acts as an opsonin in its own right and activates the classical complement pathway by binding C1q to augment opsonization. MBL is a member of the collectin family, which includes C1q, which it resembles in its structure. We have already seen how MBL activates complement (see Section 2-7) and how it binds to pathogen surfaces (see Fig. 2.28). Like CRP, MBL can act as an opsonin in its own right, in addition to activating complement. SP-A and SP-D are surfactants A and D, both of which are collectins that coat bacterial surfaces, facilitating their phagocytosis. Photograph courtesy of J. Emsley. Photo from Nature 1994, 367:338-345. © 1994 Macmillan Magazines Limited.
  • Fig. 2.8, part 1 of 2. Overview of the main components and effector actions of complement. The early events of all three pathways of complement activation involve a series of cleavage reactions that culminate in the formation of an enzymatic activity called a C3 convertase, which cleaves complement component C3 into C3b and C3a. The production of the C3 convertase is the point at which the three pathways converge and the main effector functions of complement are generated. C3b binds covalently to the bacterial cell membrane and opsonizes the bacteria, enabling phagocytes to internalize them. C3a is a peptide mediator of local inflammation. C5a and C5b are generated by cleavage of C5b by a C5 convertase formed by C3b bound to the C3 convertase (not shown in this simplified diagram). C5a is also a powerful peptide mediator of inflammation. C5b triggers the late events in which the terminal components of complement assemble into a membrane-attack complex that can damage the membrane of certain pathogens. C4a is generated by the cleavage of C4 during the early events of the classical pathway, and not by the action of C3 convertase, hence the *; it is also a peptide mediator of inflammation but its effects are relatively weak. Similarly, C4b, the large cleavage fragment of C4 (not shown), is a weak opsonin. Although the classical complement activation pathway was first discovered as an antibody-triggered pathway, it is now known that C1q can activate this pathway by binding directly to pathogen surfaces, as well as paralleling the MB-lectin activation pathway by binding to antibody that is itself bound to the pathogen surface. In the MB-lectin pathway, MASP stands for mannan-binding lectin-associated serine protease. MBL important in early childhood and essentially act in lieu of antibodies C4 cleavage exposes thioester bond that covalently bonds to nearest surface Alternate pathway does not depend on a pathogen binding protein (spontaneous cleavage of C3)
  • Non adaptive recognition receptors called Pathogen Recognition Receptors (PRR). These recognize PAMPs or pathogen associated molecular patterns. This leads to activation of immune response. Receptors can exist on the surface of the cell or intracellular in endocytic compartments. Recognition is based on two principles 1. microbial non-self (PRR/PAMP) 2. Missing self Inhibitory receptors (NK cells) Factor H of Complement In this lecture we will focus on receptors that recognize the pathogen. NK cells will be discussed later and you have already discussed complement. However, we will touch on the receptors of the complement system that the innate immune system uses for recognition. Example: Recognition of a pathogen causes to signals to be released. co-stimulator signals cytokines
  • Innate immunity lecture

    1. 1. Innate immunity Prof M.I.N. Matee Department of Microbiology and Immunology School of Medicine
    2. 2. Immunity: All mechanisms used by the body to protect itself against all things foreign Immunity: innate or acquired
