Chemotaxis and Phagocyte Infiltration into tissue Flashcards Preview

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Flashcards in Chemotaxis and Phagocyte Infiltration into tissue Deck (45):
1

define Chemotaxis

The movement of cells in response to a chemical stimulus

2

why is chemotaxis required?

Enables cells to accumulate where most needed

3

how does chemotaxis work?

Cell motility achieved by temporary attachment of
“front” of cell to a surface, and by the formation of
actin filaments which pull the back of the cell towards the front

4

in nature where does chemotaxis and killing occur?

in tissues

5

How do the leukocytes “know where to go”?

Signals release by damaged or infected tissues change the local blood vessels

6

what is a localized acute inflammatory response?

vasodilation, vascular permeability, leukocyte migration

7

what is the role of neutrophils

central role (get there 1st)
attracted by IL-8 (CXCL8), C3a, C5a, Prostaglandins

8

whats the role of macrophages?

arrive 5-6 hr later,
attracted by CC chemokines, C3a, C5a
secrete IL-1, IL-6, IL-8 (CXCL8),TNF localized and systemic effects

9

name the 5 Groups of Chemical Mediators of Inflammation and Chemotaxis

A) Cytokines
B) Plasma enzyme systems
C ) Vasoactive amines
D) Arachidonic acid metabolites
E ) Chemokines

10

which cells secrete cytokines?

activated macrophages

11

name 5 cytokines

CXL8
IL-12
IL-6
IL-1b
TNF-a

12

describe the action of IL-1b

Activates vascular endothelium and lymphocytes
local tissue destruction
increases access of effector cells

13

describe the action of TNF-a

- Activates vascular endothelium
- increases vascular permeability increasing entry of IgG, cells to tissues and fluid drainage to lymph nodes.

14

what are the systemic affects of IL-6, IL-1b and TNF-a?

IL-1b- fever and IL-6 production
TNF-a- Fever, mobilisation of metabolites and shock
IL-6- Fever and induces acute phase protein production.

15

what is the action of IL-6?

- Lymphocyte activation
- increased Ab production

16

describe the action of CXCL8?

recruits neutrophils, basophils and T cells

17

describe the action of IL-12

- activates NK cells,
- differentiate CD4 T cells into T helper cells.

18

what do Plasma Enzyme Systems do?

activates innate immune system even before microbes have entered or been detected

19

give an example of a Vasoactive amine

Histamine

20

what does Histamine do?

- In granules of mast cells, basophils, platelets
- Released by degranulation (triggered by C3a, C5a, etc.)
- Promotes arteriolar dilation, smooth muscle contraction, and venular endothelial contraction,
- Results in widening of interendothelial cell junctions with increased vascular permeability
- Vascular actions similar to Bradykinin

21

describe the action of Arachidonic Acid Metabolites

- AA released from cell membrane by Phospholipases which have been activated by various stimuli and/or inflammatory mediators
- AA metabolism occurs via two major enzyme pathways:
lipoxygenase and cyclooxygenase

22

name 3 Arachidonic Acid Metabolites in chemotaxis

prostaglandins, platelet activating factor and leukotriene b4

23

whats the effect of prostaglandins?

increase vascular permeability
vascular dilation
neutrophil chemotaxis

24

whats the effect of leukotriene B4?

neutrophil chemotaxis

25

whats the effect of PAF?

platelet aggregation
eosinophil chemotaxis
neutrophil activation

26

name 2 Important anti-inflammatory drugs that interact with the Phospholipid pathway

steroids and aspirin

27

what does aspirin inhibit?

cyclooxyrgenase pathways

28

what do steroids inhibit?

phospholipase

29

what are Chemokines?

Small polypeptides, approx 100 amino acids in general, 7-16 kDa

30

what are the Four families of chemokines?

CXC
CC
C
CX3C (fractalkine) 38 kDa

31

what do Chemoattractant cytokines do?

