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Phase 2A > ICS week 3 > Flashcards

ICS week 3 Flashcards

1
Q

what are the types of PRRs?

A
  • soluble

- cell associated

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2
Q

what do PRRs respond to?

A

pathogens and associated pathogen associated molecular patterns (PAMPs)

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3
Q

how do soluble PRRs respond to PAMPs?

A
  • direct attack of microorganism by soluble PRR molecules
  • enhancement of phagocytosis of PRR-bound PAMPs
  • proteolytic cascade resulting in lysis of microorganism
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4
Q

how do cell associated PRRs respond to PAMPs?

A
  • phagocytosis of PAMP and associated microorganism
  • activation of immune cell encountering PAMP
  • release of inflammatory mediators to amplify response
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5
Q

what are DAMPs? what are they released by?

A
  • danger associated molecular patterns
  • necrotic cells
  • apoptotic cells typically don’t release DAMPs
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6
Q

what is the response to severe injury?

A
  • production of DAMPs
  • uncontrolled cell death (necrosis)
  • release of DAMPs
  • processing of DAMPs by soluble and cell-associated PRRs
  • immune response
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7
Q

what is the response to physiological stimuli or mild injury?

A
  • DAMPs produced
  • regulated cell death (apoptosis)
  • DAMPs remain hidden in the cell
  • recognition and phagocytosis of apoptotic cell by macrophage
  • immune system remains quiscent
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8
Q

how is recognition of nonself entities achieved by the immune system?

A

array of pattern recognition receptors and proteins that have evolved to detect components of infectious agents that are not usually present in the body

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9
Q

what are PAMPs?

A
  • pathogen-associated molecular proteins
  • components of infectious agents that are normally present in the body
  • not normally in the body, but is a common feature of many frequently encountered pathogens
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10
Q

what are some examples of PAMPs?

A
  • carbohydrates not normally exposed in vertebrates
  • proteins only found in bacteria e.g. flagellin
  • double-stranded RNA that is typical of RNA viruses
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11
Q

what soluble (humoral) pattern recognition molecules are bound to the infectious agents? what does this lead to?

A
  • complement
  • mannose-binding lectin
  • C reactive protein
  • lysozyme
    leads to killing through destruction of microbial cell wall constituents and breaching of the plasma membrane due to protein actions
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12
Q

what does engagement of infectious agents with cell associated pattern recognition receptors lead to?

A
  • can lead to phagocytosis followed by its destruction within phagocytic vesicles
  • leads to activation of signal transduction pathways that culminate in the release of soluble messenger proteins (cytokines, chemokines etc) that mobilise components of the immune system
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13
Q

what do several PRRs bind to?

A
  • several are lectin-like
  • bind multivalently with considerable specificity to exposed microbial surface sugars with their characteristic rigid three-dimensional geometric configurations
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14
Q

what do PRRs often not bind to?

A

array of galactose or sialic acid groups that are commonly the penultimate/ultimate sugars on surface polysaccharides

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15
Q

other than sugars, what else can PRRs bind to?

A
  • detect nucleic acids derived from bacterial and viral genomes by virtue of modifications not found within vertebrate nucleic acids or conformations not normally found in the cytoplasm
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16
Q

what are families of PRRs?

A

TLRs, CTLRs, NLRs, RLRs and scavenger receptors

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17
Q

how many PRRs could be expressed by a phagocyte at a given time?

A

in excess of 50 distinct PRRs

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18
Q

what are TLRs?

A

toll like receptors

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19
Q

how did TLRs get their name?

A
  • similarity to the Toll receptor in the fruit fly (Drosophila)
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20
Q

what is the function of TLRs?

A
  • triggers an intracellular cascade generating the expression of antimicrobial peptides in response to microbial infection
  • series of cell surface TLRs acting as sensors for extracellular infections have been identified
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21
Q

what are cell surface TLRs activated by?

A

microbial elements e.g.:

  • peptidoglycan
  • lipoproteins
  • mycobacterial
  • lipoarabinomannan
  • yeast zymosan
  • flagellin
  • other pathogen derived ligands
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22
Q

what are examples of TLRs that are not displayed on the cell surface? where are they located?

A

some are responsive to intracellular viral RNA and unmethylated bacterial DNA

  • e.g. TLR3 and TLR 7/8/9
  • are located in endosomes and become engaged when encountered with phagocytosed material
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23
Q

what does engagement of TLRs with their respective ligaments lead to?

A

drives activation of nuclear factor kB (NFkB) adn members of the interferon-regulated factor (IRF) family of transcription factors
- depends on specific TLR

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24
Q

where are TLRs located?

A

within the plasma membrane or endosomal membrane compartments

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25
Q

what does NFkB and IRF transcription factors do?

A

after being produced by TLRs, they direct the expression of numerous anti-microbial gene products, e.g. cytokines and chemokines, and proteins that alter the activation state of the cell

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26
Q

what is an example of combinatorial activation of TLRs?

A
  • TLR2 can respond to a wide diversity of PAMPs and typically functions within heterodimeric TLR2/TLR1 or TLR2/TLR6 complexes
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27
Q

what is the structure of TLRs?

A
  • all have the same basic structural features, with multiple N-terminal leucine-rich repeats (LRRs) arranged in a horseshoe/cresent shaped solenoid structure
  • this acts as the PAMP-binding domain
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28
Q

what are LRRs? how are they arranged in TLRs?

A

N-terminal leucine-rich repeats

  • arranged in horseshoe/crescent shaped solenoid structure
  • acts as a PAMP-binding domain
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29
Q

what signalling events happen when PAMP binds to TLR?

A
  • tranduce signals into the cell via C-terminal motifs called TIR domains which can recruit adaptor proteins within the cytoplasm with similar TIR motifs
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30
Q

what are CTLRs?

A

calcium-dependent (C-type) lectin receptors

- transmembrane proteins

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31
Q

what displays CTLRs? what is an example?

A

phagocytes display CTLRs

- macrophage mannose receptor is an example

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32
Q

what is the function/mechanism of CLTRs?

A
  • multiple carbohydrate recognition domains whose engagement with their cognate microbial PAMPs generates an intracellular activation signal
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33
Q

what are NLRs?

A

nod-like receptors

- soluble proteins that reside in the cytoplasm where they act as receptors for PAMPs

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34
Q

what is the structure/function of NLRs?

A
  • typically contain an N-terminal protein-protein interaction motif that enables them to recruit proteases or kinases upon activation
  • central oligomerization domain and C-terminal LRRs
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35
Q

what does the central oligomerization domain and C-terminal LRRs in NLRs act as?

A

acts as the sensor for pathogen products

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36
Q

in what state do NLRs exist in? what function does this serve?

