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3rd Year Biomed > Immunology (Liz - Extravasation) > Flashcards

Immunology (Liz - Extravasation) Flashcards

1
Q

What is the first action when a bacteria invades a tissue?

A

Tissue macrophages release cytokines and chemokines

  • Vasodilation and increased vascular permeability
  • Inflammatory cells migrate to the tissue
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2
Q

What are the 4 signs of inflammation? What are they caused by?

A
  • Redness
  • Heat
  • Swelling
  • Pain

First 3 causes by vasodilation and increased vascular permeaility

Pain causes by release of inflammatory mediators by inflammatory cells

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3
Q

Why do lymphocytes continually circulate around the body?

A

To give maximum chance of interacting with foreign antigens and microorganisms within the tissue or on APCs in the lymph nodes

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4
Q

How many lymphocytes are specific for and will bind to a particular antigen?

A

1 in 100,000

Essential that lymphocytes travel widely in body

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5
Q

What is needed before a lymphocyte can enter an inflammed tissue or a peripheral lymphoid organ?

A

Must ADHERE to and PENETRATE the layer of endothelial cells lining the wall of blood vessels

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6
Q

What is extravasation?

A

The process by which lymphocytes pass through the walls of blood vessels

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7
Q

Where is the only place that lymphocytes can migrate from the blood into the lymph nodes?

A
  • Specialised areas in the post capillary venules called high-endothelial venules (HEVs)
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8
Q

What is the role of cell adhesion molecules (CAMs)?

A
  • Vital for allowing cells to adhere to correct endothelium
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9
Q

Where are CAMs expressed and what do they bind to?

A
  • Expressed on the endothelial cells lining the blood vessels
  • Capable of binding to ligands found on the surface of leukocytes
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10
Q

Are CAMs expressed constitutively, only during an inflammatory response or both?

A

Both

  • Some CAMs expressed all the time
  • Some expressed in response to localised concentrations of cytokines produced during an inflammatory response
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11
Q

What cells have CAMs that bind to vascular endothelium?

A

Recirculating lymphocytes, monocytes and granulocytes

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12
Q

What other immune interactions are CAMs used in?

A
  • Th cell binding to an APC
  • Th cell interacting with a B cell
  • Tc cell binding with a target virally infected cell

The ‘glue’ that holds cells together while antigen presentation takes place

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13
Q

What are the 4 families of CAMs?

A

1) The SELECTIN family
2) MUCIN-LIKE
3) INTEGRIN
4) IMMUNOGLOBULIN super-family

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14
Q

What are SELECTINS and what do they bind to?

A
  • Family of membrane glycoproteins containing a lectin-like domain
  • Lectin-like domain binds to specific carbohydrate (CHO) group on Mucin-like CAMs
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15
Q

What selectin is found on leukocytes?

A

L-selectin

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16
Q

What selectins are found on vascular endothelial cells during an inflammatory respose?

A

E-selectin and P-selectin

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17
Q

What Mucin-like CAMS on endothelial cells do L-selectins bind to?

A
  • CD34

- GlyCAM-1

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18
Q

What is the first step of extravasation and what adhesion interaction is responsible?

A
  • Adhesion between a fast-moving lymphocyte or neutrophil and the static endothelial layer
  • Selectin/Mucin CAM interaction
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19
Q

What are MUCIN-LIKE CAMs and what do they bind to?

A
  • Group of serine/threonine rich proteins
  • Heavily glycosylated
  • Many carbohydrate side chains that bind to SELECTINS
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20
Q

Give some examples of MUCIN-LIKE CAMs and what they bind to?

A

CD34 and GlyCAM-1 on endothelial cells both bind to L-selectin of leukocytes

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21
Q

What are INTEGRIN CAMs and where are they found?

A

Group of heterodimeric proteins

  • consist of alpha and beta chain
  • Expressed on surface of leukocytes
22
Q

Integrins are grouped into categories based on what?

A

Which beta subunit they contain

23
Q

What influences tight binding of leukocytes to endothelial surfaces?

A

Chemokines that activate the intergrin expression (e.g LFA-1) on the leukocyte

24
Q

What do integrins bind to?

A

IMMUNOGLOBULIN-LIKE CAMs

25
Q

What are IMMUNOGLOBULIN LIKE CAMs? Where are they found?

A

Group of CAMs that contain a variable number of immunoglobulin-like domains

Expressed on vascular endothelial cells

26
Q

What do immunoglobulin-like CAMs bind to? Give some example molecules

A

Bind specifically and tightly to INTEGRINS on the surface of leukocytes

e.g.

