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Flashcards

Neutrophils

Eleanor Smith Cellular pathology English 49 cards

Cards in this deck (49)

  1. 1Mast cellsFirst described by Ehrlich (1878)
    Present in all tissues close to blood vessels and mucosae
    Granules contain heparin and histamine
    Also release LTC4, PGD2 and cytokines (TNFalpha)
  2. 2We like mast cells becauseThey defend against helminth infection
    They defend against snake venom
    They trigger acute inflammation
    We suspect they modulate inflammation
  3. 3We dislike mast cells becauseThey drive immunopathy in asthma and atopic allergy
  4. 4Types of human mast cellMCT - heparin, tryptase
    MCTC - heparin, tryptase, chymase, MC-CPA
  5. 5Mast cells in the pathophysiology of allergic asthmaInhaled antigens get into lower respiratory tract
    Antigens cause mast cell degranulation and local inflammation
    Results in increased vascular permeability, fluid accumulation and oedema which can obstruct the airways
    Bronchial construction can occur due to smooth muscle contraction which can lead to airway obstruction seen in asthma
  6. 6Mast cells in the GI tractIncrease fluid secretion and peristalsis causing an expulsion of GI tract contents (diarrhoea and vomiting)
  7. 7Mast cells in the airwaysDecreased diameter and increased mucus secretion causing congestion and blocking of airways (wheezing, coughing, phlegm) and swelling and mucus secretion in nasal passages
  8. 8Mast cells in the bloodstreamIncreased blood flow and vessel permeability causing increased fluid in tissues causing increased flow to lymph nodes, increased cells and protein in tissues and increased effector response in tissues
  9. 9Normal white blood cell countsNeutrophils: 30-75%
    Eosinophils: 0-6%
    Basophils: 0-2%
    Monocytes: 0-10%
    Lymphocytes: 20-45%
  10. 10Neutrophil basicsProliferation and differentiation takes place in the bone marrow
    DNA synthesis and granule biogenesis driven by the cytokines GM-CSF and G-CSF (granulocyte colony stimulating factor)
    approx. 50% of nucleated leukocytes are PMNs (reserve pool)
    Neutrophils are mobilised from BM to blood in response to infection (granulocytosis, neutrophilia)
  11. 11Agranulocytosis (neutropenia)Patients have a reduced number/no neutrophils (e.g. X-irradiation, chemotherapy)
    Patients are susceptible to bacterial and fungal infection
  12. 12Development of mature PMNsMyeloblast
    Progranulocyte
    Myelocyte
    Band neutrophil
    Mature PMN
  13. 13OpsoninPlasma proteins that facilitate phagocyte recognition and attachment to targets (x100)
    Discovered in 1903 (Wright & Douglas)
  14. 14Examples of opsoninsIgG antibody
    Complement C3b
    Surfactant proteins A and D
    C-Reactive Protein
  15. 15Which cells perform phagocytosisMost cells are capable of phagocytosis but some cells perform it as part of their main function and these are referred to as professional phagocytes which include neutrophils, macrophages, monocytes, dendritic cells, osteoclasts and eosinophils
  16. 16Receptors which neutrophils mainly use for phagocytosisFc gamma receptors
    Complement receptors 1 and 3
  17. 17Proteases found in neutrophil granulesCollagenase
    Gelatinase
    Serine proteases
    Myeloperoxidase
    Lactoferrin
    Antibiotic proteins
  18. 18How to block phagocytosisBlock actin polymerisation as actin cytoskeleton assembly is essential
  19. 19Problems that can occur during phagocytosisRegurgitation while feeding
    Frustrated phagocytosis (exocytosis)
    Surface phagocytosis
    Evasion of phagocytosis
    The end result is tissue damage
  20. 20Frustrated phagocytosisIf a phagocyte fails to engulf its target, toxic agents can be released into the environment to try and kill the cell. As these agents are also toxic to host cells they can cause extensive damage to healthy cells and tissue
  21. 21Surface phagocytosisCellular defence reaction that occurs in the absence of antibody, as categorised by Wood et al. (1946) who injected a pneumococci-phagocyte mix into rats and showed via Gram-Wiegert's technique for staining that PMNs and macrophages phagocytosed pneumococci within an hour where there was no possible source of intermediary opsonin
  22. 22Phagocytosis receptors in macrophagesFc gamma RIIa
    Fc gamma RIIb
    CR3
    SR-AI
    MARCO
    CD36
    Dectin-1
    MICL
    CD206
    CD169
  23. 23Oxygen-dependent bacterial killingRelease of the superoxide radical is catalysed by the enzyme NADPH oxidase in cell membranes. The superoxide radical is broken down rapidly to give hydrogen peroxide, neither of which are very bactericidal and are used to generate bactericidal molecules (hydroxyl radicals and oxidised halogens)
  24. 24Genetic defect in NADPH oxidaseChronic granulomatous disease:
    failure to clear bacterial infections, pneumonia, abscesses, septic arthritis, skin lesions, osteomyelitis, frequent development of granulomata
  25. 25Non oxygen-dependent bacterial killingProteases
    Phospholipases
    Nucleases
    Lysozyme
    Cationic proteins (BPI & ECP)
    Lactoferrin
    Defensins (AMP)
  26. 26Tissue damage by neutrophilsGenerated by ROS and degranulation especially neutrophil elastase and other neutral proteinases
    Activation of plasma cascades (complement, coagulation, kinins)
    Proteases are counteracted by potent anti-proteinase inhibitors e.g. alpha1 antitrypsin, alpha2 macroglobulin
    PMN activation can lead to endothelial, lung and renal injury
  27. 27Important clinical conditions involving PMN activationEmphysema (COPD)
    Glomerular nephritis
    Sepsis and septic shock
    Adult respiratory distress syndrome (ARDS)
