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IMM3031 > WEEK 2 NEUTROPHILS > Flashcards

WEEK 2 NEUTROPHILS Flashcards

1
Q

What is the main immune cell that eliminates bacterial pathogens?

A
  • Neutrophils
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2
Q

Who are people with insufficient numbers of neutrophils and what does this mean for infection?

A
  • Chemotherapy patients or immunocompromised people

- Means that they are at high risk of severe bacterial infection

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3
Q

What are two conditions that occur as a result of dysfunctional neutrophils?

A
  • chronic granuloma disease

- Leukocyte adhesion deficiency

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4
Q

What occurs in CGD and what are the long term effects of this?

A
  • Failure to produce reactive oxygen species required for microbial killing
  • Repeated infections and reduced lifespan
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5
Q

What occurs in Leukocyte Adhesion deficiency (LAD) I, II, III and what are the long term effects of this?

A
  • Failure to recruit neutrophils to sites of infection

- Results in repeated infections and reduced lifespan

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6
Q

What are the 3 main roles of the neutrophil?

A
  1. Detect and eliminate invading bacteria and fungal pathogens
  2. Detect and eliminate dead and dying cells
  3. Aid in tissue repair
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7
Q

Where are neutrophils generated?

A
  • in the bone marrow
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8
Q

What is the neut. half life in the circulation?

A
  • 8 hrs but longer if inflammation occurs
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9
Q

In humans, what % of circulating leukocytes are neutrophils?

A
  • 50-70%
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10
Q

Are neutrophils released as immature or mature cells under normal conditions?

A
  • Mature cells
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11
Q

What are the 4 main nautrophil granules and their types of proteins?

A
  • Azurophililic –> primary: MPO
  • Specific (seocndary): Lactoferrin
  • Gelatinase (Tertiary) : Gelatinase
  • Secretory vesicles: CD11b formyl peptide receptor (cell surface molecules)
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12
Q

What are the three main types of neutrophil granule contents?

A
  1. Anti-microbial proteins/peptides e.g. Defensins
  2. Matrix-degrading enzymes e.g. Collagenase
  3. Neutrophil membrane proteins e.g. CD11b
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13
Q

Are all the neutrophil granule contents released at the same time?

A
  • NO
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14
Q

What is the neutrophil granule release controlled by and what is the order of release?

A
  • A chemokine gradient
  • Released upon increasing strength of the stimulus
  • First the Secretory granules are released e.g.g CD11b
  • Then the secondary and tertiary granules are released )FPR1, gelatinase B
  • Lastly, the primary granules are released: MPO, eastase etc. where the immune complex is
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15
Q

What cytokines, chemokines, ans growth factors are involved in tissue injury and repair?

A
  • cytokines: IL-1beta, TNF
  • Chemokines: CXCL8, CCL3, CCL19
  • Growth Factors: VEGF, G-CSF
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16
Q

What are the three mechanisms by which neutrophils can kill bacteria?-

A
  • Phagocytosis, degranulation, NETs
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17
Q

In neutrophil phagocytosis, what is bacteria uptake assisted by?

A
  • Fc receptors for antibody coated bacteria

- Complement receptors for complement opsonised bacteria

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18
Q

What are the general events in neutrophil engulfement?

A
  • Bacteria are in a phagosome
  • ROS generated within phagosome
  • Anti bacterial proteins (cathepsins, defensins, lactoferrin, lyzozyme) released into phagosome and bacteria killed
19
Q

How is the phagosome in neutrophil engulfement generated?

A
  • Fusion of specific granules with cell membrane
20
Q

In neutrophil engulfment, what does the NADPH oxidase complex do?

A
  • Generates O2- and converts to H2O2
21
Q

In the neutrophil phagocytosis, what does MPO do?

A
  • It is discharged into the phagosome and uses H2O2 to catalyse the formation of oxidants –> HOCl (potent antibacterial)
22
Q

What can people with Chromic Granulomatis disease not generate?

A
  • O2-

- because they have mutations in NADPH oxidase

23
Q

How are bacteria killed by degranulation?