ICAM-1, -2, -3 (immunoglobulin) binds to VLA-4 (integrin)

LFA-3 binds to LFA-1

27
Q

Summarise the 4 stages in extravasation, briefly stating the molecules involved

A

1) Rolling
- L-selectin

2) Activation
- CCL21 (chemokine)

3) Adhesion
- LFA-1 (integrin)

4) Diapedesis (passage of cell through the wall)
- CCL21, CXL12
(chemokines)

28
Q

Using neutrophils as an example, describe the rolling phase

A

1) E-selectin is induced on vascular endothelial cells by inflammatory signals
2) E-selectin binds to the sialyl-Lewis-x tetrasaccharide on a mucin-like CAM molecule on the neutrophil
3) Interaction is weak and therefore neutrophil rolls along the endothelium

29
Q

Using neutrophils as an example, describe the activation phase

A

1) A chemokine (e.g. CXCL8) binds to its specific receptor (CXCL8R) on the neutrophil
2) This triggers the activation of integrins such as LFA-1

30
Q

Using neutrophils as an example, describe the adhesion phase

A

1) TNF-alpha induces expression of ICAM-1 on endothelium
2) LFA-1 expressed on neutrophils binds to ICAM-1
3) Tight binding stops rolling completely

31
Q

Using neutrophils as an example, describe the diapedesis phase

A

Neutrophil moves through endothelium using a number of factors:

1) Chemotaxis through tissue CXCL8 and CXCL8R
2) Interactions between CD31 (PE-CAM) on both neutrophil and endothelium physically pulls cell through
3) Metalloproteinases produces by neutrophils cut through the matric of the basement membrane
4) Leukocytes then follow IL-8 chemokine to infection area

32
Q

How is homing of naive T cells to endothelial tissue achieved?

A
  • L-selectins found on naive T cell surface

- L-selectins recognise carbohydrates on Mucin-like CAMs on endothelial tissue

33
Q

What Mucin-like CAMs to T Cells bind to on both lymph node and mucosal endothelial?

A

Lymph node:

  • CD34
  • GlyCAM-1

Mucosal:
- MAdCAM-1

34
Q

Where do lymphocytes move from vascular endothelium into lymph nodes?

A
  • Regions of vascular endothelium found in the post-capillary venules of the lymphoid organs called High Endothelial Venules (HEVs)
  • They are composed of an area of specialed cells with plump cuboidal shape
35
Q

How many lymphocytes extravasate every second through HEV areas into a single lymph node?

A

14,000

36
Q

What influences the development and maintenance of HEVs?

A

Influenced by cytokines produced in response to foreign antigens

37
Q

What is HOMING?

A

The mechanism by which lymphocytes traffic to the appropriate location

38
Q

Where do naive T cells home to and why?

A

Homing to secondary lymphoid tissue in order to become activated via antigen/MHC recognition by APCs

39
Q

Where do effector T cells home to and why?

A

Home directly to inflamed vascular endothelium to help fight an infectious agent

40
Q

What are chemokines?

A

A family of small polypeptides (90-130 AAs) that selectively control the adhesion, chemotaxis and activation of many types of leukocytes

41
Q

Signalling pathways stimulated by chemokines cause what 2 changes?

A

1) Cell adhesion

2) Cytoskeletal changes that allow migration in a paticular direction and then adherence

42
Q

Inflammatory cytokines are typically produced in response to what?

A

Infection and/or secretion of pro-inflammatory cytokines e.g. TNF-alpha

43
Q

How does chemokine signalling occur and what is the result?

A
  • Signals through binding to receptors coupled with heterotrimeric large G proteins
  • Results in modifications to target cell allowing chemotaxis towards infected tissue
44
Q

What dictates the migration pattern of leukocytes?

A

The pattern of expression of chemokine receptors

45
Q

Which leukocyte type has the greatest variety of chemokine receptors and why?

A

T cells, so they can migrate everywhere

46
Q

Describe the cascade of cells arriving at injected tissue due to chemokine action

A

1) Neutrophils arrive first and bind to CXCL8 chemokine using CXCL8R and produce a respiratory burst

(Respiratory burst generates ROS and they therefore release their granules to kill tissue microbes)

2) Monocytes and DCs arrive next in response to chemokines
- become activated
- allows then to present antigens to Th cells as they arrive

3) Then Th cells arrive
- attracted via a large range of chemokines via specific chemokine receptors

47
Q

What are the strucutres of CC and CXC chemokines and what receptors do they bind to?

A

CC:

  • Have 2 cysteine residues next to each other
  • BInd to CCR G protein-coupled receptors 1-9

CXC:

  • Same cysteine residues but are separated by one AA
  • Bind to CXR G protein-coupled receptors 1-6
48
Q

To summarise …

A

As different chemokine receptors are found on different types of immune cell, a particular chemokine can be used to attract a particular cell to a particular tissue

49
Q

How are HEVs and chronic inflammatory disease related?

A

HEV-like regions (plump endothelial cells) observed in a number of chronic inflammatory diseases
- Allow large scale influx on leukocytes expressing L-selectins, contributing to inflammation of the affected area

50
Q

What is Leukocyte Adhesion Deficiency (LAD)?

A
  • An inherited disease preventing leukocytes from homing to and entering infected tissue
51
Q

What causes LAD?

A
  • Deficiency in the leukocyte integrin subunit CD18
  • CD18 common beta chain of 2 intergrins: LFA-1, CR3 and CR4
  • Levels of leukocytes high in the blood because they cannot migrate to and enter infected tissue to fight infection
52
Q

What is the result of LAD?

A
  • Repeated bacterial infections
  • Problems with wound healing
  • Inflammation of the gums (gingivitis)

3rd Year Biomed (44 decks)

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