Immunology wk 1

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  1. B cell differentiation
    • Bone marrow in most mammals
    • bursa of fabricius in birds
    • appendix in rabbits
    • ileal peyer's patches in ruminants/pigs/dog
  2. T-cells move __________ as they mature
    toward the medulla of thymus lobule
  3. secondary immune tissues
    • lymph nodes
    • spleen
    • mucosa-associated lymph tissue (MALT) consisting of bronchial (BALT) and gut-associated (GALT)
  4. Lymph node consists of
    • Cortex, where B cells (in through blood/HEV and out through efferent lymphatic) hang out and have germinal centers (with FDCs and a few T cells)
    • Paracortex, where T cells hang out.  Contains High Endothelial Venules (HEV) where B and T meet. If B bound to antigen, differentiate (Plasma, med cords) or proliferate (germinal center, cortex)
    • Medullary cords, where Plasma cells and soluble IgM lives
  5. Follicular dendritic cells (FDCs), Follicular cells
    load antigen-antibody or antigen-complement complexes on surface for B-cells to "trial and error" in germinal centers.  No hematopoietic or antigen presenting cells
  6. Spleen
    • red pulp is RBC for storage and removal of old cells
    • white pulp are like tiny lymph nodes.  B cell zone and germinal centers, PALS (periarteriolar lymphoid sheath) around central arteriole (from trabecular artery, from splenic artery from hepatic artery).
  7. three parts of immune system
    • unspecific (barriers, blocks everyone. Includes commensal bacteria.  Physical, chemical and microbiological componenets to block microbial access)
    • innate (no memory, broad groups)
    • adaptive (memory, recognizes specific single molecules.  Vertebrates only)
    • Require ALL
  8. defensins (and cathelicidins)
    • cationic so attracted to negative microbial surface (host cells usu +).  
    • Aggregate and form a pore (amphipathic)
    • water rushes in
    • non-specifically lyse bacteria
  9. Neutrophils/Polymorphonuclear phagocytes (PMNs)
    • major cell in the blood
    • granulocyte precursor
    • short-lived, constitutive production
    • highly phagocytic
    • pre-formed granules: azurophils (primary) anti-microbial proteins, peptides, myeloperoxidases; Specific (secondary) have lactoferrin (competitive) and NADPH oxidase (ROS)
    • Mobilized from bone marrow by cytokines TNF-alpha, IL-6
    • recruited to site of infection by chemokine IL-8
  10. Eosinophils
    • granulocyte precursor, with granules (lots of stuff, different than neutrophils.  Pre-formed)
    • present in HEALTHY TISSUE
    • parasites and allergy
  11. basophils
    • granulocyte precursor (heparin sulfate and histamine granules)
    • circulate in blood, present in healthy, parasites and allergy
  12. monocytes
    • NO GRANULES--different precursor (shared with mast)
    • circulate in blood
    • precursor of macrophage and dendritic
  13. macrophage (2 kinds)
    • tissue resident: sentinels of infection, present in HEALTHY TISSUES, phagocytic, secrete inflammatory cytokines (TNF-alpha, IL-1, IL-6), first to detect microbes (embryologic seeding), rapid/immediate responders.  
    • Elicited: differentiate in tissues from blood monocytes, recruited to infection after PMN, dominant cell after 1-2 days.  Chronic inflammatory cell
    • can become M1 (prime other macrophages, type 1 inflammation) or M2 (deposit matrix and kill encapsulated parasites, type II inflammation) in different tissues with different signals (induced and produce different cytokines, Th1 vs 2)
  14. Dendritic Cells
    • link between innate and adaptive
    • most potent antigen presenting cell.  
