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Lecture 2 Innate immunity

Lecture 2 Innate immunity. General features of innate immunity Example of an inducible innate immune mechanism interferon Example of a preformed innate immune mechanism complement Reading: Parham chapters 1 and 7.15 to 8.10. Innate defense is both preformed and inducible. Example:

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Lecture 2 Innate immunity

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  1. Lecture 2 Innate immunity • General features of innate immunity • Example of an inducible innate immune mechanism • interferon • Example of a preformed innate immune mechanism • complement • Reading: Parham chapters 1 and 7.15 to 8.10

  2. Innate defense is both preformed and inducible Example: Complement (C’) Example: Interferon See Fig 8.38 Parham

  3. Figure 8.1

  4. Figure 8.6 Defensins (epithelium)

  5. Progression of Immunity Figure 8.5 At least three cell types reside within or beneath the epithelium and induce inflammation in response to trauma or microbial products: Macrophages, Mast Cells, and Langerhan’s cells (a skin dendritic cell)

  6. Features of innate immunity • Cellular components: • Phagocytic cells, granulocytes: release toxins, release cytokines, some can move rapidly • High precursor frequency of reactive cells • Multiplicity of receptors for conserved aspects of microbes • Soluble components: • Blood plasma proteins that recognize (tag) microbes • Plasma proteins that destroy microbes • Proteins that sequester molecules needed for microbial nutrition

  7. Components Principle Functions Barriers Epithelial layers Prevent entry Defensins and Cryptidins Microbial killing Circulating and Tissue Effector Cells Neutrophils Early phagocytosis and killing of microbes Mast Cells Release of inflammatory granules Macrophages Efficient phagocytosis and killing of microbes: cytokines Eosinophils Nasty toxic cells designed to kill helminths (worms) Natural killer (NK) cells Lysis of infected cells, activation of macrophages Circulating Proteins Complement (C’) Killing of microbes, opsonization of microbes, actvn leukocytes Mannose-binding protein Opsonization of microbes and activation of C’ C-reactive protein Opsonization of microbes and activation of C’ Lysozyme Bacterial cell wall lysis Cytokines TNF, IL-1, 6, 18 Inflammation IFN a, b Resistence to viral infection IFN g Macrophage activation IL-12 IFNg production by NK cells IL-15 Proliferation of NK cells, memory T cells IL-10, TGF b Control of Inflammation Components of Innate Immunity Adapted from: Abbas (Saunders)

  8. Figure 1.6ij Macrophages are important first responders to infection and tissue damage. Alveolar macrophages (lung) Histiocytes (connective tissue) Kupffer cells (liver) Mesangial cells (kidney) Microglial cells (brain) Tissue macrophage

  9. Figure 1.13 Macrophages phagocytose and degrade foreign particles, bacteria and dead (and dying) host cells. Receptors on Macrophages: LPS receptor-CD14 Toll-like receptors Fc receptors Mannose receptor Complement receptors IFNg receptor Chemokine receptors

  10. Figure 1.6ef Express some of the same receptors found on macrophages. These cells are specialized in killing and swallowing microbes High affinity FceRI receptor. Effective against worm infections. Granules contain mediators-smooth muscle contraction and worm toxicity

  11. Figure 8.8 LPS receptor: CD14 toll-like receptor-4 CR3,4: Complement (C’) receptors (C3b) Scavenger receptor: sialic acid-bearing protein Mannose receptor: Binds mannose on bacteria, activates C’ Glycan receptor: Polysaccharides IN ADDITION: TLRs

  12. Figure 2-6

  13. Figure 1.6gh Function in disease, not entirely understood Contains high affinity receptors for IgE, and preformed granules that contain inflammatory mediators including: histamine; heparin; TNFa; chondroitin sulfate; neutral proteases; and other. Mast cells can also secrete: cytokines to induce inflammation; chemokines to induce infiltration by monocytes, and neutrophils, leukotriences to induce muscle contraction and increase vascular permeability Mast cells are capable of inducing an inflammatory cascade

  14. Mast cells are also found in the tissues Figure 1.14 TNF Mast cells can release histamines which induce inflammation Neutrophils and monocytes are recruited Redness, swelling (erythema, edema)

  15. Lymphocytes are entirely involved with acquired immunity. The come in two types: T lymphocytes (T cells) that differentiate in the thymus and B lymphocytes or B cells that differentiate in the bone marrow. B cells can further differentiate after antigen-activation to plasma cells that produce antibodies Figure 1.6ab

  16. Natural Killer Cells play several interesting roles in the immune system. One is to monitor cells for identification. If a cell doesn’t reveal its identity papers, it is killed. You’ll see this later in the course. Dendritic cells are the most important antigen presenting cells (APCs) in the immune system Figure 1.6cd

  17. Figure 8.10 ** **The most important inflammatory cytokine (at least in this course)

  18. Figure 8.14

  19. The story of interferon LIVE Influenza virus Dead cells + more virus incubate Chick cells

  20. The story of interferon LIVE Influenza virus Heat killed Influenza virus 3-4 hrs Chick cells Resistance to infection! Isaacs and Lindenmann 1957

  21. interferon The story of interferon LIVE Influenza virus Virus free supernatant from cells treated with killed virus Resistance to infection! Isaacs and Lindenmann 1957

  22. Concepts • The cells that produced interferon were non-specialized, i.e, non-immune cells. • The heat killed influenza was recognized as foreign. • Interferon in this context behaved as a danger signal to nearby cells. • Questions • What was seen as foreign? • What rendered the warned cells resistant to infection?

