Inflammation and Immunity

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jbaalmann
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Inflammation and Immunity
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2010-11-16 10:36:25
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  1. What is the difference between central and peripheral tolerance?
    • Central tolerance: occurs in the bone marrow or thymus; primary deletion; negative selection mediated by apoptosis; cells are negatively slected if they exhibit too strong of brinding to MHC
    • Peripheral tolerance: normal flora or antigens in diet are encountered by cells after they exit the bone marrow and thymus; clonal anergy (TCR signaling in absence of co-receptor signaling causes cells to become unresponsive and die) and active suppression by Treg cells and cytokines (IL-10 and TGFbeta)
  2. What are the 4 theories regarding the etiology of autoimmunity?
    • Molecular mimicry theory: Sequence similarities between foreign and self peptides are sufficient to result in the corss activation of T and B cells in the presence of those foreign peptides; rheumatic fever and the papilloma virus cross reacting with insulin receptors are examples of this
    • Polyclonal lymphcyte activation theory: autoantibody is induced by polyclonal activation of lymphocytesl these antibodies are created and pumped out so fast that they may not undergo negative selection fast enough; sepsis and GVHD are two examples; BUT, these antibodies are typically low affinity and not long lasting
    • Sequestered antigen theory: Trauma to organ causes release of crytpic autoantigens which stimulates autoantibody production; sperm agglutinating antibodies in some vasectomized males is an example
    • Co-stimulator theory: inappropriate or over-expression of co-receptors on target cells activates Th cells; MHC class II on pancreatic beta cells in diabetes Type I is an example
  3. Define epitope spreading theory
    Initial autoantigen with multiple epitopes (part of Ag recognized by immune system); one may be dominant and stimulate the immune system, increasing number of B cells (proliferation) specific for that epitope; epitope is processed and placed on surface of MHC receptors; however, some of these additional epitopes may have autoimmunogenic qualities; results in intra-molecular spreading of immunity becuase immune system changes from targeting primary epitope to targeting other ones
  4. Define horror autotoxis
    Proposed by Paul Ehrlich, this theory states that the body is incapable of mounting a response against itself; while he was implying autoimmune diseases were possible, the majority believed this meant that anything that attacked the body was abnormal/the result of human disease/not part of the body
  5. What are Witebsky's postulates?
    • These are used to determine whether or not a given condition can be considered autoimmune.
    • 1. Demonstrate presence of autoantibody or autoreactive T cells in the condition
    • 2. Identify the autoantigen (thing causing the autoAbs); define specificity
    • 3. Immunize a naive individual and produce the autoimmune response
    • 4. Transfer disease manifestations from a diseased individual to a normal host with autoantibody or T cells
    • Experimental autoimmune encephalomyelitus and thrombocytopenia purpura were 2 of the first conditions to pass all the above conditions
  6. How is tissue immunofluorescence used in diagnosing autoimmune diseases?
    • Detects tissue bound antigens
    • Goodpasture's syndrome and lupus nephritis
  7. How is ANA used in diagnosing autoimmune diseases?
    • anti-nuclear antibody
    • Detects circulating autoantibodies using immunofluorescence; including Abs to DNA, histones, and nucleolus
    • Lupus, Sjoren syndrome, Scleroderma
  8. How is ANCA used in diagnosing autoimmune diseases?
    • Anti-neutrophil cytoplasmic antigen
    • Detection of circulating autoantibodies using immunofluorescence
    • Nephritis and Vasculities (Wegner's granulomatosis)
  9. How is Rheumatoid factor used in diagnosing autoimmune diseases?
    • IgM/G/A antibody to the Fc of IgG
    • It's an immune precipitation toest; positive reading can mean rheumatoid arthritis but it can read positive in other mixed connective tissue diseases as well
  10. How is Coombs test used in diagnosing autoimmune diseases?
    • Tests Ab to human IgG agglutinates; this is commonly positive in drug-induced hemolytic anemias and thrombocytopenias
    • Direct: Detects IgG Abs present on patient's RBCs (patient RBC + Coombs reagent); implies autoAb reacts with endogenous RBC Ag or hapten (i.e. penicillin or quinidine) bound to RBC
    • Indirect: detects Ab present in patient's serum (patient serum + normal RBC + Coombs reagent); implies autoAb that crossreacts with normal RBC antigens (ex. Rh)
