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PA20351 > Adhesion and chemotaxis > Flashcards

Adhesion and chemotaxis Flashcards

1
Q

Where do leukocytes move to from the blood?

A

Sites of inflammation and immune activation.

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2
Q

What is directional control coordinated by?

A

Tissue expression of adhesion molecules and chemical stimuli for leukocyte migration.

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3
Q

What happens to leukocytes when they arrive at sites of inflammation?

A

They participate in host defence, inflammation and repair and resolution.

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4
Q

What is leukocyte diapedesis?

A

A major event in the migration of leukocytes from the blood circulation to sites of inflammation. or tissue injury.

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5
Q

What are the steps in leukocyte diapedesis?

A

Circulation, tethering/rolling, firm adhesion and transmigration.

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6
Q

What happens in tethering and rolling?

A

Fast moving leukocytes are tethered to the vessel wall and are guided by specific homing receptors and their ligands.

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7
Q

What mediates leukocytes rolling along the blood vessel wall?

A

Selectins.

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8
Q

What do lectins bind?

A

Particular groups of molecules - carbohydrates on the endothelial surface of the leukocyte surface.

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9
Q

What are selectins?

A

Lectin-like adhesion molecules that bind carbohydrate structures weakly.

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10
Q

What are L-selectins expressed by?

A

Leukocytes.

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11
Q

What are P-selectins expressed by?

A

(platelets) endothelium.

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12
Q

What are is E-selectin expressed by?

A

Endothelium.

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13
Q

What are selectins important in?

A

Initial tethering of leukocytes to vascular cells.

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14
Q

What does leukocyte activation lead to?

A

Transient increase in avidity (molecules cluster on the surface) and rapid shedding by proteolytic cleavage - shedase.

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15
Q

What is transient adhesion?

A

When they are firmly bound to the endothelial surface.

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16
Q

What are the features of P-selectin?

A

It is constitutive in platelets and endothelium and is stored in granules. It is rapidly translocated to the cell surface on cell activation.

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17
Q

What are the features of E-selectin?

A

Endothelial expression is induced by cytokines or LPS, and expression requires de novo protein synthesis (slow - 2-6 hours)..

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18
Q

What is expression of E-selectin inhibited by?

A

Glucocorticoids.

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19
Q

What is LAD II?

A

Leukocyte adhesion deficiency II - patients suffer recurrent infections due to no pus being produced.

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20
Q

What are the features of LAD II?

A

There are large numbers of neutrophils circulating in the blood, but none in the tissues. There is defective fucose metabolism and there is decreased rolling response on E/P selectins. There is severely impaired neutrophil accumulation in skin inflammation.

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21
Q

What is adhesion and flattening?

A

The leukocytes flatten and stick onto the endothelial surface, involving integrins.

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22
Q

What does rolling of leukocytes on the endothelial surface activate?

A

Integrins - subsequent to receiving signals from chemokines on endothelial surfaces.

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23
Q

How does firm adhesion occur?

A

Via integrins - heterodimeric proteins are expressed on the surface of leukocytes and most other cells.

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24
Q

What subunits are leukocyte integrins made up of?

A

Beta2 and 3 types of alpha subunits.

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25
Q

What are the three forms of the alpha chains in leukocyte integrins?

A

Alpha1, alphaM, alphaX>

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26
Q

How many heterodimers of leukocyte integrins are present?

A

3 heterodimers - alpha1/beta2, alpham/beta2 and alphax/beta2.

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27
Q

What does leukocyte activation induce?

A

Conformational change which increases affinity for ligands and clustering of integrins.

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28
Q

What are the three forms of integrin protein?

A

Bent, extended and ligand-bound.

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29
Q

What are the different states of integrin protein regulated by?

A

Binding of cytoskeletal or signalling factors to the intracellular domains or by ligand binding.

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30
Q

What are the characteristics of integrins in the bent form?

A

The head region points inwards towards the cell surface and has a low affinity for other molecules.

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31
Q

What are the characteristics of integrins in the extended form?

A

The head region points away from the surface allowing it to engage other molecules. The different domains making up the head domain also alter the shape, increasing the affinity of ligand binding.

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32
Q

What are the characteristics of integrins when bound to ligands?

A

There is stabilisation of outward swing of the subunit, and allows variable leg separation.

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33
Q

What is LAD I?

A

Leukocyte adhesion deficiency.

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34
Q

What are the symptoms/signs of LAD I?

A

Patients suffer recurrent bacterial infections without pus.

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35
Q

What causes LAD I?

A

Leukocytes do not adhere to extracellular material or endotheliu in vitro.

36
Q

What happens to leukocytes in LAD I?

A

They will roll but do not progress from a rolling response to the adhesion response.

37
Q

What are the integrin ligands?

A

ICAMs - intercellular adhesion molecules.

38
Q

What are the most common integrin ligands?

A

ICAM2 and ICAM1. ICAM2 is basally expressed on the endothelium and ICAM1 is induced by cytokines IL-1 and TNF.

39
Q

What types of molecules are ICAMs?

A

Proteins - immunoglobulins - they don’t have the high specificty but have membrane bound antibodies.

40
Q

What are some other integrins?

A

Alpha4beta1 - expressed on eosinophils, monocytes and T cells.

41
Q

What ligands does alpha4beta1 integrin bind?

A

Vascular cell adhesion molecule VCAM1, similar to ICAM.

