Immunology Chapter 2

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Immunology Chapter 2
2013-01-28 22:23:06
Innate immune system

Innate immunity
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  1. Definition: Innate Immunity
    • Host defense mechanism that acts from the start of infection and does not adapt to a particular pathogen.
    • Rapid
    • Fixed
    • Constant
    • Limited to a number of specificities
  2. 3 ways pathogens can kill cells and damage tissues:
    • Exotoxins at the surface of the host cell
    • Endotoxins released when pathogen is phagocytosed. Cause local or systemic symptoms
    • Direct cytotoxic effect by pathogens living within cells
  3. Cons of being an intracellular pathogen and an extracellular pathogen
    • Extracellular: exposed to soluble molecules of immune system
    • Intracellular: can be attacked by NK cells and when host is ruptured, exposed to immune particles
    • Intracellular: living in a cell can trigger it to increase production of antimicrobials
  4. What is the most important complement?
    C3. Without it, people are prone to successive infections.
  5. How is C3 activated? What do it's components do?
    1.  Proteolytically cleaved into C3a and C3b

    2.  C3b's thioester bond is subject to NU attack by AA and -OH groups of carbs and proteins on pathogen surface markers.

    3.  Then C3b and pathogen are phagocytosed.

    4.  C3a is an anaphylatoxin causing inflammation
  6. What are the 3 pathways of complement activation?
    1st: Alternative

    2nd: Lectin (induced by infection and takes time to build) (mannose-binding lectin binds to pathogen's surface)

    3rd: Classical (both innate and adaptive) (C-reactive protein)
  7. What CCP molecules regulate C3 convertases?
    • Properdin (factor P)
    • Factor H
    • Factor I
    • Decay-accelerator factor (DAF)
    • Membrane co-factor protein
  8. What does properdin do?
    Increases the speed and power of C3 convertase C3bBb on microbial surfaces by preventing degradation by proteases
  9. What does Factor H do?
    • Counters effects of properdin
    • Reduces number of C3b molecules coating the surface of pathogens
    • Works with Factor I
  10. What does Factor I do?
    • Counters effects of properdin
    • Combines with Factor H to reduce number of C3b molecules on pathogen
    • Without it, can't phagocytose because too much compliment to "swallow"
  11. What does decay-accelerator factor (DAF) do?
    Deactivates C3 convertase by binding C3b
  12. What does membrane co-factor protein do?
    Inactivates C3 convertase and also allows it to be cleaved by Factor I (double inhibition)
  13. What is opsonization?
    • The coating of the surface of a pathogen or other particle with a molecule that makes it more readily ingested by phagocytes.
    • Phagocytic cells carry receptors for the markers.
    • Ex: antibody and complement
  14. What does complement receptor 1 (CR1) do?
    • Binds C3b fragments in high density spots on a pathogen via the alternative pathway
    • Disrupts C3 convertase making it more susceptible to Factor I cleavage
  15. What are the functions of CR1, CR3 and CR4?
    To work together to phagocytose pathogens coated with complement
  16. What do CR3 and CR4 do together?
    • Bind iC3b fragments to facilitate phagocytosis.
    • Integrins that are unrelated to CR1
  17. Steps to compliment receptor recognition and phagocytosis:
    • Compliment activation deposits C3b on pathogen
    • CR1 binds C3b on pathogen
    • CR1 signals for endocytosis
    • Membrane bound vesicle forms
    • Lysosomes fuse
  18. What do transmembrane proteins C5-C9 do to pathogens?
    Form a transmembrane pore (MAC) to lyse bacteria
  19. How is the MAC complex formed?
    • Initiated by C5 cleavage by C5 convertase to C5a and C5b
    • C5b initiates MAC and C9 completes the transmembrane pore
    • Pathogen is lysed
  20. How is the MAC complex prevented on human cells?
    Homologous Restriction Factor and CD59 (protectin) prevent recruitment of C5-C9
  21. What are anaphylatoxins?
    • C3a and C5a fragments
    • Induce anaphylactic shock/acute inflam
    • C5a is more stable and more potent

    • Degranulation of mast cells
    • Increased capillary permeability
    • C5 is chemoattractant and adherant for WBC
    • Contraction of smooth muscle
  22. How do plasma proteins limit spread of infection?
    Coagulation system causes blood clots to immobilize pathogens and prevent blood loss

    Kinin system produces bradykinin to cause vasodilation allowing innate immunity to reach infected site