  11. How are serum complement changes used in diagnosing autoimmune disease?
    Decreased C1, 2, 3, and 4 due to consumption by AgAb immune complexes; detect these via component immunoassays (depressed during acute disease exacerbations)
  12. How is plasmophoresis used to treat autoimmune disease?
    • Reduces circulating Abs or immune complexes
    • Effective in: Graves disease
  13. How are NSAIDs used to treat autoimmune disease?
    • reduce pain and inflammation
    • Effective in: Rhematic diseases (arthritis and fever)
  14. How are corticosteroids used to treat autoimmune diseases?
    • anti-inflammatory effects
    • Effective in: RA and SLE
  15. How are cytotoxic drugs used to treat autoimmune diseases?
    • Inhibit lymphocyte activation
    • Effective in: SLE
    • Azathioprine is an example
  16. How are anti-cytokine reagents used to treat autoimmune diseases?
    • Block pro-inflammatory effects
    • Effective in: Crohn's disease and RA
  17. How is corrective surgery used to treat autoimmune diseases?
    • Removal of damaged tissues
    • Effective in: Crohn's disease, Hashimoto's thyroditis, and RA
  18. How are transfusion and transplantation used to treat autoimmune disorders?
    • Organ or tissue replacement
    • Effective in: Hemolytic anemia and Type I diabetes
  19. What is the function of MHC/HLA?
    • Human leukocyte antigen
    • MHC presents antigen to T cells (located on APCs) which is important for T cell activation, development (shapes the TCR repertoire during T cell differentiation in teh thymus, controls antigen recognition by T cells in peripheral lymphoid tissues, "MHC restriction"), regulates NK cell cytotoxicity, and is the principal barrier to tissue transplantation between species
  20. What is the difference between an alloantigen and and MHC alloantigen?
    • Alloantigen: Antigen expressed by some, but not all members of a species (ABO blood types)
    • MHC alloantigen: Cell surface antigens that define individuals immunologically; your internal fingerprint; recognized by T cells and induce graft rejection; they are btoh polymorphic (multiple alleles) and polygenic (multiple loci); there are no gene rearrangements
  21. What are the similarities between MHC class I and class II?
    Each has a heterodimeric structure, an Ig-like domain, a peptide-binding groove, and is highly diverse
  22. Describe the MHC class I glycoprotein structure
    • Regulates CD8 T cell activation by antigen
    • Expressed on almost all nucleated cells (not trophoblasts or RBCs); so a fibroblast on one individuals might express the following haplotype (A1, A3 B2, B7 C1, C2)
    • Heterodimeric: Alpha chain (transmembrane proteins with 3 globular domains; polygenic; most common are HLA A, B and C; each of these will encode an alpha chain and then pair up with the beta 2 microglobulin; genetic polymorphisms occur between alpha1 and alpha2 domains) and beta2 microglobulin (invariant and not encoded by MHC gene)
  23. Describe the MHC class II glycoprotein structure
    • Regulates CD4
    • Expressed on professional APCs only (dendritic cells, macrophages, and B cells); so a macrophage from one individual might express the following haplotype (A1, A3 B2, B7 C1, C2; DQ7, DQ3 DP1, DP15 DR4, DR6); remember that macrophages will express both
    • Heterodimeric: alpha and beta; but unlike class I, both span the cell membrane and both are encoded by MHC and both are polymorphic
    • Polygenic, but the most common are HLA-DP, DQ, and DR; for whatever reason, an alpha DQ will not pair up with a beta DP
  24. Describe the peptide binding groove on MHC class I and II. Are they similar?
    • Yes, for the purposes of this class, they are the same thing
    • 2 proximal domain for structural support on the MHC molecule and 2 distal alpha chains form the peptide-binding groove
    • Peptide binding groove contains polymorphic residues
  25. Define promiscuous binding in reference to MHC gene products
    • The ability of a single MHC to present to multiple antigens; allows MHC to get away with not having as much diversity as the 10^9 antibodies
    • Each proteintaht is presented also contains multiple antigenic determinants
  26. In reference to MHC formation, what are the different polygenic loci?
    • Class I polygenic loci: HLA-A, B, and C; there are 3 loci with multiple alleles
    • Class II polygenic loci: HLA-DP, DQ, and DR; there are 3 loci with multiple alleles
    • In every cell in your body you have 2 alleles at each loci=12 different; allows for heterozygosity at each locus
    • Multiple polymorphisms at each locus; over 3,000 alleles in the HLA system; >500 HLA-As, 900 Bs, and 300 Cs
