Immuno Complement/Inflammation (9, 10)

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Immuno Complement/Inflammation (9, 10)
2013-11-03 21:01:53

Exam 4
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  1. immuno 9
  2. complement
    • a series of proteins that work in a cascading fashion to generate important host defense mechanisms
    • can be activated in 3 ways:
    • 1. classical
    • 2. alternative
    • 3. MBL (mannan binding ligand)
  3. classical complement pathway
    • triggered by antibodies bound to antigens on the microbial surface
    • results in the recruitment of inflammatory cells
  4. What are the predominant activators of the classical pathway?
    • antigen-antibody complexes
    • this pathway is a major effector pathway of the humoral adaptive immune response
  5. Classical Complement Pathway Cascade
    • 1. when an antibody binds an antigen fragment, a region on it's Fc (heavy chain) becomes exposed & C1q may bind to it
    • 2. immediately C1r & C1s bind to C1q (q --> r & s)
    • 3. this triad = the enzyme C1 esterase
    • 4. C1 esterase cleaves C4 --> C4a (released) & C4b (stays covalently bound)
    • 5. C14b complex binds C2, which is cleaved by the C1 esterase --> C2a (released) & C2b (stays bound)
    • 6. C14b2b splits C3 --> C3a & C3b
    • 7. C14b2b3b splits C5 --> C5a and C5b
    • 8. C5b stays attached to C14b2b3b & from there binds to C6
    • 9. this initiates the formation of the MAC: C14b2b3b5b + C6, C7, C8, & C9
    • ORDER: 1, 4, 2, 3, 5, 6-9

  6. C1-inhibitor (C1-INH)
    inhibits the binding of C1 to the Fc region of an antibody bound to an antigen

  7. Membrane Attack Complex (MAC)
    • made up of C14b2b3b5b + late components C6-9
    • triggered by C3b attaching to membrane surfaces & cleaving C5 --> C5b sticks & the late components stick to IT
  8. most important ways complement defends against infectious organisms:
    • 1. production of opsonins: coating infected cells w/ Ig & C3b enhances the ability of macrophages + neutrophils to phagocytose them
    • 2. chemotaxis of cells toward injury & production of anaphylatoxins: C3a & C5a induce local & systemic inflammatory responses
    • 3. c8 & c9 direct killing/lysis of organisms
  9. phagocytic activity of neutrophils, neutrophils w/ antibody, & neutrophils, antibody AND complement (C3b)
  10. C3a & C5a
    • stimulate inflammation by
    • 1) attracting neutrophil polymorphs chemotactically to the site of infection
    • 2) stimulating the release of anaphylatoxin (eg. histamine) by degranulating basophils + mast cells
  11. C9
    • late components/part of the MAC
    • protein that forms pores in a pathogen's membrane through which fluid can rush, lysing the foreign cell
  12. alternative complement pathway
    • triggered by C3b binding directly to bacterial/viral products, especially lipopolysaccharide (LPS) aka endotoxin from the cell walls of gram - bacteria & some yeasts
    • results in the opsonization of pathogens
  13. Which parts of the alternative complement pathway are unique and which are also used by the classical complement pathway?
    • UNIQUE: the serum factors B & D, and properdin (factor P)
    • shared: C3, C3b, C5, C6, C7, C8, & C9

  14. Why must activation of the alternative complement pathway be tightly controlled?
    because C3b is normally present in the circulation in small amounts as a result of spontaneous hydrolysis of C3 - it's always primed & ready to go
  15. Factor H & Factor I
    two inhibitory proteins that constantly inactivate C3b, inhibiting the alternative complement pathway
  16. C3BbBP
    C3 convertase formed during activation of the alternative complement pathway after C3b has detected a foreign particle (eg. LPS) and complexed with/undergone a series of reactions involving factors B & D, properdin
  17. lectin complement pathway (MBL)
    • or mannan binding ligand complement pathway
    • initiated when mannan-binding lectin binds to carbohydrates on the surface of microbes
    • results in lysis & death of pathogens
    • activation results in the cleavage of the classical complement pathway components C4 & C2 to form C4b2b
  18. What proteins are important for the lectin complement pathway? (5)
    • MBL (mannose binding lectin)
    • MASP 1
    • MASP 2
    • C4
    • C2
  19. What kind of bacteria cannot activate the lectin complement pathway?
    • gram positive
    • they DO NOT have mannose on their surface
  20. The alternative & lectin complement pathways are part of which immune system?
    they are both effector arms of the INNATE immune system b/c they occurs in the absence of antibody
  21. A deficiency in which complement protein would cause a more serious condition than missing a proteins that acts preliminarily in one of the 3 complement pathways?