A

thought to exist in an autoinhibited state with their N-terminal domains folded back upon their C-terminal LRRs
- this conformation prevents the N-terminal region from interacting with its binding partners in the cytoplasm

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37
Q

what triggers the activation of NLRs?

A
  • most likely triggered through direct binding of a PAMP to the C-terminal LRRs
  • this disrupts the interaction between the N- and C-termini of the NLR
  • permits oligomerization into a complex that can recruit an NFkB-activating kinase (e.g. RIP-2) or members of the caspase family that can proteolytically process and activate the IL-1beta precursor into a mature cytokine
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38
Q

what is the precursor to cytokines?

A

IL-1beta

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39
Q

what is the inflammasome?

A
  • assembled in response to a number of PAMPs
  • important for the production of IL-1beta and IL-18
  • it is a multiprotein oligomer responsible for the activation of inflammatory responses
  • promotes maturation and secretion of pro-inflammatory cytokines IL-1beta and IL-18
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40
Q

what are RLRs? what is their function?

A
  • RIG-like helicase receptors

- recently discovered group of proteins that act as intracellular sensors for viral-derived products

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41
Q

where are RLRs found?

A
  • found in the cytoplasm
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42
Q

what are RLRs activated by? what is their function?

A
  • all appear to be activated in response to double-stranded RNA
  • capable of directing the activation of NFkB and IRF3/4 that cooperatively induce antiviral type I interferons (IFNalpha and beta)
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43
Q

what are scavenger receptors?

A
  • represent a further class of phagocytic receptors
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44
Q

what is the function of scavenger receptors?

A

recognize a variety of anionic polymers and acetylated low-density proteins

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45
Q

what is an example of a scavenger receptor?

A

CD14

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46
Q

what is the function of CD14?

A

has a role in the handling of Gram-negative lipopolysaccharide endotoxin (LPS)

  • failure can lead to toxic shock
  • biologically reactive lipid A moiety of LPS is recognised by a plasma LPS-binding protein
  • the complex that is captured by the CD14 scavenger molecule on the phagocytic cell activates TLR4
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47
Q

what happens when encountering ligands of PRRs?

A
  • end result is a switch in cell behaviour from a quiescent state to an activated one
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48
Q

what do activated macrophages and neutrophils do?

A
  • phagocytose particles that engage their PRRs

- release a range of cytokines and chemokines that amplify the immune response further

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49
Q

what is the function of NFkB?

A

it is a transcription factor which controls the expression of numerous immunologically important molecules e.g. cytokines and chemokines

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50
Q

where is NFkB located? what is its inhibitor?

A
  • sequestered in the cytoplasm by its inhibitor IkB

- IkB masks a nuclear localisation signal on NFkB

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51
Q

what happens to NFkB when a PAMP binds to its cognate PRR?

A
  • it is liberated from IkB due to the actions of a kinase that phosphorylates IkB and promotes its destruction
  • NFkB is now free to translocate to the nucleus, seek out its target genes and initiate transcription
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52
Q

how do TLRs promote NFkB-dependent transcription through activation of the IKK complex?

A
  1. PAMP binds to PRR
  2. adaptor proteins: TIR domain, MyD88, IRAK, TRAF6
  3. TAK1 protein
  4. activate the IKK complex
  5. the IKK complex phosphorylates the inhibitor of NFkB (IkB), which degrades it
  6. NFkB is liberated and can translocate into the nucleus and initiate transcription of multiple genes
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53
Q

what degrades IkB?

A

IKK complex

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54
Q

what PAMP does TLR1 bind to?

A

bacterial

  • lipopeptides
  • lipoproteins
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55
Q

what PAMP does TLR2 bind to?

A

bacterial

  • lipopeptides
  • lipoproteins
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56
Q

what PAMP does TLR4 bind to?

A

bacterial

- LPS

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57
Q

what PAMP does TLR5 bind to?

A

bacterial

- flagellin

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58
Q

what PAMP does TLR6 bind to?

A

bacterial

  • lipopeptides
  • lipoproteins
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59
Q

what PAMP does TLR10 bind to?

A

unknown

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60
Q

what PAMP does TLR11 bind to?

A

toxoplasma gondii

- profilin

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61
Q

what does binding of plasma membrane TLRs (1,2,4,5,6,10,11) lead to?

A
  • activation of NFkB and IRF (interferon-related factor) transcription factors
  • direct the expression of numerous anti-microbial gene products, e.g. cytokines and chemokines
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62
Q

what PAMP does TLR3 bind to?

A

viral

- dsRNA

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63
Q

what PAMPs do TLR7 and TLR8 bind to?

A

viral

  • ssRNA
  • nucleotide analogues
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64
Q

what PAMP does TLR9 bind to?

A

bacterial

- unmethylated CpG DNA

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65
Q

what TLRs are in the endosomal compartment?

A

TLR 3,7,8,9

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66
Q

what does binding of TLR3 lead to?

A

activation of IRF-3

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67
Q

what does binding of TLR7 and TLR8 lead to?

A

activation of IRF-7

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68
Q

what does binding of TLR9 lead to?

A

activation of NFkB and IRF-5

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69
Q

what does activation of NK cells do?

A
  • secretion of cytokines, e.g. IFNgamma
  • delivery of signals to their target cells via Fas ligand or cytotoxic granules which can kill the cell that provided the activation signal
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70
Q

what receptors do NK cells have?

A

activating and inhibitory receptors

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71
Q

what do activating NK cell receptors do?

A

trigger cytotoxic activity upon recognition of ligands that should not be present on the target cell

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72
Q

what do inhibitory NK cell receptors do?

A

restrain NK cell killing by recognising ligands that should be present

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73
Q

how are bacteria and fungi handled?

A

phagocytosis and killing

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74
Q

how are viruses handled?

A

cellular shut down, self sacrifice, cellular resistance

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75
Q

who proposed PRR concepts?

A

Charles Janeway 1943-2003

- self/non-self discrimination by recognition of unchanging patterns of microbes

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76
Q

what are types of patterns?

A
  • limited characteristics
  • Gram +ve/-ve
  • dsRNA
  • CpG motifs
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77
Q

what are antimicrobial peptides that are secreted? give examples

A
  • secreted in lining fluids from epithelia and phagocytes

- defensins, cathelicidin

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78
Q

what are lectins and collectins?

A

carbohydrate-containing proteins that bind carbohydrates or lipids in microbe walls
- activate complement, improve phagocytosis

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79
Q

what are examples of lectins and collectins?

A
  • mannose binding lectin

- surfactant proteins A and D

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80
Q

what are functions of collectins in innate immunity?