  27. What superfamily do MHC class I and II molecules belong to?
    Ig Supergene family
  28. How is HLA inherited within a family?
    • The HLA pattern is inherited as a haplotype (set of alleles contained on a single chromosome of an individual; unlikely that it will be separated); assuming no genetic recombination has occured, parents are always haploidentical with their children; each child has a 75% chance of haploidentity witha sibling; each child has a 25% chance of complete HLA identity with a sibling
    • Co-dominant expression (if you get A1 from your mother, and A2 from your father, you will express both)
    • Cell specific expression (certain cells may not express class II (only APCs express), while other cells may not express class I (nucleated cells only))
    • HLA class I loci are clustered at the 3' end of chromosome 6
    • HLA class II loci are clustered at the 5' end of chromosome 6
    • Thus, the specificity of an individual's T cells is an inherited trait (MHC loci do not rearrange prior to expression)
  29. What is the difference between the cystolic pathway of antigen presentation and the endosomal pathway?
    • Cystolic pathway: Class I; endogenous antigens from within the APC cell are processed and presented on the APC to CD8 T cells; cytosolic proteins antigens are partially digested by the proteasome and presented (ubiquitination initiates proteosome degredation; use LMP proteins 2, 7, and 10 to change specificity of the proteasome); processed proteins are then transported to the ER by TAP (transporter of antigenic peptides); synthesis and folding of class I by chaperones in the ER; class I/peptide complex goes to the GA to be processed and then to the cell surface for presentation
    • Endosomal pathway: class II; exogenous antigens are taken up by phagocytosis or receptor-mediated endocytosis; the acidic endosomal proteases degrade protein ags; MHC will fall apart without antigen or some protein bound to it, so the MHC class II receptor sits inside the membrane of an endosome and uses fake Ag protein called an invariant chain to bind the pocket and hold the receptor together; cleavage of the ivnariant chain leaves a piece of the protein (CLIP) within the pocket; endosoem with cleaved peptide Ag and endosome with MHC class II come together and since CLIP has lower binding affinity, it is replaced; class II/peptide complex goes to cell surface for presentation
  30. What happens when a foreign glycolipid enters the body?
    CD1 (an MHC class I like molecule) recognizes the glycolipid Ag and presents it to NKT cells
  31. What is the difference between an isograft, and allograft, and a xenograft?
    • Isograft: genetically identical individuals (either identical twins or from your own tissue)
    • Allograft: genetically dissimilar individuals; typically rejected, but there are a few we can tolerate; HLA-A1, A2-->HLA-A1, A1 will result in rejection because recipient recognizes A2 as foreign; the more disparities you have, the more vigorous the rejection will be; MHC classes I and II differences are additive; prior immunization is not necessary for strong allograft rejection
    • Xenograft: cross species transplant
  32. What cells are involved in recognizing and rejecting foreign tissues from transplantations?
    • Cytotoxic T lymphocytes recognize allogeneic MHC class I and kills via perforin and granzyme, Fas mediated apoptosis, and TNFalpha apoptosis; remember that growth of CD8s is promoted by release of IL-2 from CD4 Th1 cells, so there's a connection there
    • Th cells recognize allogeneic MHC class II and produce Th1 and Th2 cytokines (Il-2 brings in T/B cells and nK cells; IFNgamma activates macrophages; and IL4 induces differentiation of B cells, switching to anti-HLA antibodies and production of chemokines which leads to cell recruitment
    • Macrophages undergo frustrated phagocytosis and cause cytokine mediated damage to class II differences
    • NK cells recognize targets via ADCC and NK receptors; kills via Fas-dependent or perforin/granzyme mechanisms and produces IFNgamma
  33. When a foreing HLA antigen is recognized by the host immune system, what is the magnitude of the reaction?
    up to 15% of all T cells can respond to a single MHC alloantigen
  34. Define ADCC
    • Antibody-dependent cellular cyotoxicity
    • Macrophages and NK cells only recognize antigen or allograft when it is bound to Ab; the Fc receptor on these cells will bind to it