42
Q

What is VCAM stimulated by?

A

Cytokines.

43
Q

What does transmigration involve?

A

CAMs and chemoattractants.

44
Q

What is the other name for chemoattractants?

A

Chemotaxins.

45
Q

How can leukocyte adhesion blockers be used in therapy?

A

They can be used in multiple sclerosis and inflammatory bowel disease.

46
Q

What is an example of an anti VLA-4 (alpha4) antagonist?

A

Nataluzimab,

47
Q

What else can leukocyte adhesion blockers be used for in therapy?

A

Dry eye syndrome.

48
Q

What leukocyte adhesion blockers can be used to treat dry eye syndrome?

A

Anti CD11a (alpha1) receptors.

49
Q

What is an example of an anti CD11a ?

A

Lifitegrast.

50
Q

What is Natalizumab?

A

A monoclonal antibody against alpha4 integrin. It inhibits T lymphocyte interactions with brain endothelium, causing decreased trafficking into the brain.

51
Q

What can natalizumab be used for?

A

Therapy for MS to prevent T cell infiltration.

52
Q

What is chemotaxis?

A

Directed leukocyte movement,

53
Q

What are chemotaxins?

A

They attract and activate leukocytes resulting in integrin affinity and avidity change and movement.

54
Q

What is the source of chemotaxins?

A

The site of inflammation.

55
Q

What happens to some chemotaxins?

A

They are immobilised and presented to leukocytes - endothelial cell surface presentation and are bound to extracellular matrix.

56
Q

What are the different types of chemotaxins?

A

Non-selective and selective.

57
Q

What are some examples of non-selective chemotaxins?

A

LTB4, C3a, C5a, formyl peptides.

58
Q

What are some examples of selective chemotaxins?

A

Chemokines - chemotactic cytokines.

59
Q

What are chemokines?

A

A structurally defined group of chemotaxins that are produced in response to IL-1, TNF and bacteria.

60
Q

What are the receptors for chemokines?

A

G-protein coupled receptors - unlike most cytokines.

61
Q

What are the systematic names of chemokines?

A

L for ligand and R for the receptor.

62
Q

What are CXC chemokines?

A

Chemokines that are composed of a CXC group, a loop and another cysteine. They are mainly neutrophil and T cell attractants.

63
Q

What is a commomn CXC chemokine?

A

Interleukin 8.

64
Q

What is the receptor for interleukin 8?

A

CXCR1, CXCR2.

65
Q

What is the target of interleukin 8?

A

Neutrophils.

66
Q

What are CC chemokines?

A

Not neutrophil attractants.

67
Q

How many types of CC chemokines are there?

A

14.

68
Q

What is the difference between chemokines and chemotaxins?

A

Chemokines are a structurally defined subset of chemotaxins - many chemotaxins are NOT chemokines. Almost all chemokines are chemotaxins.

69
Q

What other molecules are also chemotaxins?

A

Plasma proteins, lipids, bacterial products.

70
Q

What is Fingolimod?

A

An S1P1 receptor agonist that can be used for lymphocyte trafficking in multiple sclerosis. If the receptor is blocked on the lymphocyte it can stop the movement into inflammatory regions.

71
Q

What is DP?

A

A prostaglandin D receptor antagonist that can be used in asthma treatment.

72
Q

What are H4 antagonists involved in?

A

Mediating lymphocyte chemotaxis.

73
Q

Which cells move fastest in the inflammatory response?

A

Neutrophils, monocytes then lymphocytes.

74
Q

What types of inflammation are the different immune molecules involved in?

A

Neutrophil - acute inflammation, monocytes and lymphocytes - chronic inflammation.

75
Q

How do tissues show selectivity in the inflammatory response?

A

Tissues have different selectin and CAM expression and different chemokine expression.

76
Q

How do leukocytes show selectivity?

A

They have different integrin expression and different chemokine receptor expression.

77
Q

What is extravasation of leukocytes?

A

A chain of events resulting in the release of inflammatory substances into the sites of inflammation.

78
Q

What happens when there is an injury/pathogen in terms of extravasation of leukocytes?

A

There is cytokine-induced activation of adhesion molecules, increased E selectin, chemokine release from tissue cells.

79
Q

What happens to the surface of the endothelium in extravasation of leukocytes?

A

The surface becomes more sticky.

80
Q

What does increased E selectin levels in extravasation result in?

A

Ligation of the carbohydrate structures on the surface, inducing the rolling response and giving the leukocyte better ability to sense various substances in the local environment.

81
Q

What will happen to some of the chemokines released by tissue cells in extravasation?

A

Some will diffuse through the endothelial barrier and stick onto the surface.

82
Q

What happens when leukocytes are flattened in extravasation?

A

They can sense they are near the source of the stimulus and progress through integrin mediated migration.

83
Q

What is leukocyte transmigration?

A

Leukocytes escape from circulation and accumulate at sites of injury.

84
Q

What role do selectins have in leukocyte transmigration?

A

They are used to tether leukocytes on the endothelium near the inflammatory site.

85
Q

What are integrins used for in leukocyte transmigration?

A

Stronger adhesion of chemokine activation of leukocytes.

86
Q

What are CAMs involved in with leukocyte transmigration?

A

They are expressed by endothelium as ligands for integrins.

87
Q

What is leukocyte movement directed by?

A

Chemotaxins.

PA20351 (11 decks)

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