A
  • mediate pathogen aggregation
  • enhance phagocytosis of opsonization directly
  • stimulate oxidative burst in phagocytes
  • modulate cytokine secretion by sensing LPS through cell surface receptors
  • scavenge LPS
  • MBL permeabilizes membrane of microogranisms by complement activation, and SP-A and SP-D do it by unknown mechanisms
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81
Q

how do mannose binding lectin and surface protein A and D permeabilise membrane of microorganisms?

A
  • MBL does it by complement activation

- SP-A and SP-D do it by unknown mechanisms

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82
Q

what are pentraxins?

A

proteins like CRP, which have some antimicrobial actions, can react with the C protein of pneumococci, activate complement and promote phagocytosis

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83
Q

what are types of bacteria that are attach to PPRs?

A
  • lipoproteins/LTA
  • flagellin
  • CpGs
  • LPS
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84
Q

what are types of viruses that attach to PPRs?

A
  • dsRNA

- SsRNA

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85
Q

what intermediate proteins are there for lipoproteins/LTAs?

A
  • MyD88

- Mal/TIRAP

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86
Q

what intermediate proteins are there for flagellins?

A
  • MyD88
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87
Q

what intermediate proteins are there for CpGs?

A
  • MyD88
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88
Q

what intermediate proteins are there for LPS?

A
  • MYD88/MAL

- TRAM/TRIF

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89
Q

what intermediate proteins are there for dsRNA?

A
  • TRIF
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90
Q

what intermediate proteins are there for SsRNA?

A
  • MyD88
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91
Q

what does activation of MyD88/ Mal/TIRAP lead to?

A
  • signalling cascade including IRAKs, TRAF6, TAB2, TAK1 and IKKs leads to activation of NFkB, MAPK cascades, PI-3 kinase
  • leads to cell activation, anti-microbial responses and pro-inflammatory gene trasncription
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92
Q

what does activation of TRAM/TRIF lead to?

A
  • later activation of NFkB from TRIF via activation of RIP
  • activation of a cascade including IKK and TBK1 leads to induction of IRF3 and production of interferon beta -> induction of interferon-dependent gene transcription
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93
Q

what exogenous ligands do TLR1/2 bind to?

A

gram positive lipopeptides

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94
Q

what exogenous and endogenous ligands does TLR3 bind to?

A

exogenous: double stranded RNA
endogenous: mRNA

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95
Q

what exogenous and endogenous ligands does TLR4 bind to?

A

exogenous: LPS, pneumolysin, viral proteins
endogenous: heat shock proteins, HMGB1, hyaluronan, fibrinogen

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96
Q

what exogenous ligand does TLR5 bind to?

A

flagellin

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97
Q

what exogenous ligand does TLR2/6 bind to?

A

gram positive lipopeptides

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98
Q

what exogenous and endogenous ligand does TLR7 bind to?

A

exogenous: single stranded RNA
endogenous: RNA?

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99
Q

what exogenous ligand does TLR8 bind to?

A

single stranded RNA

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100
Q

what exogenous and endogenous ligands does TLR9 bind to?

A

exogenous: CpG DNA
endogenous: DNA, mitochondrial DNA? (context may matter)

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101
Q

what is the special case of TLR4?

A
  • pg amounts of LPS can signal
  • as little as 10 molecules/cell
  • polymorphisms in TLR affect endotoxin responsiveness, associated with human plagues etc
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102
Q

what is the process of signalling with TLR4?

A
  1. LBP/Lipid A go past CD14
  2. ligand binding to TLR4/MD-2
  3. TLR4-oligomerization
  4. signaling
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103
Q

what does activation of the IKK complex produce?

A

NFkB, which produces TNF

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104
Q

what does activation of the TBK-1 complex produce?

A

IRF3, which produces IFN-beta

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105
Q

what does activation of the IRAK-1 complex produce?

A

IRF7, which produces IFN-alpha

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106
Q

what can IRF5 produce?

A

TNF

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107
Q

what are other membrane bound PRRs that may participate in pathogen recognition and in pathogen phagocytosis?

A
  • mannose receptor on macrophages
  • Dectin-1; widespread on phagocytes, helps recognise beta glucans in fungal walls
  • scavenger receptors on macrophages
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108
Q

how do bacteria e.g. salmonella multiply?

A

burst out from the phagolysosome and multiply in the cytoplasm of macrophages

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109
Q

how many NLRs are there? what do they do?

A
  • rapidly expanding family of another 22 human proteins that detect intracellular microbial pathogens
  • detection of peptidoglycan, muramyl dipeptide etc
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110
Q

what are the best known NLRs?

A

NOD1, NOD2, NLRP3

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111
Q

what is NOD2? what is its function?

A
  • widely expressed NLR
  • recognises muramyl dipeptide (MDP), a breakdown product of peptidoglycan
  • activates inflammatory signalling pathways
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112
Q

what is a non-functioning mutation of NOD2?

A

Crohn’s disease

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113
Q

what is a hyperfunctioning mutation of NOD2?

A

Blau syndrome (rare, chronic granulomatous inflammation of skin, eyes and joints)

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114
Q

what is MDP?

A

muramyl dipeptide, a breakdown product of peptidoglycan

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115
Q

what is Blau syndrome? what is it caused by?

A
  • hyperfunctioning mutation of NOD2

- rare, chronic granulomatous inflammation of skin, eyes and joints

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116
Q

what are the best known RLRs? what are their functions?

A
  • RIG-I and MDA5
  • detect intracellular double-stranded viral RNA and DNA
  • couple effectively to activate interferon production, which enables an antiviral response
117
Q

what are examples of the roles of PRRs in homeostasis?

A
  • blood neutrophil numbers may be dependent upon TLR4 signalling, independent of LPS in homeostasis
  • induction of endotoxin tolerance in the newborn gut
  • maturation of the normal immune system
  • maintaining a balance with commensal organisms
118
Q

what theory did Polly Matzinger propose?

A

damage hypothesis: hydrophobicity, dynamic interactions

119
Q

what are the roles of PRRs in damage recognition?

A
  • TLRs adapted to recognise a range of endogenous damage molecules, which may share characteristics of hydrophobicity
  • appearance of host molecules in unfamiliar contexts can activate TLRs
  • TLR signalling by cellular damage products activates immunity to initiate tissue repair and perhaps enhance local antimicrobial signalling
120
Q

what are extracellular damage molecules?

A

fibrinogen, hyaluronic acid, tenascin C

121
Q

what intracellular damage molecules?

A

HMGB1, mRNA, heat shock proteins, uric acid (and uric acid crystals), stathmin

122
Q

what are the roles of PRRs in adaptive immunity?

A
  • activation of TLRs and other PRRs drives cytokine production by APCs that can increase the likelihood of successful T cell activation
  • TLR4 agonists already used as vaccine adjuvants
  • TLR7/8/9 adjuvants in development
123
Q

what are the roles of PRRs in disease?