  35. How do we minimize chances or rejection prior to transplantation?
    • Tissue typing: determines recipient and donor HLA classes I and II Ags
    • ABO typing: ABO is expressed on endothelial cells; it's difficult to match these and MHC, so it limits the number of certain types of transplants we can do (i.e. cardiac); however, it was recently found that ABO incompatibility is acceptable in HLA-matched hearts into very young children because isohemagglutinins that mediate hyperacute rejection develop slowly in neonate
    • Major cross-matching: detects pre-formed recipient anti-donor Abs; must incubate patient serum with donor cells and check HLA reactions
    • Mixed lymphocyte reaction (MLR): detects class II disparity; potential for Th AND tc cell activation; must irradiate donor's cells first so that only proliferation that occurs in culture will be recipient and anti-donor
    • Th cell mediated rejection: recognizes HLA-DP, DQ, and DR matching (type II for CD4 cells)
    • Cytotoxic T cell-mediated rejection: recognizes HLA-A, B, C; type and match ABC antigens (type I)
  36. What is transplantation tolerance?
    • transplant recipients become tolerant to foreign organ grafts over time, despite significant disparities; this is not uncommon; establishment of donor-recipient chimerism
    • Things that favor tolerance: pre-transplantation lympho-ablation (immunosuppressed), continual exposure of recipient to HLA antigens of donor and induction of active suppressor (Treg) cells, and blocking CD28/B7 and CD40/CD154 co-stimulatory signaling (anergy results)
  37. Define haploidentical
    • Sharing at least one haplotype
    • Enough to justify transplant between parents and offspring (more likely to be haploidentical anyway)
  38. If xenograft (animal) transplants exhibit so many problems, why are they still medically significant?
    • Shortage of transplant donors
    • Ability to genetically engineer
    • Potential to overcome problems in the future
  39. What are the classes of immunosuppressive drugs?
    • Calcineurin inhibitors: Cyclosporin and FK506 (means that NFAT is not dephosphorylated and cytokines are not further transcribed)
    • Biologicals: deplete T cell population; Anti-CD3, anti-CD25 (IL2R)
    • Corticosteroids: block phospholipase A from starting the arachidonic acid pathway (without this pathway you can't activate NKkappaB and no cytokine/pro-inflammatory production); Prednisone
    • Anti-metabolites: purine and pyrimidine synthesis inhibitors; no B and T cell proliferation
  40. When would HSCT (hematopoietic stem cell transplantation) be considered a viable treatment option?
    • Following chemotherapeutic treatment for cancer (advantage of graft vs. tumor effects), congenital deficiencies of hematopoietic system, some primary immune deficiencies, some autoimmune disorders, immunotherapy of cancer (i.e. targeting cells with monoclonal Abs)
    • Specifically: SCID, CGD, Wiskott-Alrdich, LAD type I, MS, SLE, Systemic sleroderma syndreom, aplastic anemia, and sickle cell disease
    • Cancers: acute lymphblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, hodgkin's/nonlymphoma, and multiple myeloma
  41. Where are hematopoietic stem cells primarily derived from in humans?
    • Bone marrow (large structures in the iliac crest, pluripotent CD34 cells)
    • Can also mobilize stem cells from the bone marrow into the peripheral blood using G-CSF
  42. What are the advantages and disadvantages of treating an HSCT patient with immunosuppressives?
    • Pros: minimize graft rejection and GVHD
    • Cons: expose patient to opportunistic pathogens; less graft vs. tumor benefits
  43. What are the potential positive and adverse outcomes of HSCT?
    • Positive: it works and cells develop from engrafter stem cells; possibly even some transfer of mature donor lymphocytes and memory cells; recipient develops microbial resistance to opportunistic pathogens; and donor cells (graft) attacks any tumor cells that might be present
    • Adverse: recipient attacks donor (HvG disease); GVHD; opportunistic infections; tumor relapse
    • Monitor graft failure by watching the blood cell counts
  44. How are HSCTs rejected?
    • Same way as solid organ transplant; CD4, CD8, NK cells, macrophages, neutrophils, antibody
    • But add on GVHD (can be fatal)
  45. Aside from typing and MLRs, what can be done clinically to improve the success of HSCT?
    • Microbe free rooms (laminar airflow)
    • Prophylactic antibiotics
    • IVIG
    • Hand washing
    • Pediatric vaccines 1 year post-transplant
  46. What is the difference between allergy, hypersensitivity, and atopy?
    • Allergy: harmful response to environmental antigens (pre-existing Abs or T cell responses)
    • Hypersensitivity: clinical signs or symptoms of host tissue damage due to immune response to foreign antigen
    • Atopy: "out of place" affected regions that were not in contact with the allergen
  47. What are the 2 phases of immediate immune tissue injury?
    Sensitization and elicitation
  48. How does mast cell activation through FcepsilonR1 take place?
    • Cross-linking of receptors from IgE and FceR1
    • Calcium causes arachidonic acid pathway and release of leukotrienes and PGD2s; also causes degranulation (histamines and such)