  28. 28AMPsAMPs of fewer than 50 amino acids are an evolutionarily conserved part of the innate immune response e.g. LL-37. beta-defensins, histatins, magainins
    AMPs can kill GP and GN bacteria in in vitro assays and even mycobacteria, fungi and viruses
    They typically contain positively charged amino acid residues, many hydrophobic residues and have a high Bowman index
    They kill bacteria by direct interaction with bacterial cell membranes so are equally active against antibiotic resistant and antibiotic sensitive strains
  29. 29What do cells use to make nitric oxideArginine
    NADPH
    Oxygen
  30. 30The products of making nitric oxide areNitric oxide
    NADP
    Citrulline
  31. 31Carl Nathan et al. (1999)Showed that mice deficient in phagocyte oxidase and inducible nitric oxide synthase were incredibly susceptible to bacteria
  32. 32NETsFirst described by Zychlinsky et al. in 2004
    Dying PMNs extrude nuclear material, DNA and histones making a net to which antimicrobial proteins e.g. MPO are tightly bound
    NETs can kill pathogens extracellularly in vitro
  33. 33Proteins present on NETsHistone H1, H2a, H2b, H3, H4
    Neutrophil elastase
    Cathepsin G
    Myeloperoxidase
    Lactoferrin
    Gelatinase (MMP2, MMP9)
    Peptidoglycan recognition proteins (PGRPs)
  34. 34How might bacteria escape NET killing?a) bacterial catalase interferes with NET formation
    b) bacterial nuclease degrades NETs
    c) capsule protection prevents binding NETs
  35. 35Positives of NET formationRapid (10-120 minutes) - faster than apoptosis
    Active against a wide range of bacteria and yeast
    Trap bacteria locally to prevent spread through tissues
    PMNs keep on killing bacteria even when they are dead
  36. 36Goal of complementPunch holes in pathogen membranes or ensure more efficient phagocytosis via opsonisation
  37. 37On which cells are CR1 (CD35) found?RBCs
    Monocytes
    Macrophages
    B cells
    PMNs
    Follicular dendritic cells
  38. 38On which cells are CR2 (CD21) found?B cells
    Follicular dendritic cells
  39. 39On which cells are CR3 (CD11b/CD18) found?Monocytes
    Macrophages
    PMNs
  40. 40On which cells are CR4 (CD11c/CD18) found?Monocytes
    Macrophages
    PMNs
    Dendritic cells
  41. 41Mannose binding lectinA secreted PRR that initiates the lectin pathway of complement activation when it recognises bacterial or fungal glycolipids and glycoproteins bearing terminal mannose and fucose sugars in a particular spatial conformation
  42. 42How do host cells protect themselves from complementSialic acid - plasma membrane molecule that prevents complement proceeding on their surface. Sialic acid is a carbohydrate moiety, a common constituent of cell surface glycoproteins and glycolipids, which pathogens generally lack. Some pathogens e.g. N. gonorrhoea coat themselves in a layer of sialic acid to hide from the complement system
  43. 43Kim et al. 1992Examined the ability of PMNs to phagocytose sialylated and non-sialylated gonococci and observed a decrease in complement-dependent phagocytosis of sialylated gonococci compared with that of non-sialylated gonococci - contributes to the pathogenicity of gonococcal infections
  44. 44Inactivation of complementSpecific inhibitor proteins in the blood or on the surface of host cells terminate the cascade by either binding or cleaving certain complement components
    Many of the activated components in the cascade are unstable so unless they bind immediately to either the next component in the cascade, or to a nearby membrane, they rapidly inactivate
  45. 45Activation of the classical pathwayC1q binds to Ab-Ag complexes (and direct to pathogens)
    6 molecules of C1q associated with C1r and C1s
    C1q binding causes C1r to cleave C1s to an active form
    C1s cleaves C4 and C2 to generate C4b and C2b
    C4b,2a is an active C3 convertase
  46. 46Which antibody is the most efficient activator of complement?IgM - in theory, a single IgM molecule bound to its antigen is sufficient to generate a nidus for complement activation. Free IgM in the plasma does not activate complement, however binding to antigen through its 5 antigen binding domains generates a major structural change affecting the whole molecule causing it to transition from a planar to staple conformation, exposing complement binding sites in the Fc regions of each of the 5 subunits that initiate complement activation
  47. 47IgG in complement activationMultiple IgG molecules bound close together on the target, termed an immune array, are needed to trigger complement activation.
    Not all IgG subclasses posses complement binding sites: IgG1 and IgG3 are strong complement activators, whereas IgG2 is a weak activator and IgG4 does not activate complement at all
  48. 48Critical features of complement cascade1) amplification at each of the enzymatic steps is crucial for efficient activation
    2) nascent thioester groups in C4 and C3 are crucial components of complement activation - without these entities, complement activation on surfaces would be an impossibility and the system would not function
  49. 49Host protection against complementC1 inhibitor (C1INH) dissociates C1r and C1s from the active C1 complex
    DAF, C4BP and CR1 displace C2b from the C4b2b complex. C4b bound by C4BP, MCP or CR1 is cleaved by a soluble protease I to inactivate forms C4d and C4c
    CD59 prevents the final assembly of MAC at the C8 to C9 stage

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Cellular pathology Flashcards on Neutrophils, created by Eleanor Smith on 24/08/2020.
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Eleanor Smith
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