Lecture 22 - Cytokines and Chemokines Flashcards

1
Q

What is the mechanism of intercellular crosstalk?

A

Cytokines

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2
Q

What is the definition of a cytokine?

A
  • Small molecule
  • Peptide or protein
  • Upon release and binding to specific receptors mediate distinct immunological functions
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3
Q

What are some of the immunological functions of cytokines?

A
  • Intercellular signalling, e.g. IL-7
  • Autocrine feedback loops e.g. IL-2
  • Promotion of release of other cytokines, e.g. IL-2
  • Inhibition of the release of other cytokines, e.g. IL-10
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4
Q

Describe the mechanism of action of cytokines

A
  1. Released by a cell
  2. Bind to specific receptors on the cell surface
  3. Transduction pathway, e.g. JAK / STAT pathway
  4. Gene expression
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5
Q

What is the structure of cytokine receptors?

Where are they located?

A

• Located on the cell surface

Structure:
• Multimers
• Some chains are shared between different receptors

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6
Q

What type of molecule are cytokines?

A

Peptide or protein

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7
Q

What is transpresentation?

A

e.g. IL-15

  1. IL-15 “transpresented” by DC with IL-15Rα
  2. Binds to receptor on CTL or NK cell

IL-15Rα needed to elicit a response in the target cells

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8
Q

What is the TNF superfamily?

What are the major functions?

A

19 structurally related protein ligands
Bind to one or more receptors
A given receptor will be bound by many ligands in the TNF superfamily

Functions:

  1. Inflammation
  2. Cell survival / growth
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9
Q

What is TNF-α?

What are some of the effects?

A

Strong pro-inflammatory cytokine

Effects:
 • Neutrophil activation
 • Catabolic metabolism
 • Apoptosis (of tumour cells)
 • Perpetuation of pro-inflammatory cytokine loops
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10
Q

For which disease does TNF-alpha play an important pathological role?

Treatment?

A

Rheumatoid arthritis

Infliximab (Remicade, Humira) MAbs against TNF-alpha are a good therapeutic

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11
Q

What is the common γ chain?

A

Common subunit in cytokine receptors

aka CD132

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12
Q

What are some common γ chain cytokines?

A
IL-2
IL-4
IL-7
IL-9
IL-15
IL-21

These all bind to cytokine receptors which contain the common γ chain (CD132)

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13
Q

What is the function of IL-2?

A

T cell growth factor

  • Following T cell activation, IL-2 expression is up-regulated
  • IL-2 binds to IL-2R on T cell
  • Autocrine signalling
  • T cell enters cell cycle and proliferates rapidly
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14
Q

For what is IL-4 important?

A
  • Differentiation and function of Th2 cells
  • IgE class switching
  • Role in allergy
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15
Q

For what is IL-7 important?

A

Central role in T lymphocyte development

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16
Q

For what is IL-9 important?

A
Activation of
 • Eosinophils 
 • Mast cells
 • Endothelium
 • B cells
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17
Q

For what is IL-15 important?

A
  • NK cell development

* T cell homeostasis

18
Q

For what is IL-21 important?

A

Important for Tfh cells: Stimulation of B cell responses in germinal centres

19
Q

What is a chemokine?

What are the key functions?

A

“Chemotactic cytokine”

Functions:
• Recruitment of circulating leukocytes from blood into tissues
• Regulation of traffic of lymphocytes through lymphoid organs
• Migration of DCs from tissues into LNs

20
Q

How many known chemokines are there?

21
Q

How are chemokines classified?

A

Cystein residues in the N-terminus
• CC
• CXC

22
Q

Describe the mechanism of action of chemokines

A
  1. Released by cells
  2. Bind to GPCRs
  3. Chemotaxis of cell towards source, amoeboid
23
Q

What is the receptor for CCL19/21?

24
Q

Describe the interaction between CCR7 and CCL19/21

A
  • CCL19/21 constitutively expressed in LNs
  • CCR7 expressed on naïve T & B lymphocytes and DCs
  • CCR7 expressing cells are guided towards the LNs
25
Which cells produce CCL19/21?
* LN Stromal cells | * Endothelial cells lining HEVs
26
What is the ligand for CXCR5?
CXCL13
27
Describe the interaction between CXCR5 and CXCL13
* CXCL13 produced in B cell follicles * Naïve B cells express CXCR5 * Naïve B cells attracted towards B cell follicle * Activated B cell start expressing CCR7 as well, so that they migrate to the T-B cell border * Tfh express both CXCR5 & CCR7, so they migrate to the T-B cell border
28
What produces CXCL13?
FDCs in B cell follicles
29
Describe how activated B cells and Tfh cells meet
• Upon activation B cells start expressing CCR7 (in addition to CXCR5) → migration towards paracortex • Tfh start expressing CXCR5 (in addition to CCR7) → migration towards B cell follicle The two cells meet in the middle in the marginal zone
30
Where will CCR7 expression localise a cell? Compare this with CXCR5
CCR7: T cell zone CXCR5: B cell follicle
31
Describe an example of discovery of a cytokine having a clinical application
TNF-α role in Rheumatoid arthritis mAbs against TNF has been effective in treatment of RA
32
What was TNF-α called cachexin?
This molecule induces cachexia through stimulation of catabolic metabolism It is seen clinically in chronic diseases (cancer, infections, AIDS) in which there is wasting
33
Why is TNF so called?
When added to tumours, the cells die
34
Is TNF-α anabolic or catabolic? | Suggest a reason this might occur in infection
Catabolic: breaking down of material Generation of heat → fever → body no longer at the optimal temperature for bacteria
35
What is CD132?
Common γ chain Seen in many cytokine receptors
36
What is seen in individuals who have a mutation in the gene for the common γ chain?
SCID: severe combined immunodeficiency | X-linked, as the common γ chain is encoded on the X chromosome
37
Compare the structure of the moderate and high affinity IL-2Rs Where are these found?
Moderate affinity IL-2R: naïve T cells • alpha subunit not present • less potent response in the cell High affinity: • in activated T cells • highly potent response in the T cell
38
Compare the size of cytokines and chemokines
Chemokines are much smaller than cytokines They are often only polypeptides
39
What are the chemokine receptors? | Which pathway is activated?
GPCRs | → cAMP pathway stimulated
40
What is the effect of pertussis toxin?
Block all GPCR | → block action of all chemokines
41
When do DCs express CCR7?
Once it encounters foreign antigen Now the DC is responsive to CCL19/21 and will be attracted to the lymph nodes
42
What sets up the anatomical structure of lymphoid organs?
Chemokines | e.g.. CCL19/21 expression in paracortex brings T cells to this area