  49. What types of compounds can degranulate mast cells independently of IgE?
    • Drugs: Morphine, codeine, calcium ionophores, vancomycin
    • Anaphylatoxins: C3a, C4a, C5a; bind to receptors on mast cells and trigger degranulation
    • Neuropeptides: substance P
    • Lectins: found in some foods; can cross-link IgE and cause food allergies
  50. What are the 3 types of mediators produced by mast cells?
    • Preformed (primary) mediators: stored in granules; include histamine, heparin, chemotactic peptides, and proteases
    • Newly synthesized (secondary) mediators: from membrane phospholipids; includes platelet activating factor, prostaglandins, leukotrienes
    • De novo expression: TNF, IL-3, and IL-4; result in ICAM1 expression (+ feedback) and mast cell growth
  51. What are the specific functions of the primary mediators of mast cells?
    • Histamine: itching sensation, vasodilation, increased vascular permeability, smooth muscle contraction, gut peristalsis
    • Heparin: anti-coagulation
    • Chemotactic peptides: chemotaxis of eosinophils and neutrophils
    • Proteases: chymase, tryptase (mucus secretion), and complement activation (protease cleavage of the anaphylatoxins)
  52. What are the functions of the secondary mediators of mast cells?
    • platelet activating factor: increased vascular permeability, smooth muscle contraction, platelet aggregation
    • prostaglandins: increased vascular permeability, vasodilation
    • leukotrienes: mucus secretion, smooth muscle contraction, increased vascular permeability
  53. What is the point of skin testing and RAST for diagnosis of allergic conditions?
    • Skin test: used to test atopic allergies; wheal and flare=edema and erythema reaction; can either be epicutaneous (skin prick) or intradermal (semiquantitative); includes food challenges which can be IgE-dependent (most adults) or IgE independent (a lot of children)
    • RAST: radioallergosorbent assay; use radioactive anti-IgE to locate IgE presence; used especially in patients on anti-histamines that would dampen skin test; but not really used that often anymore
  54. Outline the pathogenesis of cytotoxic immune tissue injury
    • Type II hypersensitivity
    • Onset=hours to days
    • Cell/tissue-bound Ags recognized by IgM and IgG
    • Responding cells=complement (classical) and some neutrophils and macrophages
    • Clearance by CR1-bearing RBCs and Fcgamma receptor bearing splenic and hepatic macrophages
  55. Outline the pathogenesis of immune complex tissue injury
    • Type III hypersensitivity
    • Onset=hours to days
    • Soluble circulating antigens recognized by IgM and IgG; in systemic circualtion, these Ag-Ab complexes deposit in the tissue
    • Responding cells=complement, neutrophils and macrophages (the phagocytic cells)
    • Signs and symptoms=nephritis, arthritis, skin lesions, and vasculitis
  56. What is the difference between DTH skin testing and diagnostic skin testing?
    • DTH skin testing is delayed type hypersensitivity, thus, it measures the rate through a different pathway
    • Takes longer; must wait 48-72 hours (TB test is a good example)
  57. What are some ways one can prevent allergic reactions?
    • Avoidance
    • Immunotherapy (repeated intradermal injections with the allergen; trying to change the nature of response from IgE to IgG)
    • Anti-IgE Fc (reduce the expression of circulating Fcepsilon receptor and IgE)
    • Block Fcepsilon signaling
    • Leukotriene receptor antagonists (Singulair)
    • Corticosteroids (inhibit histamine synthesis and increase IkappaB)
    • Desensitization (short term block of mast cell activation by administering allergen)
  58. What are physiologic and pathologic characteristic of IgE?
    • Present in nanogram levels in the serum
    • Synthesis regulated by Th cells (IL-4 and IL-13)
    • Good for protecting against parasites (improves clearance by 2 days)
    • Fcepsilon receptor interaction (high affinity receptor on mast cells and basophils; low affinity on macrophages and platelets)
    • Hyper IgE syndrome: recurrent and severe staph skin abscesses and penumonia; Th1/Th2 imbalance results in decreased production of IFNgamma which inhibits the Th2 response
  59. What tests are used to detect IgE Ab?
    • Skin tests with selected Ags
    • Radioallergosorbant test (RAST)
    • ELISA
  60. What are the main occupational health hazards?
    • chemical (toxidromes and household toxicants)
    • Physical (heavy lifting can lead to hernias, back pain, other injuries)
    • Biologic
    • Noise induced (over 80-85 decibles)
    • Ergonomic (carpal's tunnel with prolonged typing or repetitive movements)
  61. What are the 3 major routes of chemical exposure in the environment?
    • Inhalation
    • Ingestion
    • Absroption
  62. What is the hierarchy of controlling exposure to workplace hazards?
    • Engineering (remove the hazard)
    • Administrative (follow proper procedures, shift rotation, maintain equipment, etc.)