    Protease inhibitors such as alpha-macroglobulin encase proteases to prevent breakdown of tissue
  23. What are defensins? What are the two different types?
    Amphipathic, antimicrobial peptides that punch holes in microbial membranes

    Alpha and Beta
  24. What do beta-defensins do? Where are they expressed?
    • Located on epithelial cells
    • Function as zymogens
    • Punch holes in pathogen membranes
  25. What do alpha-defensins do? Where are they expressed?
    • Expressed on neutrophils and Paneth cells of the small intestine
    • Punch holes in pathogen membranes
  26. What do Paneth cells secrete?
    • alpha-defensins
    • antimicrobial agents like lysozyme
    • cryptins: HD5 and HD6
  27. What are lectin and scavenger receptors?
    Cell-surface receptors on macrophages that bind microbial parasites causing receptor mediated endocytosis and destruction

    Lectin receptors are mannose and glucan, which bind microbial carbohydrates

    Scavenger receptors bind negatively charged particles on Gram - bacteria
  28. What are Toll-Like Receptors (TLR) and how do they work?
    TLR's are a family of signalling receptors that initiate innate immunity & set the stage for adaptive. Sense presence of infection.

    Contain leucine repeat regions w/diff specificities for bacterial markers

    Transmembrane proteins convey info from outside to alter gene expression for inflammatory cytokines

    Toll interleukin receptor: cytoplasmic domain that responds to IL made by other macrophages for + feedback
  29. What is MyD88? What pathways is it used in?
    It is an adaptor protein to bridge other signalling proteins together. It is used in TLR pathways

    Activation leads to release of transcription factor NFKB and release of cytokines IL-6 and TNFa
  30. What is the TLR3? What pathways is it used in?
    It is used in TLR pathways

    TLR3 through TRIF, activates transcription factor Interferon Response Factor 3 (IRF3)

    Produces cytokines called Type I Interferons
  31. How does TLR4 work?
    MyD88 releases transcription factor NFKB to release inflammatory cytokines IL-6 and TNFa

    TRIF leads to IRF3 and production of Type I Interferons
  32. What are the local and systemic effects of IL-1?
    • Local:
    • Increases vascular permeability
    • Activates lymphocytes
    • Local tissue destruction
    • Increases effector cell access

    • Systemic:
    • Fever
    • IL-6 production
  33. What are the local and systemic effects of TNFa?
    • Local:
    • Increases vascular permeability, which increases flow of complement and drainage into lymph nodes

    • Systemic:
    • Fever
    • Septic shock. DO NOT WANT
  34. What are the local and systemic effects of IL-6?
    • Only Systemic:
    • Fever
    • Acute-phase protein production by liver
  35. What are the local and systemic effects of CXCL8?
    • Only Local:
    • Chemotaxis of neutrophils and basophils to site of infection
  36. What are the local and systemic effects of IL-12?
    • Only Local:
    • Activates NK cells
  37. What are neutrophils? Where are they stored and what do they do?
    • Capture, engulf and kill microorganisms
    • First to initiate and inflammatory response
    • Stored in bone marrow
    • Contribute to innate immunity
  38. What are the 4 structural classes of adhesion molecules?
    • Selectins
    • Mucins called vascular addressins
    • Integrins
    • Immunoglobulins
  39. What is extravastion? What clinical outcome can it refer to?
    When neutrophils migrate out of blood capillaries to sites of infection. Drawn to chemokine CXCL8.

    Also defined as the movement of cells or fluid from blood vessels to surrounding tissue like in a hemorrhage.
  40. What are the steps of extravastion?
    Rolling adhesion of leukocytes by binding selectins. P-selectins from WP bodies and E-selectins from LPS exposure of TNFa

    LFA-1 and CR3 on the neutrophil bind to ICAM-1 on the endothelium. Binding is enhanced with CXCL8 exposure.

    Diapedsis occurs when neutrophil latches on to CD31 in tight junctions and crosses BM by secreting proteases

    Neutrophil follows CXCL8 gradient to infection in blood
  41. What are the two types of neutrophil granules?

  42. What do azurophilic granules of neutrophils contain?
    • lysozyme
    • defensins
    • myeloperoxidase
    • neutral proteases
    • bactericidal proteins: bind LPS & kill Gram-
  43. What do specific granules of neutrophils contain?
    • lactoferrin
    • lysozyme
    • NADPH oxidase