A
  • recognition of host molecules in autoimmune disease
  • failure to recognise pathogens or increased inflammatory responses
  • atherosclerosis, arthritis, COPD, IBD etc
124
Q

how can knowledge of PRRs be translated to therapy? give examples for each

A
  • enhance TLR signalling: improve immunity, adjuvants
  • inhibit TLR signalling: sepsis syndromes, inflammation, arthritis
  • modify adaptive immune response: bias Th and Treg responses
125
Q

what is innate immunity? what does it consist of?

A
  • present from birth
  • includes physical barriers (e.g. intact skin and mucous membranes)
  • chemical barriers (e.g. gastric acid, digestive enzymes and bacteriostatic fatty acids of the skin)
  • phagocytic cells
  • complement system
126
Q

what is acquired immunity?

A
  • specific, adaptive

- specific to a single organism or a group of closely related organisms

127
Q

what are the mechanisms for acquiring immunity?

A

active and passive

128
Q

what does active immunity involve?

A
  • cellular responses
  • serum antibodies
  • combination acting against one or more antigens on the infecting organism
129
Q

how can active immunity be acquired?

A

by natural disease or by vaccination

130
Q

what is the purpose of vaccines?

A

provide immunity similar to that provided by the natural infection, but without the risk from the disease or its complications

131
Q

what categories can active immunity be divided into?

A

antibody- mediated and cell-mediated components

132
Q

what is antibody-mediated immunity provided by?

A

B lymphocytes and their direct descendants, plasma cells

133
Q

what happens in the process of antibody-mediated immunity? how do antibodies provide immunity?

A
  • when a B cell encounters an antigen that it recognises, it is stimulated to proliferate and produce large numbers of plasma cells secreting an antibody to the antigen
  • the antibody provides immunity by neutralising toxins, blocking adhesion and cell entry by organisms, neutralising and preventing viral replication or complement-mediated killing
134
Q

what regulates replication and differentiation of B cells into plasma cells?

A
  • contact with the antigen

- interactions with T cells, macrophages and complement

135
Q

what is cell-mediated immunity controlled by? what happens in the process?

A
  • controlled by T lymphocytes: help, suppression and cytotoxicity
  • T helper cells stimulate the immune response of other cells
  • T suppressor cells play an inhibitory role and control the level and quality of the immune response
  • cytotoxic T cells recognise and destroy infected cells and activate phagocytes ot destroy pathogens they have taken up
136
Q

what is passive immunity?

A

protection provided from the transfer of antibodies from immune individuals, most commonly across the placenta or less often from the transfusion of blood/blood products including immunoglobulin

137
Q

what are characteristics of protection provided by cross-placental transfer of antibodies?

A
  • more effective against some infections (e.g. tetanus and measles) than others (e.g. polio and whooping cough)
  • temporary protection; usually for only few weeks or months
138
Q

how do vaccines work?

A
  • produce their protective effect by inducing active immunity and providing immunological memory
  • immunological memory enables the immune system to recognise and respond rapidly to exposure to natural infection at a later date
  • prevent/modify the disease
139
Q

where can antibodies be detected?

A

blood or serum

- even in absence of detectable antibodies, immunological memory may still be present

140
Q

what can vaccines be made of?

A
  • inactivated (killed) or attenuated live organisms
  • secreted products, - recombinant components
  • constituents of cell walls
141
Q

what are examples of viruses that contain inactivated bacteria or viruses?

A

pertussis and inactivated poliomyelitis virus (IPV)

142
Q

what are examples of vaccines that contain inactivated toxins/products of the cell?

A
  • tetanus and diphtheria vaccines contain inactivated toxins (toxoids)
  • influenza vaccine contains a surface protein called haemagglutinin
  • pneumococcal vaccine contains the polysaccharide from the capsule
143
Q

what are examples of live attenuated vaccines?

A
  • yellow fever
  • MMR
  • BCG
144
Q

what is the effect of vaccines on childrens’ immune systems?

A
  • from birth and early infancy, humans are exposed to foreign antigens and infectious agents in the everyday environment responding to these helps the immune system develop and mature
  • compared with exposure in the natural environment, vaccines provide specific stimulation to a small number of antigens
  • responding to specific antigens uses a tiny proportion of the capacity of the immune system
145
Q

what have studies investigating whether vaccines increase susceptibility to serious infections shown?

A
  • no evidence of this effect

- infection rates are generally lower in vaccinated children

146
Q

what does injection of an inactivated vaccine/toxoid in an individual without prior exposure produce?

A
  • produces a primary antibody response
  • response is dominated by IgM antibody initially, followed by IgG antibody
  • two or more injections may be needed to elicit such a response in young infants
147
Q

what is the primary course in relation to vaccines?

A

two or more injections of an inactivated vaccine or toxoid in young infants
- dominated by IgM initially, then IgG

148
Q

what is the secondary response in relation to vaccines?

A

further injections will lead to an accelerated response dominated by IgG

149
Q

what is the function of further reinforcing doses of vaccine?

A
  • boost immunity

- provide longer term protection

150
Q

which vaccines have poor protection and poor response?

A
  • plain polysaccharide antigens do not stimulate the immune system as broadly as protein antigens such as tetanus, diphtheria or influenza
  • protection from these enzymes is not long lasting and protection is poor
151
Q

how are polysaccharide vaccines enhanced?

A

enhanced by conjugation; polysaccharide antigen is attached to a protein carrier (e.g. Hib and MenC vaccines)
- enables immune system to respond more broadly to the antigen to provide immunological memory, even in young children

152
Q

what are examples of protein antigen vaccines?

A

tetanus, diphtheria and influenza

153
Q

what are examples of vaccines where the polysaccharide has been conjugated with a protein carrier?

A

Hib and MenC

154
Q

what are adjuvants?

A

substances sometimes put in inactivated vaccines that enhance the antibody response

155
Q

what adjuvants do most combination vaccines contain?

A

aluminium phosphate or aluminium hydroxide

156
Q

what are live vaccines? what is an example?

A
  • live attenuated virus vaccines, e.g. MMR, usually promote a full, long-lasting antibody response after one or two doses
157
Q

what is the mechanism of live vaccines?

A

to produce an immune response, the live organism must replicate (grow) in the vaccinated individual over a period of time (days or weeks)

158
Q

can live vaccines cause diseases?

A
  • the immune system responds to live vaccines in the same way it does to natural infection
  • usually does this without causing the disease itself (as it’s weakened/attenuated)
  • for some vaccines, a mild form of the disease may rarely occur
159
Q

what are the ways in which vaccines can fail?

A

primary or secondary vaccine failures

160
Q

when does primary vaccine failure occur? what is an example?