    • PPE (personal protective equipment)
  63. What is the difference between OSHA and NIOSH?
    • OSHA: Occuptional and Safety health administration; responsible for creating and enforcing workplace safety and health regulations; sets permissible exposure levels
    • NIOSH: National Institute for Occupational Safety and Health; assures safety and healthful working conditions by providing research, information, education and training in the field of occupational health and safety
  64. What are the key components of an MSDS?
    Product infor, ingredients, physical data, fire and explosion hazard data, health data, reactivity data, special protection, environmental data, and shipping data
  65. When should you take a more specific occupational/environmental history?
    • With specific disorders: injury, neuropathy, asthma, acute bronchitis, pneumoconioses, hepatitis, dermatitis, reproductive, new onset depression, headaches, renal failure, anemia, and n/v of unknown origin
    • With high risk jobs: machinery, chemical, repetitive motion, heavy lifting
  66. The detailed history components for assessing dose of toxin exposure include:
    • concentration
    • duration of exposure
    • frequency of exposure
    • PPE compliance
  67. What are the classic signs of acute inflammation?
    • redness (rubor)
    • swelling (tumor)
    • heat (calor)
    • pain (dolor)
    • and loss of function (functio lasea)
  68. What is the difference between transudate and exudate?
    • Exudate: movement of cells and fluid out of the vessel; involves edema and pus (neutrophils and remnants of dead cells)
    • Transudate: ultra filtrate of plasma; only the fluid leaks out (edema); caused by increased hydrostatic pressure (i.e. congestive heart failure) or decreased colloid osmotic pressures (i.e. kidney and liver disease)
    • Important to distinguish these because exudate is treated with Abs while trans is treated with diuretics
    • Tap effusion and send it lab for a cell count, gram stain, protein level, and bacterial culture
  69. What are the stages of acute inflammation?
    • Initiation: stimulation or injury with changes in microvasculature; can be caused by infections, trauma, physical/chemical reagents, tissue necrosis (MI), foreign bodies, or immune reactions (hypersensitivity); vascular structures are dilated (slows down blood flow and allows neuts to roll to the site of injury); plasma proteins and leukocytes go to site of injury and become activated
    • Amplification: soluble mediators and cellular inflammatory systems are activated and amplified (IL-8, c5a, Tgfbeta, PDGF, IL-1, TNF, CSF, etc.)
    • Termination: accomplished by specific inhibition via stop signals (anti-inflammatory lipoxins from arachidonic acid); mediators are produced in rapid bursts and only as long as the stimulus persists (short half-lives)
  70. What must happen before leukocyte extravasation?
    • Vasodilation; mediated by histamine and nitric oxide (NO); dilate the vasculature and cause endothelial cells to contract to loosen their tight packing; activated endothelium also puts receptors on membrane to help bind leukocytes; process is rapid and short-lived
    • Stasis then begins to take place; slows down blood flow; slow moving red cells make the area of inflammation red; key for leukocytes to begin extravasation
  71. Regarding chemotaxis, what are the exogenous and endogenous players?
    • Exogenous: N-formyl methionine terninal acids from bacteria and LPS or other damaged membranes
    • Endogenous: complement proteins c5a, chemokines (IL-8), and arachidonic acid products (leukotriene B4)
    • These all bind to 7 transmembrane G protein coupled receptors on surface of leukocytes and signal polymerization and direct movement of the cell
  72. What happens inside the cell during leukocyte activation?
    LPS binds to CD14, which binds to TLR4 which causes the production of cytokines and ROS followed by phagocytosis of microbe into phagosome
  73. What is the difference between chronic inflammation and acute inflammation?
    • Acute: accumulation of fluid and plasma components in the affected tissue; intravascular stimulation of platelets; presence of polymorphonuclear leukocytes (PMNs, granulocytes, and neutrophils; neuts=acute)
    • Chronic: plasma cells, lymphocytes, and macrophages; little or no swelling; fibrosis (attempt to repair)