    • migrate to LN to activate T cells
    • mature in response to microbial stimuli, change everything to change function (from phago to APG)
  15. Mast cells
    • present in HEALTHY
    • sentinals
    • produce lipid mediators (prostaglandins, leukotrienes, platelet-activating factor)
    • produce cytokines, chemokines, angiogenic, growth factors
    • recruit macrophages, monocytes, dendritic cells, T cells, neutrophils, basophils, eosinophils
    • degrade snake venom, endogenous toxic mediators.  Change epithelial activity, phagocytosis
    • granules (pre-formed. Histamine, heparin, proteases, chondroitin sulfates, TNF, antimicrobial)
    • long-lived
    • near vasculature
    • pathologic in allergy
  16. NK cells
    • Innate that develops from lymphoid precursor
    • cytotoxic to abnormal cells (virus, tumor, bacteria)
    • granules (perforin and granzyme) to elicit cell death (cytotoxicity)
    • BALANCE of inhibiting, activating.
  17. Direct and indirect recognition of bacteria by the immune system
    • direct: Pattern Recognition Receptor (MAMPS, DAMPS) leading to phagocytosis/destruction
    • indirect: complement activation leading to opsonization and MAC attack
  18. Three complement pathways
    • alternative: C3 spontaneously activates
    • Lectin: mannose-binding lectin (specific proteases) activates C4, C2
    • Classical (antibody-antigen complex): C1(qrs) activates C4, C2
  19. alternative complement pathway
    • spontaneous activation of C3 to C3a (chemokine) and C3b, which is HIGHLY reactive and sticks to whatever is nearby.  
    • Host cells have Decay Accelerating Factor (DAF) to remove C3b and Factor H and Factor I to degrade.  
    • On microbes C3b binds B and Factor D activates it to Bb (C3bBb) which amplifies and gets more C3b onto surface, opsonizing
    • C3b links to CR1 (complement receptor 1) on macrophage, causing endocytosis, phagosome, phagolysosome
    • OR 
    • C3bBb calls/activates C5b which calls C6, 7, 8.  C5b678 calls C9, which forms a pore in the MAC ATTACK (Membrane Attack Complex)
  20. Lectin Pathway (complement)
    Mannose Binding Lectin (MBL) finds mannose (and other things) on microbe, MASP (MBL ASsociated Protease) activates C4 to C4b and C2 to C2a, they find each other (C4b2a) and activate C3 to C3b, which lands on a microbe, amplification.  The rest proceeds as written (opsonization to CR1 on macrophage or MAC attack C5b678 + C9)
  21. Classical pathway (antigen-antibody complex) of complement
    • ADAPTIVE, happens after antibodies are produced
    • C1 acts like MBL/MASP.  C1q is an antibody sensor (bound antigens trigger), C1r and C1s are proteases)
    • activate C4 to C4b and C2 to C2a, proceed to C3bBb to amplify and cause opsonization (CR1 on macrophage) or MAC attack (C5b678+C9)
  22. C3a and C5a
    • C3a is a chemokine, calls more immune cells
    • C5a is an anaphylatoxin, increases permeability of blood vessels and induces inflammation, recruitment
  23. Signaling pattern recognition receptors (PRR)
    • Toll-like Receptors (TLR): transmembrane
    • NOD-like receptors: cytosolic
    • RIG-I-like receptors: cytosolic
  24. Opsonic pattern recognition receptors (phagocytic)
    • mannose binding lectin receptor
    • complement receptor
    • C-reactive protein receptor
  25. non-opsonic/direct phagocytic pattern recognition receptor
    C-type lectin receptor
  26. Toll-like Receptor (TLR)
    • signaling pattern recognition receptor (transcription factor) finding MAMPs
    • expressed on plasma membranes of macrophages, dendritic and B cells
    • activate antigen presenting cells (increase MCH and costimulatory, induce inflammatory cytokines, induce phagocytosis and killing
    • stimulates NFkappaB to let go of IkB-alpha and induce gene transcription
  27. RIG-I like receptors (RLR)
    • cytosolic PRR signaling receptor expressed by ALL CELLS
    • detect RNA (virus) in cytosol
    • induce type I interferon
  28. NOD-like receptors
    • cytosolic signaling PRR expressed by ALL CELLS
    • detect viral and bacterial products, stress and non-infectious particulates in cytosol
    • induces IL-1
  29. DAMPs
    damage that stimulates PRR - can be damage from infection, sterile inflammation (blunt trauma, drug toxicity, etc).
