MMI 133 Part 2.1

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MMI 133 Part 2.1
2013-02-20 20:39:56

Lecture 5
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  1. What is the immune system?
    • The body's defense system against: Pathogens, cancers, organ transplants
    • Functios to Keep microorganisms out, remove microogansims that get in, combat microorganisms that remain inside, fight cancer (mutated/transformed cells)
    • Well balanced immune system should be able to: distinguish between SELF and NON-SELF
  2. Well balanced immune system should be able to
    Distinguish between SELF and NON-SELF
  3. Immune System
    Broken into 3 parts
    • 1 st Line (Innate/Natural Immunity, non-specific responses): skin, mucuous membranes & secretion, normal flora
    • 2 nd Line (also innate): Innate immune cells, inflammation, complement, antimicrobial substances
    • 3 rd Line (Adaptive/Acquired Immunity, specific responses): Specialized Lymphocytes 1. B cells (produce antibodies) 2. T cells A. Helper T cells, B. Killer T cells
  4. Skin
    The physical barrier
  5. Mucous membranes
    • Thin and permeable barriers **line the respiratory, gastrointestinal (GI), and genitourinary tracts
    • Mechanical Removal ciliated cells in the respiratory tract (ciliary escalator); goblet cells produce mucous; mucous/other secretions flush away microorganisms; prevent pathogen binding to host cells
  6. Secretions
    • Flushing action of prevents infection
    • Tears, saliva (lysozyme, breaks down peptidoglycan)
    • Crevicular fluid, (flows into gingival crevice between teeth, similar composition to blood serum)
    • Gastric juice (pH 1-2)
    • Urine/vaginal secretions
  7. Normal Flora
    • Compete for space and nutrients
    • In the mouth (Staphylococcus epidermidis, Streptococcus salivarius, Lactobacillus sp), skin (Staphylococcus epidermidis, Candida albicans) and lower GI (Escherichia coli, Lactobacillus sp.)
  8. Innate Immune Cells
    White blood cells (leukocytes)
    • *Neutrophils (PMNL)
    • Macrophages
    • Dendritic cells
    • *Basophils
    • *Eosinophils
    • Mast cells
    • These cause direct destruction of pathogens
    • Natural killer cells -> Destroy infected host cells (intracellular bacteria, virus or transforming cells)
  9. Neutrophil
    • 60-70% of total WBC
    • "eat cells" (phagocytosis)
    • Fast moving, short life span ~ few days
    • First to arrive and dominate initial phagocytosis at the infected site
    • Have granules that contain anti-microbial proteins and inflammatory mediators
  10. Macrophages
    • 3-8% of total WBC
    • Professional phagocytes (very efficient)
    • Eat pathogens & damages cells
    • In circulation -> called monocytes
    • In tissue -> called macrophages (many types)
    • Neutrophils are first to arrive, bu the macrophages are already present
    • Can break down the infectious pathogen to peptides and bind these on it's surface (Antigen presenting cell or APC)
  11. Monocytes
    Macrophages that are in circulation
  12. Macrophages
    Macrophages in tissue
  13. Dendritic cells
    • Professional antigen presenting cell (APC)
    • Phagocytic
    • Important role inactivation of adaptive immunity (specific immune response)
    • Presents peptides from organisms to lymphocytes to kick start the adaptive system
  14. Eosinophil
    • Major role in defense against parasitic infection
    • "spit out" cytolytic enzymes upon contact with pathogens
    • Cells circulated in blood until recruited to inflamed tissue
  15. Mast Cell
    • Most abundant in submucosal tissues
    • Cell surface receptor for immunoglobulin E (IgE)
    • Important role in allergic reactions
    • Release histamine once IgE receptor is activated
  16. Basophils
    • Found in blood
    • Similar function to mast cells
    • Release histamine from granules
  17. Natural killer (NK) cells
    • Lymphocytes that do not have memory
    • First line of defense against intracellular pathogens: virally infected cells, intercellular bacteria/protozoa, tumor cells
    • Release cytolytic granules = target cell destruction
    • Kill infected host cells
    • Kill cancer cells (cells that have lost surface expression of MHC class 1)
  18. MHC Class 1
    • "displays" self (self-peptides) normally; pathogen derived peptides in infection
    • Expressed on all nucleated cells
    • Provides a way for Tc cells to scan and detect intracellular infection
    • Many viruses are able to decrease MHC class 1 expression to try to avoid detection by T cells
    • But - the organisms are not that smart! (NK cells then detect these cells that lack MHC class 1 and kill them)
    • All our cells have MHC
  19. MHC Class 2
    • Antigen presentation
    • Found only on phagocytes (antigen presenting cells or APCs)
    • Only macrophage and dendritic cells have this
  20. Lysozyme
    These are digestive enzymes that breakdown endocytosed pathogens
  21. Lytic granules
    • Phagocytosis, contain digestive enzymes (lysozyme) to breakdown endocytosed pathogen
    • Neutrophil, Macrophage, and Dendritic cell
  22. Secretory granules
    • Function to kill pathogens that are too big to eat (parasites)
    • Contain chemical messengers that attract other immune cells (chemokines)
    • Some contain inflammatory mediators (histamine)
    • Neutrophil, Eosinophil, Basophil
  23. Chemokines
    Chemical messengers that secretory granules use to attract other immune cells
  24. Sequence of events when there is infection in tissues:
    • 1. Mirgination
    • 2. Diapedesis
    • 3. Chemotaxis
    • 4. Phagocytosis
  25. Margination
    Neutrophils get a chemical signal while they are in the blood vessels, marginate and stick to blood vessel walls
  26. Diapedesis