  74. What are the 4 possible outcomes of acute inflammation?
    • Termination and resolution (the goal)
    • Abscess (liquifactive necrosis)
    • Scarring (can even happen if pathogen is successfully eliminated)
    • Persistent inflammation (chronic; failure to eliminate pathological insult)
  75. What is triple response?
    • A cutaneous response that results from firmly stroking the skin
    • Initially a red spot due to vasodilation; followed by a pale wheal due to exudation of fluids from the surrounding capillaries; followed by a flare (redness in surrounding area due to arteriolar dilation)
    • This is all due to the release of histamine; released by physical injury, Ag binding to mast cells, anaphylatoxins, neuropeptides, and cytokines; it causes dilation of the arterioles and increases permeability of venules; short duration of action
    • Serotonin acts similarly to histamine, but is found in platelets; released via platelet aggregation, PAF, and thromboxane A2; same results as histamine
  76. What is the function of the Kinin system?
    Vasoactive; These peptides are generated by proteases called kallikrein (Hagemen factor is a potent activator of this); most important product is bradykinin which results in vasodilation, is short-acting, and involved in pain response
  77. How do the coagulation pathway and fibrinolytic pathway interact?
    • The complement and counter-balance each other
    • Both systems are induced by activated factor XIIa (Hageman Factor)
    • Fibrinogen forms bridges between platelets and is the precuror to fibrin
    • Fibrin is a fibrillar protein that is polymerised to form a mesh that forms a hemostatic plug (clot) over a wound site; platelets come and fill in the meshwork
    • Thrombin is a serine protease that converts soluble fibrinogen to insoluble fibrin and assists in the coagulation cascade
    • Plasminogen binds to fibrin in clots and generates plasmin
    • Plasmin is a multifunctional protease that lyses fibrin clots, cleaves C3 to form C3a and b, and activates Hageman factor to amplify the response
  78. What is the effect of arachidonic acid on inflammation?
    • activated and released from membrane phospholipids by cellular phospholipases (A2) which are blocked by steroids and activated by other mediators (i.e. c5a)
    • Cyclooxygenase pathway forms PGs (vasodilation and increased vascular permeability); leads to balanced system of prostacyclins (vasodilation, inhibits platelet aggregation) and thromboxane (vasoconstriction, promotes platelet aggregation); pathway is blocked by COX1 and COX2 inhibitors and aspirin
    • Lipoxygenase pathway forms leukotrienes (vasoconstriction and increased vascular permeability) and chemotaxis (leukotriene B4)
  79. What's the best way to inhibit the arachidonic pathway?
    • Systemic steroids (includes corticosteroids; inhibit the transcription of genes encoding COX2, phospholipase A2, pro-inflammatory cytokines (IL-1 and TNF), and iNOS)
    • COX1 and COX2 inhibitors (NSAIDS); inhibit PG synthesis by blocking cyclooxygenases; aspirin does this irreversibly
    • Lipoxygenase inhibitors; not affected by NSAIDS; new drugs (i.e. singulair) have been developed to block either leukotriene receptors or to inhibit leukotriene production
  80. Which tissues are capable of regeneration?
    • Liver: can do 50% regeneration in a matter of days; good example of stable cells
    • Skin cells and GI tract: regenerate as long as the stem cells are not destroyed; good example of labile cells
    • Permanent cells: not capable of regenerationl i.e. CNS and heart
  81. What is the role of collagen in wound healing?
    • Procollagen is secreted from cell; becomes fibrillar collagen through induction by PDGF, FGF, IL-1, and TNF; collagen III is initially laid down over the wound; remodeled by collagenases (metalloproteinases (MMPs)) of which fibroblasts are the primary source
    • TIMPs are tissue inhibitors of metalloproteinases; produced by mesenchymal cells; help counterbalance the collagenase activity
    • After initial collagen III is removed, type I collagen will be produced to cover the wound
  82. What is the role of fibronectin in wound healing?
    One of the first structural molecules deposited in the early phases of wound healing; the glycoprotein found in tissue and plasma; synthesized by hepatocytes; binds to collagen proteoglycans, fibrinogen, fibrin, cell surfaces, bacteria, and DNA
  83. What is the function of proteoglycans and hyaluronic acid in wound healing?
    One of the first molecules laid down in wound healing; GAGs; highly hydrophilic and bind a huge amount of water; form hydrated gels; give connective tissue ability to resist compression force; useful for lubrication and resilience in joint cartilage