    3. 3. <ul><li>Innate immunity: </li></ul><ul><ul><ul><li>all elements with which we are born, </li></ul></ul></ul><ul><ul><ul><li> non-specific, has no memory, </li></ul></ul></ul><ul><ul><ul><li>does not improve after exposure to antigen </li></ul></ul></ul><ul><ul><ul><li>always present, </li></ul></ul></ul><ul><ul><ul><li>available on short notice to protect; </li></ul></ul></ul><ul><ul><li>consists of: </li></ul></ul><ul><ul><ul><ul><li> physical barriers: skin, mucous membranes </li></ul></ul></ul></ul><ul><ul><ul><ul><li>cells: phagocytes and NK cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>proteins: complement, acute phase proteins and interferons </li></ul></ul></ul></ul>
    4. 4. Functions of innate immunity <ul><li>Killing invading microbes </li></ul><ul><li>Activating the acquired (adaptive) immune mechanism </li></ul>
    5. 5. Host defense mechanisms A. Outer barriers Skin and epithelial linings Skin: keratin sweat (NaCl), sebum (unsat. fatty acids) dead skin cells are shed Mucous membranes: mucus and ciliated epithelium stomach – acid ( pH 2-3) mucus - prevent attachment & entry M cells - endocytose pathogens , aids presentation to B and T lymphocytes Tears & saliva - flushing; lysozyme Saliva - aggregation of bacteria Urinary tract - urinary flow
    6. 6. <ul><ul><ul><li>Small intestine - pancreatic enzymes, bile, intestinal enzymes, and secretory IgA </li></ul></ul></ul><ul><ul><ul><li>Peristalsis and loss of columnar epithelial cells help eliminate pathogens (shedding/sloughing off every 2-5 days) </li></ul></ul></ul>
    7. 7. <ul><li>Normal indigenous microbiota may be involved in the following ways: </li></ul><ul><ul><li>Bacteriocin production (colicin by E. coli in large intestine) </li></ul></ul><ul><ul><li>Competition for space and nutrients </li></ul></ul><ul><ul><li>Prevention of pathogen attachment </li></ul></ul>
    8. 8. B. Phagocytosis cells in blood & lymph active without exposure enhanced by immune system 1. Bacterium binds to ‘arm’ 2. Bacterium engulfed into membrane vesicle; phagosome 3. Vesicle fuses with lysosome 4. Digestive enzymes destroy bacterial cell; peroxide & superoxide also formed 5. Wastes emptied out of cell
    9. 9. Phagocytosis (MQ & PMN) <ul><li>Active process initiated by binding to pathogen </li></ul><ul><li>Pathogen is surrounded and then internalized </li></ul>
    10. 10. Fixed Macrophages <ul><li>Liver = Kupffer cells </li></ul><ul><li>Brain = microglial cells </li></ul><ul><li>Lung = alveolar macrophages </li></ul><ul><li>Lymph node = resident and recirculating macrophages and dendritic cells </li></ul><ul><li>Synovium = synovial A cells </li></ul><ul><li>Kidney = mesangial phagocytes </li></ul><ul><li>Skin = Langerhans’ cells </li></ul><ul><li>Bone = Osteoclasts </li></ul>
    11. 11. Circulating Cells <ul><li>Blood monocytes and free macrophages trafficking between tisues </li></ul><ul><li>Polymorphonuclear leukocytes (PMNLs) </li></ul><ul><ul><li>Basophils </li></ul></ul><ul><ul><li>Eosinophils </li></ul></ul><ul><ul><li>Neutrophils </li></ul></ul><ul><li>Lymphocytes </li></ul><ul><ul><li>NK cells </li></ul></ul>
    12. 12. Phagocytosis <ul><li>Professional phagocytic cells </li></ul><ul><ul><li>Macrophages and Neutrophils </li></ul></ul><ul><li>These cells have phagocytic receptors </li></ul><ul><ul><ul><li>External receptors: FcR, CR3, Mannose receptor </li></ul></ul></ul><ul><ul><ul><li>Internal receptors: TLRs </li></ul></ul></ul><ul><li>Oxygen consumption increases </li></ul><ul><li>Increased generation of superoxide (O 2 -) </li></ul><ul><li>Increased release of H 2 O 2 </li></ul><ul><li>Increased HMP activity </li></ul><ul><li>Lysosomal rupture and release of hydrolytic enzymes </li></ul>
    13. 13. Macrophages (MQ) <ul><li>Blood - monocytes (1-6% WBC) </li></ul><ul><li>Tissues - macrophages </li></ul><ul><ul><li>mature form of monocytes </li></ul></ul><ul><ul><li>normally found in tissues such as gastrointestinal tract, lung, liver and spleen </li></ul></ul><ul><li>Activation by : microbes, products, ag-ab complexes, lymphocytes </li></ul><ul><li>Functions: </li></ul><ul><ul><li>Phagocytose and kills </li></ul></ul><ul><ul><li>Produce cytokines/chemokines (initiates inflammation) </li></ul></ul><ul><ul><li>Is an antigen presenting cell </li></ul></ul><ul><li>NB have longer life than granulocytes </li></ul>