    C3 - because it functions in ALL 3 complement systems
  22. SLE (systemic lupus erythematosus)
    • caused by an absence of C1q, C2 or C4
    • deficiency of these tend to cause autoimmunity due to an impaired ability to process & clear immune complexes
    • bacterial infection is not an issue b/c the 2 nonclassical pathways can combat such immune disruptions
  23. absence of C3 causes:
    severe recurrent bacterial infections - none of the complement pathways can function
  24. absence of C5 causes:
    • bacterial infections (LESS severe than C3 deficiency)
    • won't be able to make C5a --> can't punch holes in bacteria membranes
  25. overwhelming Neisserial infections caused by:
    • an absence of C5b --> C6, C7 or C8
    • N. meningitidis & N. gonorrhea (gram -) cause an overwhelming infection because holes can't be punched in bacteria
    • are normally disposed of by complement when they enter blood stream by formation of transmembrane pores
    • without C5b --> C6, C7 or C8, bacteria can spread & infection may manifest in abnormal areas
    • chemotaxis, anaphylaxis, opsonization still function normally, which is why these people are mostly not immunocompromised
  26. absence of alternative pathway components leads to:
    recurrent bacterial infections
  27. infection predominantly in childhood is caused by:
    absence of Lectin pathway proteins
  28. pyogenic infections
    • also a deficiency of the alternative pathway component properdin, or of factors B or D
    • pyogenic = bacteria that cause pus
  29. Hereditary Angioedema (HAE)
    • a rare autosomal dominant genetic disorder caused by an inherited deficiency or dysfunction of the C1 inhibitor (C1-INH)
    • C1 binding to Ig Fc is NOT inhibited
    • there is uncontrolled cleavage of C2 & C4
    • characterized by recurrent episodes of angioedema that most often affect the skin & the mucosal tissues of the upper respiratory and gastrointestinal tracts
  30. Immuno 10
  31. acute inflammation
    • the immediate and early response of vascularized, living tissue to injury
    • in order for a tissue to be inflamed it has to be vascularized/living
  32. causes of acute inflammation
    • anything that causes tissue damage will invoke an acute inflammatory response; exposure to:
    • pathogens (eg. bacteria, viruses, fungi)
    • trauma
    • extreme heat or cold (eg. burn/frostbite)
    • caustic chemicals
    • radiation (eg. UV light, sunburn)
    • an aberrant immune response
  33. What are the 5 cardinal symptoms of inflammation?
    • redness, heat, swelling, pain, loss of function
    • 1. Rubor: caused by vasodilation
    • 2. Calor: as vessels dilate, more warm core blood from inside can move to the periphery
    • 3. Tumor: swelling's caused by increased vascular permeability at the site of inflammation
    • 4. Dolor
    • 5. Functio laesa
  34. What component of the vasculature at the site of tissue damage coordinates & modulates many activities associated with inflammation?
    • the ENDOTHELIUM lining the vasculature
    • modulates things such as blood flow, leukocyte adhesion, & leukocyte transmigration
  35. Sequence of events in acute inflammation:
    • 1. vasoconstriction: mediated by sensory nerve impulses to smooth muscle in blood vessel; only transient, lasts a few seconds
    • 2. vasodilation: promoted by inflammatory mediators
    • 3. increased blood flow: b/c of vasodilation there's less resistance & the BV has a larger lumed --> more warm core blood enters vessels at inflammation site
    • 4. increased vascular permeability: promoted by inflammatory mediators, endothelial cells separate from each other
    • 5. hemoconcentration + slowing of flow (stasis): blood is a liquid; with the endothelial cells separated from one another, plasma (liquid) leaks from the BV lumen to the surrounding interstitium, & remaining RBCs to sludge within the vessel
    • 6. leukocyte trafficking: WBCs in blood vessel lumen attack to endoth. tissues & migrate into site of inflammation
  36. leukocyte trafficking steps
    • 1. capture
    • 2. rolling
    • 3. slow rolling
    • 4. arrest
    • 5. adhesion/strengthening/ spreading
    • 6. intravascular crawling
    • 7. transcellular migration
    • 8. paracellular migration
    • leukocyte trafficking is controlled by coordinated expression of soluble mediators and adhesion molecules
    • these events occur sequentially; interruption of any ONE of these steps (w/ drugs, genetic mutation, or missing mediator) may decrease or halt inflammatory response