A
  • Extracellular bacteria killed via the release of anti-bacterial proteins –> capthesisn, defensins, lactoferrin, lyzozyme
24
Q

What occurs in the NETs?

A
  • DNA web released (highly activated neut)
  • Hsitones, MPO and elastase attached -
  • These are capable of trapping and destroying bacteria
25
Q

How has neutrophil bacterial killing resulted in evasion of NETs?

A
  • DNase dissolves the NETs so bacteria can escape

- S.aureus has evolved to express DNase as virulence factor

26
Q

What are some examples of conditions/fatals events that neutrophils are involved in?

A
  • When blood flow to area is blocked off then returns–> neuts will be HIGHLY activated and flood area causing ischemia reperfusion (could be myocardial, kidney etc)
  • Arthritis
  • Sepsis
  • Acute long injury
27
Q

How are neutrophil mediated resposnes detected?

A
  • Sentinel cells such as mast cells, DCs, tissue macrophages detect signs of infection or damage and then initiate the response
28
Q

How are neutrophil mediated resposnes initiated?

A
  • the inflammation increases interactions of circulating neuts in vascular endo. –> rolling, adhesion, migration
29
Q

Why do we have rolling, adhesion and transmigration with neuts?

A
  • To have neutrophils recruited to the site of infection so they can perform their effector functions
30
Q

What is neutrophil tethering and rolling mediated by?

A
  • Selectins and their ligands

e. g. E-selectin and P-selectin interact with PSGL-1 and L-selectin

31
Q

What is neut activation and arrest mediated by?

A
  • Chemoattractants and their receptors
32
Q

What are the transmembrane GPCRs that neutrophils express involved in activation and arrest?

A
  • CXCR1 and CXCR2 (bind to CXC chemokines e.g. IL-8/CXCL8)
  • C5aR, CR3, CR4 (complement components)
  • Platelet activating factor receptor (-PAF)
  • FPR1 and FPR2 (formylated peptides)
  • BLT1 (Leukotreine B4)
33
Q

What is neutrophil adhesion and intravascular crawling mediated by and what are the specific molecules?

A
  • Integrins and ligands
  • aLb2 (LFA-1, CD11a/CD18)
  • aMb2 (Mac-1, CD11b/CD18)
34
Q

When are the neutrophil adhesion molecules affected (in which disease?)

A
  • IN LAD ( leukocyte adhesion defficiency)
35
Q

Do neuts express multiple chemoattractant receptors?

A
  • YES

e. g. CXCR1, CXCR2 (IL-8 receptor), FPR1, FPR2 (fMLP receptors)

36
Q

How does the neutrophil decide on which gradient to follow when it comes to chemoattractants?

A
  • It follows a hierarchy
37
Q

In terms of the chemotaxis and hierarchy of chemoattractants, what are the intermediate chemoattractants and what do they do?

A
  • CXCL8 (IL-8)
  • Leukotrine B4
  • They label the blood vessels at sites of inflammation (marker)
38
Q

In terms of the chemotaxis and hierarchy of chemoattractants, what are the end-target chemoattractants and what do they do?

A
  • fMLP,
  • C5a (product of opsonisation)
  • They define the EXACT position of a microbe
39
Q

Do the neutrophils favour the intermediate or end target chemoattractants?

A
  • end-target (move to fMLP)
40
Q

What is sterile inflammation?

A
  • Inflammation that occurs in response to cell injury or death in the ABSENCE of infection
    e. g. burns, traumatic injury, ischemia/reperfusion (myocardial infarction, stroke)
  • Neuts and macros recruited to site bc. the aim is to restore homeostasis
41
Q

How do neuts detect sterile inflammation?

A

DAMPs –> released from dead or dying cells

42
Q

What are examples of intracellular DAMPs?

A
  • ATP
  • mtDNA
  • HSPs
  • Uric acid
43
Q

What are examples of EC DAMPs?

A
  • Byglycan
  • HA
  • Heparin Sulfate
44
Q

what does inhibition of FPR1 result in?

A
  • Reduction of neut. migration to sterile injury site

IMM3031 (3 decks)

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