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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
What are IMMUNOGLOBULIN LIKE CAMs? Where are they found?
Group of CAMs that contain a variable number of immunoglobulin-like domains Expressed on vascular endothelial cells
26
What do immunoglobulin-like CAMs bind to? Give some example molecules
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
Summarise the 4 stages in extravasation, briefly stating the molecules involved
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
Using neutrophils as an example, describe the rolling phase
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
Using neutrophils as an example, describe the activation phase
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
Using neutrophils as an example, describe the adhesion phase
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
Using neutrophils as an example, describe the diapedesis phase
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
How is homing of naive T cells to endothelial tissue achieved?
- L-selectins found on naive T cell surface | - L-selectins recognise carbohydrates on Mucin-like CAMs on endothelial tissue
33
What Mucin-like CAMs to T Cells bind to on both lymph node and mucosal endothelial?
Lymph node: - CD34 - GlyCAM-1 Mucosal: - MAdCAM-1
34
Where do lymphocytes move from vascular endothelium into lymph nodes?
- 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
How many lymphocytes extravasate every second through HEV areas into a single lymph node?
14,000
36
What influences the development and maintenance of HEVs?
Influenced by cytokines produced in response to foreign antigens
37
What is HOMING?
The mechanism by which lymphocytes traffic to the appropriate location
38
Where do naive T cells home to and why?
Homing to secondary lymphoid tissue in order to become activated via antigen/MHC recognition by APCs
39
Where do effector T cells home to and why?
Home directly to inflamed vascular endothelium to help fight an infectious agent
40
What are chemokines?
A family of small polypeptides (90-130 AAs) that selectively control the adhesion, chemotaxis and activation of many types of leukocytes
41
Signalling pathways stimulated by chemokines cause what 2 changes?
1) Cell adhesion | 2) Cytoskeletal changes that allow migration in a paticular direction and then adherence
42
Inflammatory cytokines are typically produced in response to what?
Infection and/or secretion of pro-inflammatory cytokines e.g. TNF-alpha
43
How does chemokine signalling occur and what is the result?
- Signals through binding to receptors coupled with heterotrimeric large G proteins - Results in modifications to target cell allowing chemotaxis towards infected tissue
44
What dictates the migration pattern of leukocytes?
The pattern of expression of chemokine receptors
45
Which leukocyte type has the greatest variety of chemokine receptors and why?
T cells, so they can migrate everywhere
46
Describe the cascade of cells arriving at injected tissue due to chemokine action
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
What are the strucutres of CC and CXC chemokines and what receptors do they bind to?
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
To summarise ...
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
How are HEVs and chronic inflammatory disease related?
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
What is Leukocyte Adhesion Deficiency (LAD)?
- An inherited disease preventing leukocytes from homing to and entering infected tissue
51
What causes LAD?
- 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
What is the result of LAD?
- Repeated bacterial infections - Problems with wound healing - Inflammation of the gums (gingivitis)

3rd Year Biomed (44 decks)

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