  37. Where do soluble mediators involved in acute inflammation originate?
    • plasma proteins: activated by proteolytic cleavage reactions
    • synthesized by cells: pre-formed or synthesized de novo when needed
  38. Which soluble mediators are pre-formed and stored in granules and which are synthesized de novo when they're needed?
    • pre-formed in granules: histamine, serotonin [vasoactive amines]
    • de novo: nitric oxide [NO], prostaglandins, leukotrienes
  39. Histamine
    • promotes vaso/veno/post-capillary dilation & increased vascular permeability
    • activates endothelial cells to upregulate adhesion molecules
    • is a vasoactive amine
    • pre-formed mainly by mast cells (& basophils)
    • is rapidly released upon cell activation
    • by itself can cause most of the symptoms of acute inflammation
    • *is an important mediator of type I hypersensitivity
  40. What stimulates the RELEASE of histamine from mast cells or basophils?
    • the interaction of an antigen w/ specific IgE molecules bound to the surface of mast cells or circulating basophils
    • C5a or C3a binding to their individual receptors
    • trauma
    • temperature extremes
  41. Serotonin
    • promotes venodilation + increased vascular permeability
    • activates capillary endothelial cells to upregulate adhesion molecules
    • is a vasoactive amine
    • pre-formed in platelet cells & stored in granules
    • by itself can cause most of the symptoms of acute inflammation
    • released during platelet activation
  42. Binding of which soluble mediator to local sensory nerves binding receptors produces the sensation of pain?
  43. Nitric Oxide [NO]
    • constitutively expressed by endothelial cells
    • causes vascular smooth muscle relaxation - allows blood vessels to dilated
  44. What does damage to vascular endothelium cause as a result of decreased NO produced?
    • local vasoconstriction --> atherosclerosis
    • drug used for treatment: nitroglycerine
  45. What other cells can produce nitric oxide?
    • leukocytes infiltrating inflamed tissues
    • iNOS (inducible nitric oxide synthase) is produced by activated macrophages
    • results in additional vasodilation at an infected site; participates in acute inflammation as well*
  46. Plasma Proteases
    • 1. complement system
    • 2. kinin system
    • 3. clotting system
    • certain cleavage products of each system have important roles in acute inflammation
  47. How do C3a and C5a, cleavage products of the Complement System, add to acute inflammation?
    • they promote increased vascular permeability and vasodilation by binding to specific complement receptors on mast cells --> releasing histamine
    • *C5a is also a chemotactic for leukocytes: promotes their adhesion to endothelium
  48. The Kinin System
    • potent vasoactive peptides are generated by a cascade of enzymatic reactions following activation of clotting Factor XIIa (12a)
    • Factor XII activates Kallekrein which cleaves heavy molecular weight kininogen (HMWK) --> bradykinin
    • *activation of individual pathways activates each other
  49. bradykinin
    • a protein that causes vasodilation and PAIN at a site of inflammation
    • made from the cleavage of HMWK by Kallekrein
  50. Arachidonic Acid (AA) Metabolism (Eicosanoids)
    • after mechanical, physical or biochemical cell stimulation phospholipase A2 is activated and cleaves arachidonic acid from the plasma membrane
    • AA is precursor for both inflammatory mediators PG & LT
  51. What inhibits phospholipase A2?
    • corticosteroids
    • therefore no arachidonic acid is cleaved from the phospholipids of the PM, & neither PGs or LTs are made