Orchestrate leukocyte chemotaxis, adhesion, activation

32

whats the structure of CC chemokines?

Two adjacent cysteine amino acids near start of protein
Bind to CC Receptors (CCRs)

33

structure of CXC?

Have one amino acid (X) which separates the first 2 cysteines
Bind to CXC Receptors (CXCRs)

34

name a CXC Chemokine

CXCL8

35

whats the action of CC Chemokines?

Attract Monocytes not Neutrophils

36

whats the action of TNF cytokines?

TNF causes Weibel-Palade bodies in endothelial cells to be secreted

Weibel -Palade bodies contain pre-synthesised P-selectin

This enables very rapid (minutes) activation of endothelium (ie binding of leukocytes)

37

what are Adhesion molecules Required for?

Leukocyte binding to blood vessels

Leukocyte extravasation from blood vessels

Leukocyte migration (chemotaxis) towards inflamed sites

38

what are The 4 stages of Leukocyte Extravasation and Chemotaxis?

1. Rolling- Leukocyte expresses- Mucin type glycoproteins on neutrophils and sialyl-Lewis-X containing glycoproteins bind to P and E Selectin

2. Firm adhesion- express Integrins bind to ICAMs


3. Extravasation (diapedesis) Integrins and PECAM (CD31) binds ICAMs and PECAM (CD31) on endothelial cell

4. Chemotaxis through tissue- express Chemokine receptors bind to Chemokines

39

summarise local inflammation / chemotaxis

1. Initial responses
- Tissue macrophages detect microbes, release inflammatory mediators, chemokines, cytokines
- Complement activation releases chemoattractants C3a and C5a

2. Vascular effects
- Macrophages and complement products trigger:
Increase in vascular diameter / permeability
increased blood flow
reduced velocity of blood flow
accumulation of Igs, complement and other blood proteins in the tissue.
- Up-regulation of adhesion molecules on endothelial cells

3. PMN and Monocytes adhere and extravasate
- Selectins on endothelial cells recognize leukocyte glycoproteins (Lewis X) causing them to roll.
- ICAM-1 on endothelium interacts with LFA-1 (CD11a/CD18) and CR3 (Mac-1 or CD11b/CD18) so that leukocytes attach firmly to the endothelium, cross the vascular endothelial wall and enter site of infection

4. Leukocytes migrate up chemotactic gradient
- CXC chemokines promote migration of neutrophils
e.g. IL-8
- CC chemokines promote migration of monocytes
e.g. MCP-1, MIP-1b, RANTES
- Complement components C3a C5a attract both
- Also molecules given off by microbe, e.g. fMet

40

what do fMet peptides do?

- As well as being an important chemotactic stimulus for phagocytes, fMet peptides have anti-leukocyte properties

- fMLP inhibits killing of Staphylococcus epidermidis in vitro

41

name a Bacterial chemotactic compound

- Mycobacterium tuberculosis Lipoarabinomannan (LAM) is chemotactic for macrophages but not neutrophils- maybe used by MTB to encourage granulomas to enhance bacterial survival / dormancy?

- LAM also inhibits macrophage phagocytosis

42

how have bacteria evolved mechanisms to block chemotaxis of phagocytes?

S. aureus inhibits leukocyte chemotaxis using the CHIPS protein

43

what is CHIPS?

- Chemotaxis-inhibitory protein of S. aureus
- CHIPS is produced by 80% of S. aureus strains
- CHIPS has potential as a novel anti-inflammatory drug

44

how does CHIPS work?

- CHIPS blocks chemotaxis receptors on leukocytes (fMet R, also affects C5a receptor, a related 7 transmembrane G-protein linked receptor)
- inhibits leukocyte recruitment

45

Role of formylated peptides in chemotaxis?

- Bacterial protein synthesis starts with fMet-tRNA
- Staphylococcus aureus formylated peptides cause chemotaxis