A
  • occurs when an individual fails to make an initial immunological response to the vaccine
  • e.g. 5-10% of children don’t respond to the measles component of the first dose of MMR. an additional dose would reduce risk of measles
161
Q

when does secondary vaccine failure occur? what is an example?

A
  • occurs when an individual responds initially but then protection wanes over time
  • may acquire infection that is a modified, milder form of disease; less likely to suffer serious complications compared to those who have never been vaccinated
  • an example is pertussis vaccine, when protection against whooping cough after 3 doses is high but declines. a fourth booster dose is needed
162
Q

what is the primary aim of vaccination?

A

to protect the individual who receives the vaccine

163
Q

what are the benefits of vaccination?

A
  • protects individual and others

- reduces the risk of unvaccinated individuals being exposed to infection

164
Q

what is population/herd immunity?

A

individuals who cannot be vaccinated will still benefit from the routine vaccination programme

165
Q

what is an example of the benefit of population/herd immunity?

A
  • babies below age of two months are too young to be immunised
  • are at greatest risk of dying if they catch whooping cough
  • are protected because older siblings and other children have been routinely immunised
166
Q

what can happen when the vaccine coverage is high enough to induce high levels of population immunity?

A
  • infections may be eliminated from the country, e.g. diphtheria
  • if high vacination coverage were not maintained, the disease could return
167
Q

what disease was eradicated from the world by vaccination?

A

smallpox, in 1980

168
Q

what is the WHO working on eradicating?

A

poliomyelitis

169
Q

what can passive immunity be provided by? how long does this protection last?

A

injection of human immunoglobulin, which contains antibodies to the target infection and temporarily increases an individual’s antibody level to that specific infection
- protection afforded within a few days, may only last a few weeks

170
Q

what is HNIG? what is it derived from?

A
  • human normal immunoglobulin
  • derived from pooled plasma of donors
  • contains antibodies to infectious agents that are currently prevalent in the general population
171
Q

give examples of use of HNIG

A

used for protection of immunocompromised children exposed to measles
- individuals after exposure to hep A

172
Q

what diseases are specific immunoglobulins available for?

A
  • tetanus
  • hep B
  • rabies
  • varicella zoster
173
Q

where are specific immunoglobulins obtained from?

A

from the pooled blood of donors who:

  • are convalescing from the target infectious disease, or
  • have been recently immunised with the relevant vaccine, or
  • are found on screening to have sufficiently high antibody titres
174
Q

what is the overall aim of the routine immunisation schedule?

A

to provide protection against the following vaccine-preventable infections:

  • diphtheria
  • Haemophilus influenzae type b (Hib)
  • hepatitis B
  • human papillomavirus (certain serotypes)
  • influenza
  • measles
  • meningococcal disease (certain serogroups)
  • mumps
  • pertussis
  • pneumococcal disease (certain serotypes)
  • polio
  • rotavirus
  • rubella
  • shingles
  • tetanus
175
Q

what is the age where the first vaccines are given?

A

8 weeks old

176
Q

what vaccines are given at 8 weeks old? how?

A
  • dipheria, tetanus, pertussis, polio, Hib and hep B (one injection)
  • pneumococcal conjugate vaccine (one injection)
  • meningococcal B (one injection)
  • rotavirus (one oral application)
177
Q

what vaccines are given at 12 weeks old? how?

A
  • diphtheria, tetanus, pertussis, polio, Hib and hep B (one injection)
  • rotavirus (one oral application)
178
Q

what vaccines are given at 16 weeks old? how?

A
  • diphtheria, tetanus, pertussis, polio, Hib and hep B (one injection)
  • meningococcal B (one injection)
  • pneumococcal conjugate vaccine (one injection)
179
Q

what vaccines are given at one year old? how?

A
  • Hib/MenC booster (one injection)
  • pneumococcal conjugate vaccine booster (one injection)
  • MenB booster (one injection)
  • MMR (one injection)
180
Q

what vaccine is given to eligible paediatric age groups annually? how?

A
  • live attenuated influenza vaccine (LAIV) (nasal spray)
181
Q

what vaccines are given at three years and four months old?

A
  • diphtheria, tetanus, pertussis and polio (one injection)

- MMR (one injection)

182
Q

what vaccine is given at 12-13 year? how?

A
  • HPV (course of two injections at least 6 months apart)
183
Q

what vaccine is given at 14 years old?

A
  • tetanus, diphtheria and polio (one injection)

- meningococcal ACWY conjugate (one injection)

184
Q

what vaccine is given at 65 years old? how?

A

pneumococcal polysaccharide vaccine (one injection)

185
Q

what vaccine is given at 65+ years? how?

A

inactivated influenza vaccine (one injection annually)

186
Q

what vaccine is given at 70 years? how?

A

shingles (one injection)

187
Q

what are hypersensitivity reactions?

A

reactions where recognition of foreign antigen by the immune system causes incidental tissue damage as well as the intended destruction of the antigen

188
Q

what are the main types of hypersensitivity reactions? who defined them?

A

Gell and Coombs defined four main types:

  • type I: immediate hypersensitivity, or allergy, due to activation of IgE antibody on mast cells or basophils
  • type II: antibody to cell-bound antigen
  • type III: immune complex reactions
  • type IV: delayed hypersensitivity mediated by T cells
189
Q

what is immediate hypersensitivity (type I)?

A

reactions in which antigen interacts with IgE bound to tissue mast cells or basophils

190
Q

on what cells is IgE located?

A
  • embedded in membranes of mast cells

- exposes the antigen-binding sites of the molecule to the microenvironment of the cell

191
Q

what happens when IgE is exposed to specific antigens?

A
  • bridges two adjacent IgE molecules

- this bridging effect between Fc receptors for IgE triggers the mast cell to release its mediators

192
Q

what are groups of mediators released by mast cells?

A
  • preformed

- newly synthesised

193
Q

what are examples of preformed mediators released by mast cells?

A

histamine, lysosomal enzymes, chemokines and heparin

194
Q

why are immediate hypersensitivity reactions rapid?

A
  • preformed mediators from mast cells

- effects begin within 5-10 minutes and peak around 30 minutes

195
Q

what happens during skin prick tests?

A
  • if the antigen is pricked into the skin of an allergic individual, a ‘wheal and flare’ reaction rapidly appears
196
Q

what are IgE responses usually directed against?

A

antigens that enter at epithelial surfaces, e.g. inhaled or ingested antigens

197
Q

how much of the population has an allergy?

A

15-20% have some form of allergy

198
Q

what is atopy?

A

an inherited tendency for overproduction of IgE antibodies to common environmental antigens

199
Q

what are examples of typical atopic disorders?