  84. When do you see formation of granulation tissue in wound healing?
    • Initially, even in the repair of an injury
    • Consists of richly vascular connective tissue (capillaries, fibroblasts, variable inflammatory cells)
  85. How are dehiscence and cirrhosis related to wound healing?
    • Dehiscence: rupture of wound; most common after abdominal surgery due to increased pressure
    • Cirrhosis: destruction of the liver; scarring due to excessive tissu destruction via chronic inflammation
  86. What is the timeline for wound healing?
    • 24 hours: neutrophils appear at margins of incision
    • 24-48 hours: Epithelial cells deposit bm components to fuse and form beneath the surface of the scab; thin layer that closes the wound
    • Day 3: Neutrophils replaced by macrophages; granulation tissue invades incision space; collagen fibers are now present
    • Day 5: epidermis recovers normal thickness; collagen fibrils bridge incision
    • Week 2: accumulation of collagen and fibroblast proliferation; leukocyte infiltrate, edema, and increased vacularity disappears
    • 1 month: Scar is made up of cellular connective tissue; devoid of inflammaotry infiltrate, covered by intact epidermis; tensile strength of wound increases (but may take months for wounded area to obtain maximal strength)
    • inflammation; proliferation; and maturation
  87. What is the difference between primary intention wounds and secondary intention?
    • Primary intention wound healing: occurs with surgical wounds (clean wound with well-apposed edges), minimal clot formation, destruction of epithelium only (still have epithelium stem cells around); follows the primary intention timeline (inflammation, proliferation, and maturation)
    • Secondary intention wound healing: wound edges cannot be apposed (could be caused by infection); wounded area fills with granulation tissue from bottom up; large scar usually results; contraction caused by myofibroblasts causes faster healing since a smaller defect must be repaired; destruction of the bm has killed some of the epithelial cells
  88. What are the factors that influence wound healing?
    • Systemic: nutrition (protein and vitamin C deficiency inhibit collagen synthesis and retard healing; Vitamin C is required for hydroxylation of procollagen); metabolic status (i.e. diabetes=slower wound healing); circulatory status; and hormones (glucocorticoids have anti-inflammatory effects; no inflammation=no wound healing)
    • Local: infection (single most important cause of delay in wound healing); mechanical factors (early motion of wound delays healing); foreign bodies (i.e. glass, steel, or broken bone); size, location and type of wound
    • Radiation: ionizing radiation is bad but UV light is good (Vitamin D)
  89. What is the result of excessive scar formation?
    Kelloids: hypertrophic scars primarily composed of type III collagen; lack of proper collagenases to degrade type III collagen and lay down type I
  90. What are the primary characteristics of chronic inflammation?
    • Inciting stimulus has not been removed or microbe has some survival advantage (TB) or there is inert foreign substance present (i.e. silicone breast implants)
    • Local replicationi can lead to granulomas
    • Minimal vascular changes
    • Cellular infiltrates include mononuclear cells (macrophages, lymphocytes, eosinophils, mast cells, and plasma cells) and those associated with local replication
    • Cellular proliferation and fibrosis (in acute inflammation, there are minimal stromal changes and almost no replication); release lots of cytokines; reproduce locally at the site of injury; may present Ag to T cells producing specific hypersensitivity reactions
    • Prolonged inflammation can result in neoplastic changes (i.e. chronic sinus tracts can develop into squamous cellc arcinoma)
  91. What is granulomatus inflammation?
    • A subset of chronic inflammation
    • A granuloma is a microscopic aggregation of macrophages that transform into epithelium-like cells; lots of pink cytoplasm that looks like keratin (still macrophages)
    • Type IV hypersensitivity; effect that the immune response has on the host; destruction of tissue is primarily caused CytT cells (CTLs) and directed by macrophages
  92. What is the difference between normal blood flow and the blood flow seen in shock?
    • Normal: capillary beds perfused, sphincters controlled, AV shunts controlled, minimal hypoxia and drop of pH across capillary beds
    • Reversible phase of shock: peripheral vasoconstriction; AV shunts open (redistribution of blood from splanchnic circulation to heart and brain); decreased pH across capilalry beds; hemodilution (interstitial fluids move into vascular spaces to replace blood loss)
    • Critical phase of shock: continued decrease in blood volume and pressure; maximal peripheral vasoconstriction (an attempt to keep blood near primary organs; results in pooling and stagnation of blood); decreased capillary perfusion (endothelial hypoxia and interstitial edema); disseminiated intravascular coagulation (DIC; sludging of blood and clotting starts to occur; blood clots in capillaries); decreased function of vital organs; metabolic acidosis and eventual death

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