  30. Cardinal signs of inflammation and how they are generated
    • heat: increased blood flow from vasodilation, also energy
    • redness: increased blood flow from vasodilation
    • swelling: edema from diapedesis
    • pain: edema presses on nerves, prostaglandins (hyperalgesia)
    • loss of function: animal trying to protect/avoid pain, edema preventing use
  31. Detection of microbe through activation of endothelium
    • Microbe detected by PRR like TLR, RIG-I, NOD in macrophage, DC, mast etc
    • NFkappaB causes transcription of IL-1 and TNF-alpha
    • increases adhesion molecules on endothelium
    • Transcription of IL-8 increases neutrophil chemotaxis
    • histamine (mast) and complement (PRR, microbe detection) increase leakiness and attachment of neutrophils.
  32. Eicosanoids
    • Leukotrienes: vascular permeability, neutrophil chemotaxis
    • Prostaglandins: vascular permeability, vasodilation, hyperalgesia
    • From arachadonic acid, made in macrophages in response to signaling
  33. Margination
    • vasodilation increases diameter of vessels, causing more blood to go through at a slower speed
    • This reduced rate lets cells "fall out" and contact endothelium (activated)
    • P-selectins (from weibel-palade bodies) expressed due to TNF, IL-6 and 1, histamine) bind S-Le^x
    • weak interactions cause rolling
  34. Firm adhesion
    IL-8 causes conformation change of LFA-1 which binds ICAM-1 to make neutrophils stick to endothelium and stop rolling (pavementing).  Then crawl along looking for PECAM.
  35. steps of neutrophils leaving blood to enter tissues and find infection
    • margination
    • rolling
    • firm adhesion
    • diapedisis
  36. transmigration/diapedesis/extravasation
    Neutrophils find PECAM to figure out where break in cells is, LFA-1 and ICAM-1 continue to hold for zipper-like motion across gap junctions.  Then follow chemokines (IL-8) to infection.
  37. Fever induction
    • MAMPs recognized by TLR of tissue macrophages, NFkappaB stimualtes TNF-alpha, IL-1, IL-6.  Macrophages produce prostaglandins (COX-2), circulate to anterior hypothalamus, increase set point and allow heat gain (increase gain, decrease loss)
    • We don't know why
  38. leukocyte adhesion deficiency (LAD)
    mutation in LFA-1, prevents firm adhesion and diapedesis
  39. three main killing mechanisms of the innate immune system
    • phagocytosis
    • extracellular secretion (defensins, NETs)
    • NK killing of whole cell
  40. phagocytic cells
    neutrophils, monocytes, macrophages, mast cells, dendritic cells
  41. steps in phagocytosis
    • Detect: opsonization (complement) or direct recognition (lectin, scavenger Rs)
    • Receptor signaling: membrane/cytoskeleton changes, actin/myosin creates pseudopod
    • internalization: membrane fusion and pinching off, engulfment
    • destroy: fusion with endosomes and lysosomes to acidify, activate -ases, and generate ROS, RNS, defensins, lactoferrin and B12 binding
  42. generation of RNS
    • nitric oxide synthase: nNOS (neuronal), eNOS (endothelial), iNOS (inducible).  
    • iNOS has to be induced by neutrophils/macrophages but then produces NO forever.  The other two respond to signaling.  eNOS causes vasodilation.
  43. ROS + RNS
    • NO + superoxide = peroxinitrite (ONOO-)
    • damage surface to let other cells in to destroy
    • Reactive species are damaging, macrophages eat all cells that participated in phagocytosis afterwards
  44. Neutrophil Extracellular Traps (NETs)
    • PMNs can shoot their DNA out with histones (sticky) and granule particles to trap and kill microbes.  
    • Good for capsules, biofilm, or too big
    • Kamikaze
  45. NK cell killing
    • inhibitor (iTIM) and activator (iTAM) receptors must be balanced, or else will attach to cell.  
    • Perforin punches holes
    • granzyme induces apoptosis
  46. Respiratory burst complex
    cytosol + membrane complex (highly regulated) use NADPH to make ROS of O2 (O2- to H2O2, to HOCl and OH-)
Card Set:
Immunology wk 1
2016-10-05 01:46:47

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