    14. 14. Neutrophils (PMN) <ul><li>Present in blood (55-60% of WBC) </li></ul><ul><li>Not normally present in tissues </li></ul><ul><li>Short lifespan - 12 hours </li></ul><ul><li>Functions: </li></ul><ul><ul><li>First at the site of infection/injury </li></ul></ul><ul><li>Ingest and kill microbes after bactericidal mechanisms are activated (binding to pathogen) </li></ul>
    15. 15. Killing Mechanisms <ul><li>Phagozome - membrane bounded vesicle that becomes acidified </li></ul><ul><li>Lysozome - granules that contain products that damage or kill pathogens </li></ul><ul><ul><li>Enzymes </li></ul></ul><ul><ul><ul><li>Lysozyme - dissolves cell walls of some bacteria </li></ul></ul></ul><ul><ul><ul><li>Acid hydrolases - digests bacteria </li></ul></ul></ul><ul><ul><li>Proteins </li></ul></ul><ul><ul><ul><li>Lactoferrin - binds Fe ++ needed for bacterial growth </li></ul></ul></ul><ul><ul><ul><li>Vitamin B12-binding protein </li></ul></ul></ul><ul><ul><li>Peptides </li></ul></ul><ul><ul><ul><li>Defensins and cationic proteins - direct antimicrobials </li></ul></ul></ul>
    16. 16. Killing Mechanisms - cont. <ul><ul><ul><li>Oxygen-derived products </li></ul></ul></ul><ul><ul><ul><ul><li>O 2 - , H 2 O 2 & Myeloperoxidase </li></ul></ul></ul></ul><ul><ul><ul><li>Nitrogen-derived products </li></ul></ul></ul><ul><ul><ul><ul><li>NO (nitrogen oxide) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Produced by inducible NO synthase (iNOS) enzyme </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Enzyme is induced by cytokines (LT, TNF  ) </li></ul></ul></ul></ul>
    17. 17. <ul><ul><li>Inflammation </li></ul></ul><ul><ul><ul><li>Response to tissue injury through the release of chemical signals (inflammatory mediators – vasoactive and chemotactic factors) </li></ul></ul></ul><ul><ul><ul><ul><li>Histamine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Serotonin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Bradykinin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Prostaglandins </li></ul></ul></ul></ul><ul><ul><ul><li>Vasodilation, increased capillary permeability, influx of phagocytic cells </li></ul></ul></ul>
    18. 18. Activation of Vascular Endothelium <ul><li>Endothelium: </li></ul><ul><ul><li>Endothelial cells that line blood vessels </li></ul></ul><ul><ul><li>TNF  & IL-1 induces the expression of adhesion molecules on endothelium: </li></ul></ul><ul><ul><li>P-selectin </li></ul></ul><ul><ul><li>E-selectin </li></ul></ul><ul><ul><li>ICAM-1 </li></ul></ul><ul><ul><li>Initiates Leukocyte Extravagation </li></ul></ul>Immediately released Synthesized in 2 hours
    19. 19. Leukocyte Adhesion
    20. 20. Inflammatory Response
    21. 21. Acute-phase reactants <ul><ul><ul><li>During an acute infection, qualitative and quantitative changes in the host’s blood occur </li></ul></ul></ul><ul><ul><ul><li>Bacteria induce macrophages to make interleukin 6 (IL-6) </li></ul></ul></ul><ul><ul><ul><ul><li>The hepatocytes in the liver respond to IL-6 and produce acute phase, bacterial-specific proteins </li></ul></ul></ul></ul>
    22. 22. <ul><li>Influences inflammatory & tissue repair processes </li></ul><ul><li>Recognizes some foreign pathogens </li></ul><ul><li>Activates complement system </li></ul><ul><li>Bonds to phagocytic cells </li></ul><ul><li>Induces production of inflammatory cytokines </li></ul><ul><li>Main initiator of blood coagulation </li></ul><ul><li>Net effect may be anti-inflammatory </li></ul>
    23. 23. Secreted Pattern Recognition Molecules Acute Phase Proteins Activation of Complement Opsonization of microbial cells Primarily produced by the liver but can be produced by phagocytes