  23. Interferon produced Virus enters here dsRNA detected here by Tlr3 Signal to nucleus How was virus recognized as non-self? Virus was detected in this case by a sensor for double stranded RNA called Toll-like receptor 3 (Tlr3) Interferon can be induced with a synthetic dsRNA, poly I:C (inosine:cytidine) The RNA of normal cells typically is not double stranded, but dsRNA is often a feature of viruses. Influenza is a positive strand RNA virus that generates a negative strand by RNA-dependent RNA polymerase, a process that generates dsRNA

  24. How interferon signaling inhibits viral growth INF-a/b (interferon) INF receptor Induced synthesis (2’-5’)-oligoandenylate synthase Protein kinase PKR dsRNA (inactive) 2-5(A) ATP +ATP dsRNA Active PKR RNAseL (inactive) RNAseL (active) degraded mRNA eIF2a(translation intiation factor) Inhibition of protein synthesis Adapted from Fundamental Immunology , WE Paul, Ed. Chap 39

  25. Fig 8.7 Effects of interferon a,b Effects on viral growth Improved recognition by adaptive immunity Increased innate immune activity

  26. The toll like receptors in humans cytoplasm From Takeda and Akira 2005

  27. Non-specialized cells can detect and respond to infection by recognizing conserved motifs of microbes using Tlrs ssRNA

  28. Tlrs tranmit signals about microbial constituents detected to the nucleus, thus regulating the type of genes expressed, and the subsequent response

  29. Seen by Tlr4 Seen by Tlr2

  30. Toll family of receptors is evolutionarily ancient. Toll receptors in Drosophila were discovered first, and shown to confer resistance to bacteria and fungi by regulating the expression of anti-microbial peptides.

  31. What is the basis for innate immunity, and how does is relate to vertebrates? Drosophila melanogaster mutants were found that were susceptible to fungal and bacterial infections. Immunity in Drosophila (Innate) Toll mutant lacks defense against fungal infections 18 Wheeler lacks defense against bacteria This led to the discovery of a family of receptors known as the Toll-related receptors (TLR) present in vertebrates

  32. Complement pathways Fig 7.27 Parham

  33. Figure 2-20

  34. Figure 2-24 Mannose binding lectin is an innate recognition molecule that recruits complement

  35. Figure 2-11

  36. Figure 2-21 C1q binds to antibody:antigen complexes. Thus it recruits complement to antigen tagged by antibody. Figure 7.30 Binds to antibody:antigen complex

  37. Figure 2-19 part 1 of 2 C1q couples the innate (invariant) complement system to the adaptive immune system (Antibody). Here specificity comes from invariant molecules

  38. Figure 2-22 Complement activation is a proteolytic cascade, in which one protease activates by proteolysis the next protease. Zymogen= inactive enzyme that is activated by proteolysis For MB lectin MASP1/2 cleave C4 The rest is the same See Figs 7.33, 7.34

  39. Figure 2-25 C4 (and C3) carry a unique thioester bond Fig 7.32 ….Cys-Gly-Glu-Gln-……amino acid chain Activated C3 and C4 (C3b and C4b) rapidly bind covalently to nearby surfaces and proteins.

  40. Figure 2-28 Complement activation includes feed forward amplification steps Macrophages, neutrophils and other white blood cells carry C3b receptors that they use to rapidly phagocytose and destroy microbes C3b.

  41. Figure 7.38

  42. Figure 7.39

  43. Figure 7.35

  44. Figure 2-26 The alternative C’ pathway illustrates the important role of negative regulators. Mammalian cells protect themselves from complement-mediated lysis by expressing inhibitory proteins on the plasma membrane. Small amounts of C3b are continually being produced by spontaneous “tick over”. If C3b binds to a pathogen, the reaction continues, if it binds to a host cell in low amounts, the reaction is usually terminated. (This figure is similar to Fig 8.7 in Parham)

  45. Figure 7.43 DAF binds to C3b and C4b causing the dissociation of existing C3 convertases and preventing the assembly of new ones. CR1 and MCP bind to C3b and C4b, making them susecptible to proteolytic cleavage by factor I.

  46. Figure 7.40 Anaphylatoxins: C5a > C3a > C4a Smooth muscle contraction, degranulation of mast cells and basophils. Vasoactive effects directly on local blood vessels. Result: inflammation, edema, increased fluid flow into the lymphatics, and transfer of antigens to local lymph nodes

  47. Figure 2-9

  48. Summary of lecture 2 • Innate immune activity is preformed and inducible • Innate immunity involves all cells (e.g. interferon) • Conserved motifs of microbes are detected (ligands for Tlrs) • Innate response involves • altered circulation- increased vascular permiability • ridding mechanism- toxic mediators, NO, hydrogen peroxide • alarm mechanisms- cytokines, histamine • both local and sytemic signals are transmitted (fever, local swelling) • Leukocyte migration is important • Response is often toxic • Self cells protect themselves (e.g., complement inhibitors) • Innate immunity is coupled to adaptive immunity (classical C’ pathway) • Innate immunity is highly conserved over evolution

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