A
  • seasonal allergic rhinitis (hay fever)
  • asthma
  • atopic eczema
200
Q

what are soluble preformed mediators that are immediately released by mast cells?

A
  • histamine
  • chemokines
  • kallikrein generating factor
201
Q

what are granule associated preformed mediators that are immediately released by mast cells?

A
  • proteases
  • peroxidase
  • proteoglycans
  • inflammatory factors of anaphylaxis
202
Q

what are mediators that are newly synthesised then released by mast cells?

A
  • prostaglandins

- leukotrienes

203
Q

when can life threatening allergic reactions occur?

A

when the antigen enters the systemic circulation

204
Q

what is anaphylaxis

A

condition caused by generalised degranulation of IgE-sensitised mast cells and basophils

  • sudden hypotension
  • severe bronchoconstriction
  • collapse
205
Q

what are anaphylactoid reactions?

A
  • similar reactions to allergens that are not mediated by IgE antibodies
  • same mast cell mediators are responsible but the stimulus for release differs
  • substances inducing these reactions act directly on mast cells
206
Q

what are examples of anaphylactoid reaction inducing substances?

A
  • anaesthetic induction agents

- radiological contrast media

207
Q

what is a role of T lymphocytes in immediate hypersensitivity reactions?

A

play a major role in activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils

208
Q

what is the cause of bronchial hyper-responsiveness?

A

once the lining of the airways become inflamed, it is susceptible to any irritant, e.g. airway cooling, smoking, diesel particulates or sulphur dioxide.

209
Q

what causes the inflammatory damage to the airways in asthma? what can this lead to?

A
  • induced by eosinophils which contain major basic protein (MBP)
  • MBP can damage epithelial cells of the airways
  • damage of the epithelium by MBP, cytokines and mediators also exposes sensory nerve endings in the basement membrane and increases irritability through neural triggering
210
Q

what are type II hypersensitivity reactions triggered by?

A

triggered by antibodies reacting antigenic determinants which form part of the cell membrane on the target tissue

211
Q

what components are involved in type II hypersensitivity reactions?

A
  • complement/accessory cells and the cell metabolism involvement affects the consequences of the reaction
  • IgM or IgG antibodies are typically implicated
  • many examples involve drugs/their metabolites which have bound to the surface of red blood cells or platelets to form highly immunogenic epitopes
212
Q

what is the consequence of type II hypersensitivity reaction?

A

antibodies formed against the drug/its metabolite inadvertently destroy the cell as well (bystander lysis)
- results in haemolytic anaemia or thrombocytopenic purpura

213
Q

how can autoantibodies cause disease?

A
  • bind to the functional sites of self antigens, e.g. receptors for neurotransmitters/hormones, which mimicks or blocks the action of the hormone without causing inflammation or tissue damage
214
Q

what do some consider a class V hypersensitivity reaction? what is an example?

A
  • stimulation of cell function by antibody

- Graves’s disease where antibodies against the TSH receptor drive over production of thyroid hormones by the cell

215
Q

what are type III hypersensitivity reactions?

A
  • immune complex hypersensitivity

- result from deposition or formation of immune complexes in the tissue

216
Q

what does localisation of immune complexes depend on?

A
  • size
  • electrostatic charge
  • nature of the antigen
217
Q

what could happen if immune complexes accumulate in tissues in large quantities?

A
  • may activate complement and accessory cells

- may produce extensive tissue damage

218
Q

what is an example of type III hypersensitivity reaction?

A
  • Arthus reaction

- experimental model where an antigen is injected into the skin of an animal that has been previously sensitised

219
Q

what is the consequence of the Arthus reaction?

A
  • reaction of preformed antibody with this antigen results in high concentrations of local immune complexes
  • this causes complement activation and neutrophil attraction
  • results in local inflammation 6-24 hours after the injection
220
Q

what is acute ‘one-shot’ serum sickness an example of?

A

type III hypersensitivity reaction

221
Q

what happens in acute ‘one-shot’ serum sickness?

A
  • urticaria, arthralgia and glomerulonephritis occur about 10 days after initial exposure to the antigen
  • IgG, produced in response to antigen stimulation, reacts with remaining antigen to form circulating, soluble immune complexes
222
Q

what happens as damaging immune complexes are formed in type III hypersensitivity reactions?

A
  • antigen concentration is rapidly lowered

- this process continues only as long as circulating antigen persists, and is usually self limiting

223
Q

what is the vascular damage caused by immune complex deposition?

A
  • platelet aggregation which leads to microthrombi
  • deposition of immune complexes
  • chemotaxis of neutrophil polymorphs, and activation of complement
  • binding of antibody to neutrophil/APC
  • lysosomal enzymes released
224
Q

what is acute post-streptococcal glomeruloneohritis caused by?

A
  • occurs 10-12 days after a streptococcal infection of the throat or skin
  • results in deposition of immune complexes of IgG and C3 in the glomerular basement membrane
  • streptococcal antigens are rarely found in the complexes but nephritogenic strains of streptococci bind to the glomerular BM, so localising antibody to this site
225
Q

what accounts for most cases of chronic glomerulonephritis in humans?

A

chronic immune complex nephritis

226
Q

when will chronic immune complex formation and deposition occur?

A
  • if antigen exposure is persistent
  • if the host makes an abnormal immune response
  • if local factors, such as defective complement function, promote deposition of complexes
227
Q

when will persistent antigen exposure most likely occur?

A

if the antigen is a microorganism capable of replication despite a host response, a medically prescribed drug or an autoantigen

228
Q

what is type IV hypersensitivity reaction?

A

delayed-type hypersensitivity

- a local inflammatory response which takes 2-3 days to develop clinically

229
Q

what mediates type IV hypersensitivity reactions?

A
  • T lymphocytes which react with antigen and release IL-2, IFNgamma and other Th1 cytokines
  • once T cells have been sensitised by primary exposure, secondary challenge is followed by a delayed-type hypersensitivity reaction
230
Q

what does type IV hypersensitivity reaction consist of histologically?

A
  • infiltrating T lymphocytes, macrophages and occasional eosinophils
231
Q

what is an example of DTH?

A

tuberculin reaction

232
Q

what is tuberculin reaction caused by?

A
  • if a small amount of purified protein derivative (PPD) of Mycobacterium tuberculosis is injected intradermally into non-immune individuals, there is no effect
  • in individuals with cell-mediated immunity to tubercle bacilli, due to previous tuberculosis infection or immunisation with BCG, an area of reddening and induration develops after 24-48 hours
233
Q

what infiltrates the dermis of the reaction site in tuberculin reaction?

A
  • infiltrated by lymphocytes and macrophages around small blood vessels, with oedema and vascular dilation
234
Q

what can DTH be caused by?

