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Flashcards in Cytokines Deck (32)
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1
Q

What are cytokines?

A

Diverse group of small secreted proteins (5-25KDa) and chemical messengers which modulate the behaviour of the IS

  • Analogous to hormones of the IS
2
Q

Which cytokines are membrane-bound?

A

1) TNF
2) FASL

However, majority are secreted

3
Q

What are some functions of cytokines?

A

Illicit a range of activities on different targets:

  • mediate inflammation
  • trauma response
  • cell differentiation
4
Q

How are cytokines secreted and what type of cells do they act upon?

A

Secreted y a wide range of immune and non-immune cells.
Eg - epithelial cells secrete: IL-1, 8, 6, TGFbeta, stromal cells of BM - which secrete a large no. of growth hormones which regulate haematopoeisis of the IS

Comp. to specific endo. glands for hormones.

Usually act upon immune cells (epithelial cells respond to TNF, IL22, IFN-y)

5
Q

How are cytokines sensitive?

A

E.g. IL-6 circulates in picomolar (10-12 M) concentrations and can increase up to 1,000-fold during trauma or infection.

Hormones - circulate in nanomolar (10-9 M) concentrations and usually vary by less than one order of magnitude.

6
Q

How are cytokines detected?

A
  • ELISA (measures cytokines)
  • ELIspot
  • Flow cytometry (measures CD8+ cells and other cells)
7
Q

What does Western blotting measure?

A

Protein expression

8
Q

“Each cytokine has a unique receptor made of specific subunits”

A

True - unique receptors

False - receptors share chains and subunits

9
Q

What is ELISA?

A

Enzyme Linked ImmunoSorbent Assay

  • target protein immobilised onto plate
  • detection of “target” is achieved using an AB conjugated (linked) to an enzyme that produced a colour reaction
  • can be done directly or via an intermediate (secondary) AB
10
Q

What are the various terms for cytokines?

A
  • interferons
  • interleukins
  • chemokines
11
Q

How are cytokines produced?

A

De novo following stimulation - cells increase T&T follow when cytokines are needed for secretion

  • can be stored too
  • eg TNF-a is stored by mast cells
12
Q

How do cytokines act upon cells?

A
  • autocrine and paracrine manner, and occasionally endocrine manner over long distances eg IL-6
  • act upon target cells by binding specific cell surface receptors (frequently shared chains)
13
Q

Describe how cytokines act in an autocrine manner

A

Acts back on cell to regulate proliferation - eg IL-2 produced after maturing T cells following APC interaction

14
Q

Describe how cells act in a paracrine manner

A

Paracrine action: IL-4 released by Th2 cells to induce B cell class switching (changes isotope of ABs being produced + stimulates maturation of B cell down plasma/memory cell lineage)

15
Q

Describe how cytokines act in an endocrine manner

A

Eg. IL-6 and TNF-a modulate hypothalamic production of ACTH = elevated temp + regulates lipid metabolism

  • so, modulates locals IRS at SOI but also hormone production by hypothalamus, reg bone morphogensis, angiogenesis, etc
16
Q

What are the 5 main groups of cytokines which are functionally classified?

A

1) immunoregulatory
- IL-2, 4, 12, 15, TNFa and TGFb

3) anti-inflammatory
4) chemotactic
5) heamatopoitic

17
Q

What are the 4 types of cytokines?

A

1) Pleiotropic
2) Redundant
3) Synergistic
4) Anatagonistic

18
Q

How does a cytokine activate its target cells?

A

A cytokine will have no effect on a cell unless it expresses a receptor for that cytokine.

Regulating the expression level of the receptor is a means of controlling the effect of the cytokine.

19
Q

What do cytokine receptors share?

A

Subunits and chains

Eg - IL-2 receptor:

  • y chain critical component for a large no of cytokines/cells
  • when mutated: has a wide ranging effect
20
Q

What disease can cytokines drive and what are its characteristics?

A

RA: systemic autoimmune disease

  • chronic inflammation of joints
  • pain, loss of function, invalidity
  • multifactorial: gender, age, genetics, environment
21
Q

What is RA mediated by?

A

T cells, B cells, DC, macs, neutrophils and fibroblasts

Cytokines: TNFa, IL-1b, IL-6 and IL-7

Blocking of TNFa - can dramatically reduce inflammation and even reverse some of the cartilage damage (anti-TNF damage)

  • possibly occurs due to misregulation of cytokines
22
Q

What are redundant cytokines?

A

When different cytokines have the same effect on their target cells

Eg - activated Th2 cell produces IL-2, 3 & 5 = B cell proliferation

23
Q

What are synergistic cytokines?

A

When different cytokines augment (massively up-reg expansion) the response of each on its own

Eg - activated Th1 cell produces IFNy and mac produces TNF = both increase expression of MHC I on many cell types

24
Q

What are antagonistic cytokines?

A

When different cytokines have opposite effects on the target cell

Eg - Th2 produces IL-4 (drives class switching to IgE) and IFNy (blocks this action)

  • feedback loops
25
Q

What are pleiotropic cytokines?

A

When one cytokine can have different (completely unrelated) effects in different target cells

IL-6 = extreme example, acts in an endocrine manner

IL-4 = affects B cell class switching of IgE to IgM
Also inhibits macs + induced Th2 differentiation
26
Q

What are the cytokine families, and how are they grouped?

A

FUNCTIONALLY:
1) interleukins (IL): 4 alpha helix bundles eg IL-1,2,3..36. Also include EPO and thrombopoeitin

2) tumour necrosis factors (TNF): primarily TM, surface proteins. TNF-a, beta but also CD40L, FASL, CD30L
3) growth factors (GF): cytokines that direct proliferation (+ diff) eg TGF-b, VEGF

STRUCTURALLY:
1) interferons (IFN): structurally diverse and grouped into type I: IFN-a,b,(k,d,e), and type II: IFNy. Tend to “interfere” with viral replication

2) colony stimulating factors (CSF): secreted glycoproteins that act upon haematopoeitic cells to regulate proliferation and differentiation, G-CSF, M-CSF, GM-CSF
3) chemokines (CK): group of cytokines that direct cell movement (chemoattractants). 4 subfamilies classified by the arrangement of their cysteine bonds into the CC, CXC, CX3C groups

27
Q

What are chemokines?

A

Mediate chemotaxis (not the only cytokines that do this)

But their primary function.

Contain 2/4 cysteine residues in a conserved structural location, which form disulphides bonds. Yeah

28
Q

What are chemokines divided into?

A

4 groups depending on the number of cysteines and their spacing.

1) C chemokine
2) CC chemokine - no space, directly next to each other
3) CXC chemokine - AA spacer
4) CX3C chemokine

29
Q

What are some effects of cytokines on their target cells?

A

???? Second page

30
Q

What are T helper cells defined by?

A

The cytokines they produce

Activity and differentiation is also regulated by a small number of master regulatory TFs

31
Q

What is X-linked SCID?

A

X-linked severe combined immunodeficiency

  • X-linked recessive trait - mutated IL2-Ry chain
  • IL-2Ry shared between receptors for IL-2,4,7,9,15 and 21
  • isolation in a “bubble” was an early prophylactic treatment
  • bubble = incapable of mounting a response to bacterial/fungal/viral infections
  • BM transplant - standard treatment
32
Q

What is a cytokine storm?

A
  • IR is controlled by feedback mechanisms
  • fail = too many cells recruits and systemic IR results, releasing >150 mediators
  • high fever, swelling and redness, extreme fatigue and nausea (heightening normal inflammation)
  • causes unknown, results form infectious and non-infections diseases including (GVHD), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, SARS