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Infection and Immunity > Leucocyte adhesion and chemotaxis > Flashcards

Leucocyte adhesion and chemotaxis Flashcards

1
Q

leucocyte migration

A

Move from blood -> sites of inflammation + immune activation

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2
Q

what controls the direction of leucocyte migration?

A

coordinated by tissue expression of adhesion molecules and chemical stimul

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3
Q

what do leucocytes participate in once they arrive at site of infection?

A

host defense

inflammation

repair

resolution

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4
Q

leucocyte diapedesis

A
  1. circulating
  2. tethering/rolling
  3. firm adhesion
  4. transmigration
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5
Q

tethering/rolling

A

fast moving leucocytes tethered to wall

guided by specific homing receptors + their ligands = SELECTINS

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6
Q

what are selectins?

A

lectin-like adhesion molecules

bind to BHO structures (weakly)

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7
Q

what are the 3 types of selectins?

A

L-selectins -> expressed by leucocytes

P-selectins -> expressed by platelets endothelium

E-selectin -> expressed by endothelium

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8
Q

L-selectin

A

Constitutive expression of leucocytes

Leucocyte activation leads to - Transient increase in avidity (molecules cluster on surface)

Rapid shedding by proteolytic cleavage (‘Shedase’)

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9
Q

Leucocyte adhesion deficiency-1 (LAD1)

A

Deficient in β2 integrin

Patients suffer recurrent bacterial infections without pus

Leucocytes don’t adhere to extracellular material or endothelium in vitro

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10
Q

Leucocyte adhesion deficiency-II (LAD-II)

A

Patients suffer recurrent infections
- No pus
- Neutrophilia

Normal phagocytosis and respiratory burst in vitro

Defective fucose metabolism
- Leucocytes don’t express selectin ligands

Decreased “rolling” response on E- or P-selectins

Severely impaired neutrophil accumulation in skin inflammation (< 90% decreased)

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11
Q

what are integrins?

A

heterodimeric proteins expressed on surface of leucocytes (and most other cells)

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12
Q

role of integrins

A

receive signals from chemokines on endothelial surfaces

firm adhesion via integrins

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13
Q

types of integrins

A

common = β2 chain

3 forms of α-chain = αL, αM, αX

3 heterodimers = αLβ2, αMβ2, αXβ2

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14
Q

what does leucocyte activation induce?

A

Conformational change - increases affinity

Clustering of integrins

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15
Q

integrin ligands

A

[intercellular adhesion molecule - ICAM]

ICAM-2 = basally expressed on endothelium
ICAM-1 = induced by cytokines IL-1, TNF

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16
Q

α4β1

A

expressed on eosinophils, monocytes and T cells

binds to vascular cell adhesion molecule
-VCAM-1 similar molecule to ICAM
-induced by cytokines

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17
Q

transmigration

A

involves CAMS and chemoattractants

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18
Q

what are chemoattractants called?

A

chemotaxins

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19
Q

leucocyte adhesion blockers in therapy

A

anti VLA-4

anti αLβ2 in ‘dry eye’ syndrome

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20
Q

what type of drug is Natalizumab (Tysabri)?

A

Monoclonal antibody against α4 integrin

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21
Q

what does Natalizumab (Tysabri) do?

A

Inhibits T lymphocyte interactions with brain endothelium

Decreased trafficking into brain

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22
Q

Natalizumab (Tysabri) FDA approval

A

Trialed as a therapy for MS (prevent T cell infiltration)
- Licensed by FDA in 2004

- But significant incidence of progressive multifocal leukoencephalopathy (brain viral infection)

- Resumed approval for MS in 2006 -> improved efficacy in MS when combined with IFN-β

Licensed in US for Crohn’s disease (= inflammatory bowel disease)

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23
Q

Etrlizumab

A

Anti-α4β7 gut selectivity

Inflammatory bowel disease (Crohn’s/ulcerative colitis)

24
Q

Lifitegrast

A

Anti-CD11a in keratoconjunctivitis

25
Q

what is chemotaxis?

A

directed leucocyte movement stimulated by chemotaxins

26
Q

role of chemotaxins

A

attract and activate leucocytes

Integrin affinity and avidity change

27
Q

source of chemotaxins

A

site of inflammation

some are immobilised and presented to leucocytes -> endothelial cell surface presentation + bound onto extracellular matrix

28
Q

non-selective chemotaxins

A

LTB4

C3a, C5a

formyl peptides

29
Q

selective chemotaxins

A

chemokines (chemotactic cytokines)

30
Q

what are chemokines?

A

[chemotactic cytokines]

Structurally defined group of chemotaxins

Produced in response to IL-1, TNF, bacteria

GPCR (unlike most cytokines)

31
Q

CXC chemokines

A

mainly neutrophil and T cell attractants

32
Q

CXCL8 chemokine - ligand

A

interleukin-8

33
Q

CXCL8 chemokine - receptor

A

CXCR1, CXCR2

34
Q

CXCL8 chemokine - target

A

neutrophil

35
Q

CXCL12 chemokine - ligand

A

SDF-1

36
Q

CXCL8 chemokine - receptor

A

CXCR4

37
Q

CXCL8 chemokine - target

A

lymphocytes

stem cells

38
Q

CC chemokines

A

not neutrophil attractants

39
Q

CCL2 - ligand

A

MCP-1

40
Q

CCL2 - receptor

A

CCR2

41
Q

CCL2 - target

A

monocyte

42
Q

CCL11 - ligand

A

eotaxin

43
Q

CCL11 - receptor

A

CCR3

44
Q

CCL11 - target

A

eosinophil

45
Q

CCL…. - receptor

A

CCR3,4,5,8

46
Q

CCL…. - target

A

activated T cell

47
Q

Fingolimod

A

S1P1 receptor agonist

MS

48
Q

Plerixafor

A

CXCR4 inhibitor

Non-Hodgkin’s lymphoma

49
Q

Maraviroc

A

CCR5 antagonist

HIV-1

50
Q

Mogamulizumab

A

Anti-CCR4 mAb

T cell lymphomas

51
Q

Leronlimab

A

CCR5 antagonist

HIV

52
Q

Balixafortide

A

CXCR4 antagonist

Breast cancer

53
Q

Selectivity in the inflammatory response

A

Cells move at different rates
- Neutrophils&raquo_space; monocytes > lymphocytes

Neutrophils = acute inflammation

Monocytes, lymphocytes = chronic inflammation

54
Q

Selectivity in the inflammatory response in TISSUES

A

Different selectin and CAM expression

Different chemokine expression

55
Q

Selectivity in the inflammatory response in LEUCOCYTES

A

Different integrin expression

Different chemokine receptor expression

56
Q

Leucocyte transmigration

A

[escape from circulation and accumulate at sites of injury]

SELECTINS - used to tether leucocytes on endothelium near inflammatory site

INTEGRINS (β2, α4) - used for stronger adhesion on chemokine activation of leucocytes

CAMS (ICAM, VCAM) expressed by endothelium = ligands for integrins

Leucocyte movement directed by chemotaxins

** POTENTIAL DRUG TARGETS IN INFLAMMATION **

Infection and Immunity (17 decks)

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