A
  • normal cell-mediated immune response to infection with viruses, fungi and certain bacteria
  • notably Mycobacterium tuberculosis and Mycobacterium leprae
235
Q

what forms a granuloma?

A

collection of epitheliod cells/multinucleate giant cells

236
Q

what is contact dermatitis an example of?

A
  • type IV reaction
237
Q

what causes contact dermatitis?

A
  • agents of relatively low molecular weight and not immunogenic in their own right
  • they are highly reactive molecules that bind covalently to skin or tissue proteins
238
Q

what is a sensitising chemical called?

A

hapten

239
Q

what are the two phases of pathogenesis?

A
  • induction phase

- elicitation phase

240
Q

what happens in the induction phase? when does it happen?

A 
APC in the skin - Langerhans cells - bind the hapten carrier protein complex and present it to T lymphocytes in association with MHC class II antigen
- induction of T cells usually occurs after months of exposure to small amounts of antigen
241
Q

what is the elicitation phase?

A
  • re-exposure to the relevant antigen triggers it
  • effector T cells migrate to the skin to meet the protein complex presented to Langerhans cells in the epidermis
  • consequent cytokine release and skin inflammation
242
Q

what happens in a patch test?

A
  • a suspected contact sensitiser is applied to normal skin on the patients back and covered for 48 hours
  • reaction site is inspected after 2 and 4 days
  • in a positive response, there is inflammation and induration at the test site
243
Q

what are skin clinical indications related to allergy?

A

eczema, itching, reddening

244
Q

what are airway clinical indications related to allergy?

A
  • excessive mucus production

- bronchoconstriction

245
Q

what are GI clinical indications related to allergy?

A

abdominal bloating, vomiting, diarrhoea

246
Q

what are anaphylaxis clinical indications related to allergy?

A

airway, breathing, circulation

247
Q

what is allergy?

A

abnormal response to harmless foreign material (allergens)

248
Q

what are allergens?

A

harmless foreign material

249
Q

what is atopy?

A

tendency to develop allergies

250
Q

what are examples of allergic disease?

A
  • anaphylaxis
  • allergic asthma
  • allergic rhinitis (hay fever)
  • atopic dermatitis
  • allergic conjunctivitis
  • oral allergy syndrome
  • food allergy
251
Q

what is the pathogenesis of allergy?

A
  • usually involves IgE (also IgG4, IgA)
  • genetic factors: strong concordance in twin studies and GWAS ~50 loci
  • cells involved: mast, eosinophil, lymphocytes, dendritic, epithelial. smooth muscle and fibroblast cells
  • mediators: cytokines, chemokines, lipids, small molecules
252
Q

what are benefits of inflammation?

A

destruction of invading microorganisms and the walling off of an abscess
cavity thereby preventing the spread of infection

253
Q

what are limitations of inflammation?

A
  • disease e.g an abscess in the brain will act as a space-occupying lesson
    compressing vital surrounding structures
  • fibrosis resulting from chronic inflammation may distort tissues and
    permanently alter their function
254
Q

what happens in organisation in acute inflammation?

A
  • this is healing by fibrosis (scar formation) when there is substantial damage to the connective tissue framework and/or the tissue lacks the ability to regenerate specialised cells
  • when this occurs, dead tissues and acute inflammatory exudate are
    fist removed from the damaged areas by macrophages
  • the defect then becomes filled by the ingrowth of a specialised vascular connective tissue known as granulation tissue - this is
    organisation
  • the granulation tissue then gradually produces collagen to form a
    fibrous (collagenous) scar constituting the process of repair
255
Q

what are vascular conditions like in normal circumstances?

A
  • in normal conditions the high osmotic pressure inside the vessel, due to
    plasma proteins, favours fluid return to the vascular compartment
  • under normal circumstances, the high hydrostatic pressure at the arteriolar end of capillaries forces fluid out into the extravascular space, but this fluid returns into the capillaries at the venous end, where hydrostatic pressure is low
256
Q

where do cells low in normal circulation?

A

cells are confined to the central (axial) stream in
blood vessels, and do not flow in the peripheral (plasmatic) zone near to the
endothelium

257
Q

what is the complement system?

A
  • a complex series of interacting plasma proteins
    which form a major effector system for antibody-mediated immune reactions.
  • the major purpose of the complement system is to remove or destroy antigen,
    either by direct lysis or by opsonisation (the enhancement of phagocytosis by factors (opsonins) in plasma
258
Q

how can normal tissues be digested in acute inflammation?

A
  • enzymes such as collagensases and proteases may digest normal
    tissues, resulting in their destruction
  • this may result particularly in vascular damage for example; in type III hypersensitivity reactions (immune complexes, activation of
    complement/IgG), some types of glomerulonephritis (inflammation of the glomeruli) and in abscess cavities
259
Q

what is an example of an inappropriate inflammatory response?

A

for example in type I hypersensitivity reactions (IgE - allergic & acute) e.g hay fever whereby the provoking environmental antigen (e.g pollen) otherwise poses no threat to the individual

260
Q

what is an example of an acute inflammatory condition that resolves completely?

A

acute lobar pneumonia

261
Q

what happens when pus accumulates in a tissue in suppuration?

A

becomes surrounded
by a ‘pyogenic membrane’ consisting of sprouting capillaries, neutrophils and occasional fibroblasts - this is the start of healing
which eventually results in granulation tissue and scarring

262
Q

what is a pyogenic membrane?

A

consisting of sprouting capillaries, neutrophils and occasional fibroblasts
- surrounds pus that has accumulated in a tissue

263
Q

what is replacement by granulation tissue?

A

tissue forming in response to injury, contains many new blood vessels and, in its later stages, large numbers of fibroblasts

264
Q

what are conditions that favour organisation?

A
  • large amounts of fibrin are formed, which cannot be removed completely by fibrinolytic enzymes from the plasma or from
    neutrophil polymorphs
  • substantial volumes of tissue becoming necrotic or if the dead tissue (e.g fibrous tissue) is not easily digested
  • exudate and debris cannot be removed or discharged
265
Q

what happens during organisation in inflammation?

A
  • new capillaries grow into the inflammatory exudate
  • macrophages migrate into the are
  • fibroblasts proliferate under influence of TGF-beta, resulting in fibrosis and possible scar formation
266
Q

what causes reactive hyperplasia of the reticuloendothelial system?

A
  • local or systemic lymph node enlargement commonly accompanies
    inflammation
  • splenomegaly (spleen enlargement) is found in certain specific
    infections for example; malaria & infectious mononucleosis
267
Q

what are the haematological changes seen in chronic inflammation?

A
  • increased levels of white blood cells in the blood

- anaemia due to blood loss into the inflammatory exudate or due to haemolysis

268
Q

what causes increased number of white blood cells in the blood in chronic inflammation?