    movement of cells out of the blood vessels by squeezing out through gaps in cells into tissues to track down the intruder
  27. Chemotaxis
    Directed movement of phagocytes towards a chemical gradient set up at the site of intectio or trauma
  28. Phagocytosis
    "phago" = eat and cyto = cell; ingestion of pathogens
  29. Inflammation
    • "immune defensive response to infection or physical agents"
    • Breaching the first line of defense by physical trauma
  30. Clinical characteristics of inflammatory response
    • Swelling
    • Heat - increased blood flow into site of injury
    • A
    • Redness - vasodilation
    • Pain - pain on nerve cells
  31. Types of inflammation
    • Localized (cuts)
    • Systemic (fever)
    • Acute (trauma; S. aureus)
    • Chronic (arthritis; M. tuberculosis)
  32. Swelling
    • Damages cells release chemicals (like histamine)
    • Histamine causes blood vessels to dilate (vasodilation)
    • Expanding blood vessels get leaky; permeability increases
    • Fluids move from blood into damaged area (edema)
  33. Exudate
    Fluid shift in inflammation
    • Protein rich fluid which oozes into tissue or on surfaces
    • Also called inflammatory exudate
    • Usually means that there is a local cause of inflammation
  34. Transudate
    Fluid shift in inflammation
    • Protein poor water fluid entering tissues causes swelling
    • Usually due to systemic factors (eg. hemodynamic factors)
  35. Effusion
    Exudates and transudates may form a fluid collection in a body space
  36. If effusion is composed of pus: purulent or suppurative
    • May develop 'abscesses' which are formed in a space formed from tissue destruction
    • Or 'empyema' in a body space (eg. in pleural space of the chest between pleural membrane and lungs
  37. Different types of Exudates
    • Fibrinous
    • Purulent
    • Hemorrhagic
  38. Abscesses
    formed in a space formed from tissue destruction
  39. Empyema
    • in a body space
    • eg. pleural space of the chest between pleural membrane and lungs
  40. Acute inflammation
    • Neutrophils are the defining cell of the inflammatory infiltrate (PUS)
    • Specialized to go to site of tissue injury and infection
    • Detect formylmethionine on bacterial proteins
    • Chemotaxis: directed migration of a cell to a chemical gradient (eg. C5a)
    • Ingest and digest pathogens
  41. Chronic Inflammation
    • Takes longer to develop (days to months instead of hours)
    • More likely to involve specific recognition of pathogens (not the innate immune system)
    • Cell infiltrate is mainly mononuclear; so monocytes, macrophages and lymphocytes
    • Granuloma formation is typical
    • More likely to have permanent damage to tissue
  42. Granulomas
    • Localized collection of mononuclear phagocytes
    • Seen in TB and in fungal infections
    • Also a characteristic of Crohn's disease and sarcoidosis
    • Wall off infections from rest of body
  43. How phagocytes recognize pathogens
    • Toll-like receptors (TLRs) (also called pattern recognition receptors or PRRs)
    • Recognize pathogen -associated molecule patterns (PAMPs) on microorganisms surface
    • PAMPs: include lipopolysaccharide (LPS), peptidoglycan, flagellin, dsRNA and More!
  44. TLRs
    Toll-like receptors, recognize pathogen-associated molecular pattern on microorganisms surface
  45. PAMPs
    Pathogen-associated molecular patterns; include lipopolysaccharide (LPS), peptidoglycan, flagellin, dsRNA and more!
  46. Triggering to TLRs leads to
    • 1. chemokine release - calls in help from the circulation
    • 2. proinflammatory cytokine release - activate neighbouring cells
    • 3. increased microbiocidal activity - destroy ingested pathogens
  47. The Complement (C) System
    A group of serum proteins produced by the liver in the circulation to destroy pathogens (when pathogens get into the circulation)
  48. Antigen
    A substance, usually foreign, capable of provoking an immune response
  49. Epitope
    The specific site on an antigen recognized by immune cells or antibodies
  50. Antibody
    (aka. immunoglobulin or Ig). Protein produced by B-cells that recognizes a specific epitope or an antigen: leads to clearance of that antigen
  51. Three complement Pathways
    (but 2 major ways to activate the complement system)
    • 1. Classical pathway
    • 2. Alternative pathwas
    • 3. Lectin pathway
  52. 2nd Line: Complement (c')
    • Consists of: >30 plasma proteins in an enzymatic cascade (produced by liver)
    • Activated by: eg. LPS, antibody-antigen complex (alternative and classical pathways respectively)
    • Alternative pathway has a cascade of things that chop up each proteins, causing the cells to swell and burst when C5b, C6, C7, C8 and C9 together form the membrane attack complex
  53. MAC
    • Membrane attack complex
    • Result: LYSIS of cell!
    • pore structure formed (MAC) which allows fluid (water) to move freely across membrane
  54. OIL
    • Function of complement:
    • opsonisation, inflammation and lysis
  55. Important things to remember about complement
    • Opsonication (C3b) - Coats bacteria to enhance phagocytosis
    • Chemoattractant (C5a) - recruit phagocytes
    • Anaphylatoxin (C3a, C5a) - cause histamine release
    • Membrane attack complex (MAC) (C5-C9) - kills pathogens
  56. 2nd Line: other antimicrobial substances
    • Antimicrobial peptides (AMPs)
    • -sweat, platelets, neutrophils, macrophages
    • -form pores in bacterial plasma membrane, inhibit cell wall synthesis, breakdown DNA/RNA
    • Acute phase proteins
    • -produced in the liver during infections: increased levels indicate infection
    • -C-reactive protein (CRP) produced in liver marks bacteria for enhanced phagocytosis (aka opsonisation)
    • Interferons:
    • -Antiviral proteins produced during a viral infection by the neighbouring cells.