  52. What are the 2 pathways by which AA can be metabolized by?
    • 1.Cyclooxygenase pathway: produces prostaglandins
    • 2. Lipoxygenase pathway: produces leukotrienes & lipoxins
  53. prostaglandins (PG)
    • in general cause vasodilation & increased vascular permeability
    • PGE2: also causes hyperalgesia (increased sensitivity to pain)
    • made from arachidonic acid via the cyclooxygenase pathway
  54. leukotrienes (LT)
    • cause vasoconstriction & bronchospasm
    • typically involved with asthma
    • made from arachidonic acid via the lipoxygenase pathway
  55. 5 lipoxygenase
    • enzyme responsible for inducing the lipoxygenase pathway resulting in leukotriene production
    • blocking it's activity doesn't completely get rid of asthma because it's a complex disease
  56. What 2 enzymes mediate the cyclooxygenase (COX) pathway?
    • 1. COX 1
    • 2. COX 2
    • make prostaglandins
  57. COX-1
    • cyclooxygenase pathway enzyme constitutively expressed in most tissues (principally by endothelium and to a lesser extent, vascular smooth muscle)
    • is thought to be involved in the production of physiologic levels of prostaglandins
  58. COX-2
    • cyclooxygenase pathway enzymes produced principally by endothelial cells & vascular smooth muscle WITHIN sites of inflammation and tissue trauma
    • only produced at sites of trauma because it's upregulated BY WBCs
  59. Drugs designed to inhibit COX enzymes
    • ns-NSAIDS
    • s-NSAIDS
  60. Non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDS)
    • block BOTH COX-1 AND COX-2
    • eg. aspirin, indomethacin, ibuprofen
    • take care of inflammation, but also decrease physiologic amounts of PGs
  61. Selective NSAIDS (s-NSAIDS)
    • Specific for COX-2 and have the benefit of relieving symptoms of acute inflammation WITHOUT the undesirable side effects of
    • gastrointestinal ulceration and potential renal damage
    • eg. Vioxx and Celebrex
  62. LTB4
    • type of leukotriene chemotactic for neutrophils & ACTIVATES them
    • (remember, general leukotrienes promote vasoconstriction, increased vascular permeability (venules) and bronchospasm
  63. LTC4, LTD4, & LTE4
    main examples of leukotrienes responsible for vasoconstriction & increased vascular permeability
  64. Platelet activating factor (PAF)
    • causes vasodilation and increased vascular permeability
    • promotes leukocyte adhesion and extravascular trafficking
    • *made by activated/infiltrating leukocytes (& other cell types) at the site of inflammation
    • may be involved in Type I hypersensitivity reactions
  65. Which is more potent at vasodilating, histamine or platelet activating factor?
    PAF is 10,000 times more potent than histamine
  66. Cytokines
    • one way in which cells communicate with each other
    • orchestrate + amplify acute inflammatory response locally & systemically
    • can exert autocrine, paracrine, & endocrine effects
  67. Which cells produce TNF-α and IL-1 (cytokines) in large quantities?
    • dendritic cells and macrophages (innate immune system)
    • & other cell types at the site of tissue damage
  68. Describe the autocrine, paracrine, & endocrine effects of cytokines IL-1 and TNF-α?
    • autocrine: IL-1 and TNF-α secreted from a given macrophage may bind its receptors causing more production of itself
    • paracrine: bind on endothelial cell receptors in the immediate vicinity of the secreting cell, causing endothelial activation
    • endocrine: can be absorbed systemically & promote fever, loss of appetite, neutrophilia, ACTH, & corticosteroid release; induce the formation of acute phase reactant proteins by the liver
  69. What other indirect effects does TNF-α posses?
    • besides being particularly important in inducing acute inflammation...
    • it indirectly promotes the symptoms of endotoxic shock including hypotension, decreased blood pressure, & increased heart rate
    • it's seen especially in arthritic joints during fare ups; can help alleviate inflammation by making TNF-α antibodies OR decoy receptors which bind TNF-α & render it unable to have any affect on a target cell
    • *people can be more susceptible to infection on such treatment
  70. Interleukin 8 (IL-8)
    a chemokine that promotes neutrophil recruitment & activation within acutely damaged tissues - is largely responsible for the wave of neutrophils that move to an injured site
  71. Where is IL-8 made and stored?
    • quiescently IL-8 is made by endothelial cells and stored pre-formed in Weibel-Palade bodies for immediate release upon endothelial cell activation
    • it can also be synthesized de novo by macrophages, epithelial cells, or other cells including fibroblasts at the site of tissue injury