A
  • increased amount of neutrophils is common in pyogenic (pus causing) infections & tissue destruction
  • increased amount of eosinophils is seen in allergic disorders and parasitic infection
  • increased amount of lymphocytes is seen in chronic infection
    (e. g. tuberculosis), many viral infections and in whooping cough
  • increased amount of monocytes is seen in certain bacterial infections e.g. tuberculosis & typhoid
269
Q

how can suppurative acute inflammation progress to chronic inflammation?

A
  • if the pus forms an abscess cavity that is deep-seated, and drainage is delayed or inadequate, then by the time that drainage occurs
    the abscess will have developed thick walls composed from granulation
    and fibrous tissues.
  • the rigid walls of the abscess cavity will thus fail to come together after eventual drainage and the stagnating pus within the cavity becomes organised by ingrowth of granulation tissue, being replaced by fibrous scar
270
Q

why does indigestible material favour chronic inflammation?

A

these materials are relatively inert and are resistant to the action of lysosomal enzymes

271
Q

what causes granulomatous inflammation?

A

occurs when the immune system attempts to wall off substance but is unable to eliminate it, this forms a granuloma (a collection of epithelioid histiocytes (a stationary phagocytic cell (macrophage) found in tissue)

272
Q

what is a histiocyte?

A

a stationary phagocytic cell (macrophage) found in tissue

273
Q

what is paracrine stimulation of connective tissue proliferation?

A
  • healing involves the regeneration and migration of specialised cells
  • the predominant features in repair are angiogenesis (formation of new blood
    vessels) followed by fibroblast proliferation and collagen synthesis resulting
    in granulation tissue
  • these process are regulated by proteins called growth factors which bind to
    specific receptors on cell membranes and trigger a series of events
    culminating in cell proliferation
274
Q

what can induce granuloma formation?

A
  • a common feature of many of the stimuli that induce granulomatous
    inflammation is the indigestibility of particulate matter by macrophages
  • small traces of elements such as beryllium induce granuloma formation
275
Q

what are examples of particulate matter that is indigestible by macrophages?

A

inert minerals such as silica, or bacteria such as
tubercle bacilli (have cell walls containing mycolic acids and waxes that
resist enzymatic digestion)

276
Q

how does inflammation contribute to atheroma?

A
  • macrophages adhere to endothelium, migrate into the arterial intima and, with
    T lymphocytes, express cell adhesion molecules which recruit other cells into
    the area
  • the macrophages are involved in processing the lipids that accumulate in atheromatous plaques
277
Q

how does inflammation contribute to the nervous system?

A
  • inflammation also features in the tissue injury associated with neurodegenerative disorder of the central nervous system
  • multiple sclerosis
    is a relatively common chronic demyelinating neurodegenerative disorder in which chronic inflammation plays an important role
278
Q

what do stem cells replace?

A

cells lost through injury or normal ageing

279
Q

what happens in a minor skin abrasion?

A
  • the epidermis is lost over a limited area, but at the margins of the lesion
    there remain cells that can multiply to cover the defect
  • at first, cells proliferate and spread out as a thin sheet until the defect is covered
  • when a confluent layer has been formed, the stimulus to proliferate is switched off; this is known as contact inhibition, and controls both
    growth and movement
  • once in place, the epidermis is rebuilt from the base up until it is indistinguishable from normal - this whole process is called healing
280
Q

why don’t thrombuses form all the time?

A
  • laminar flow (travel in the centre of arterial vessels and don’t touch the sides)
  • endothelial cells lining vessels are not sticky when healthy
281
Q

what is the process of arterial thrombosis formation?

A
  1. in its earliest phase, an atheromatous plaque may consist of a slightly raised fatty streak on the intimal surface of any artery such as the aorta
  2. over time, the plaque will grow and become sufficiently raised to be able to protrude into the lumen and thus cause a degree of turbulence in the blood flow
  3. this turbulence eventually results in the loss of intimal cells and the exposed plaque surface is presented to the blood cells, including the platelets
  4. the turbulence results in fibrin deposition and platelet clumping; the bare luminal surface of the vessel will have collagen exposed and platelets will settle on this surface
  5. this process, once begun, may be self-perpetuating, as it has been shown that platelet0derived growth factor, which is contained in the alpha granules, causes proliferation of arterial smooth muscle cells - which
    are an important constituent of the atheromatous plaque
  6. the first layer of the thrombus that forms is a platelet layer - formation of this layer in turn causes
    the precipitation of a fibrin meshwork, in which red cells are trapped, and a layer of this meshwork is developed on top of the platelet layer
  7. this structure now protrudes even further into the lumen, causing more turbulence and forming the basis for further platelet deposition
  8. the structure disrupts the laminar flow of blood - whereby the cells move in the faster central lane and the plasma runs
    along the walls - thus the greatest degree of turbulence occurs at the downstream side of an arterial thrombus, as
    the blood passes over the thrombus
  9. thrombi grow in the direction of blood flow; this is known as propagation
282
Q

what are less common causes of embolus?

A
  • air - need to be careful with pressurised systems of intravenous fluids/blood
    especially in infants & children
  • cholesterol crystals - from atheromatous plaques
  • tumour amniotic fluid - rare, found in pregnant women with precipitate
    labour (rapid)
  • fat - severe trauma with multiple fractures
283
Q

how does a pulmonary embolism occur?

A

if an embolus enters the venous system it will travel to the vena cava, through the right side of the heart and will lodge somewhere in the pulmonary arteries (depending on its size)

284
Q

why can’t pulmonary embolisms get to the arterial circulation?

A

because the blood vessels
in the lung split down to capillary size (through which only single red blood cells can squeeze) so the lungs act as a filter for any venous emboli

285
Q

where can cholesterol crystals from an atheromatous plaque in the descending aorta travel to?

A

any of the lower limb and renal arteries

286
Q

where may thrombi form on in the heart?

A

thrombi may form on areas of cardiac muscle that have died as a result of a myocardial infarction since these areas will have lost their normal endothelial lining and will expose the underlying collagen to the
circulating platelets

287
Q

how can AF cause thrombosis in the heart?

A

this ineffectual movement of the atria cause blood to
stagnate in the atrial appendages and thrombosis to occur - when the
normal heart rhythm is re-established the atrial thrombus may be
fragmented and emboli broken off

288
Q

what is the definition of ischaemia?

A

a reduction in blood flow to a tissue or part of the body caused by constriction or blockage of the blood vessels supplying it

289
Q

what is the definition of infarction?

A

the death (necrosis) of part or whole of an organ that occurs when the artery supplying it becomes obstructed

Phase 2A (28 decks)

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