    24. 24. Examples of Acute Phase Reactants <ul><ul><ul><li>C-Reactive Protein (CRP) (a pentaxin) </li></ul></ul></ul><ul><ul><ul><ul><li>Binds phosphorylcholine on bacterial surface </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Activates complement </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Induces opsonization </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Membrane attack complex (MAC) is formed = cell lysis </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Serum amyloid protein (homologus to CRP, another pentaxin) </li></ul></ul></ul>
    25. 25. <ul><ul><ul><li>Mannose binding protein </li></ul></ul></ul><ul><ul><ul><ul><li>Binds mannose on bacteria </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Activates complement </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Induces opsonization </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Membrane attack complex (MAC) is formed </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Iron redistribution – Release of lactoferrin by neutrophils </li></ul></ul></ul><ul><ul><ul><ul><li>Sequestered by host = hypoferremia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Uptake of iron by liver </li></ul></ul></ul></ul>
    27. 27. <ul><ul><li>Fever </li></ul></ul><ul><ul><ul><li>Thermal set point altered in hypothalamus </li></ul></ul></ul><ul><ul><ul><li>Induced by pyrogens </li></ul></ul></ul><ul><ul><ul><ul><li>Exogenous pyrogens </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Endotoxins of Gram negative bacteria </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Staphylococcal enterotoxin </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Group A streptococcal erythrogenic toxin </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Endogenous pyrogens </li></ul></ul></ul><ul><ul><ul><ul><ul><li>IL-1 (made by macrophages) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>TNF-alpha </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>IL-6 </li></ul></ul></ul></ul></ul>
    28. 28. Result of fever <ul><ul><ul><li>Stimulates leukocytes into action </li></ul></ul></ul><ul><ul><ul><li>Enhances bacterial growth inhibition by decreasing availability of iron </li></ul></ul></ul><ul><ul><ul><li>Enhances Ab production and T cell proliferation </li></ul></ul></ul><ul><ul><ul><li>Host cells protected from the effects of TNF-alpha </li></ul></ul></ul>
    29. 29. INTERFERON <ul><li>Defense against viral infections </li></ul><ul><li>Cytokine produced & released by host cells invaded by virus </li></ul><ul><li>Prevents virus from infecting healthy cell </li></ul><ul><li>Stimulates uninfected cells to produce antiviral proteins </li></ul><ul><li>INF-  & INF-  are antiinflammatory </li></ul><ul><li>INF-  is proinflammatory and enhances cell-mediated immunity </li></ul>
    30. 30. Effects of interferons: <ul><ul><ul><li>Activation of endoribonuclease and protein kinase </li></ul></ul></ul><ul><ul><ul><ul><li>Destruction of viral mRNA </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inhibition of protein synthesis (EF-2 phosphorylation) </li></ul></ul></ul></ul><ul><ul><ul><li>Upregulation of MHC class I </li></ul></ul></ul><ul><ul><ul><li>Enhancement of T cyt activity </li></ul></ul></ul><ul><ul><ul><li>Activation of Natural Killer (NK) cells </li></ul></ul></ul>
    31. 31. <ul><ul><li>Tumor necrosis factors (a and b) </li></ul></ul><ul><ul><li>TNF alpha is released from monocytes or macrophages, natural killer cells or various lymphocytes mediate </li></ul></ul><ul><ul><ul><li>the inflammatory response, </li></ul></ul></ul><ul><ul><ul><li>enhance phagocytosis </li></ul></ul></ul><ul><ul><li>TNF beta is cytotoxic for tumor cells </li></ul></ul>
    32. 32. Alternative pathway of complement activation <ul><ul><ul><li>Does not require antibodies </li></ul></ul></ul><ul><ul><ul><li>Immediate </li></ul></ul></ul><ul><ul><ul><li>Activates the terminal complement components which destroy bacteria by creating holes (pores) in the bacterial membrane - MAC </li></ul></ul></ul>
    33. 33. Activation of C’ System - cont. b C4b + C2b C3b + Bb
    34. 34. Regulation of Adaptive Response Veterinary Immunology & Immunopathology 91: 1, 2003