8. Cytokines and chemokines Flashcards Preview

BSMS204 Theme I Immunology > 8. Cytokines and chemokines > Flashcards

Flashcards in 8. Cytokines and chemokines Deck (39)
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1

What are cytokines?

Soluble mediators that are produced by a tissue or a cell and acts at a distance (from micrometres to several cm)

2

How do cytokines act?

All cytokines act by ligating their receptor (often two subunits) and triggering a signaling cascade leading to activated transcription of specific genes

3

What determines cell differentiation and haematopoiesis?

cytokines

GM-CSF - multipotential haematopoietic stem cell

SCF, G-CSF, IL-6 = mast cell

GM-CSF -> myeloblast

EPO-> erythrocyte

TPO, IL-11 -> megakaryocyte

T-lymphocyte - Il-2

4

What are interferons?

Anti-viral mediators – Interferons, identified (1957) as products of virus-infected cells that interfere with viral replication
IFN-alpha (made by lymphocytes)
IFN-beta (made by fibroblasts)
IFN-gamma (made by lymphocytes & NK cells)

IFN-gamma is a very poor antiviral molecule.

5

Immune activators

Lymphocyte-activating cytokines (IL-1)
T cell growth factors (IL-2, -7, -9, -15; they share a co-receptor)
Macrophage-activating cytokines (IFN-gamma)

6

Cytotoxins

Cytotoxins: identified as products of activated lymphocytes or macrophages that can kill tumor cells
tumor necrosis factor; TNF, also known as TNF-alpha

TNF is, in fact, a very poor antitumor molecule.
Don't be mislead by the name

7

What happened with TNF as an anticancer agent?

In the 1980s TNF was cloned and produced with the hope it would be an anticancer agent. However, it turned out to be too toxic


Same story for IL-1, as a lymphocyte activator tested in AIDS

8

Do the effector molecules made by T cells differ?

The three main types of armed effector T cells produce distinct sets of effector molecules with different functions. Th1 (T-helper) and Th2 cells act mainly by activating other cells (see previous lectures on innate immunity)

9

CD8 T cells produce

cytotoxic effector molecules e.g. perforin, granzymes

10

Th1 cells produce

macrophage activating effectormolecules e.g. IFN-gamma and TNF-alpha

11

Th2 cells produce

B-cell activating effector molecules
e.g. IL-4, IL-5, IL-10, TGF-Beta

12

Activated Th1 cell cytokines

IFN-gamma and CD40 ligand
Fas ligand or LT-alpha
IL-2
IL-3 and GM-CSF
TNF-alpha and LT-beta

13

Immune-stimulating cytokine deficiency cause immunosuppression

component of the IL-2, IL-4 and IL-7 receptorsX-linked SCID (severe combined immunodeficiency) is caused by the genetic inactivation (by mutation) of one receptor that is a common signalling

14

How did they find out that TNF is an inflammatory mediator?

Studying immunopathegenesis of cachexia during infection

activated macrophages produce an inflammatory mediator (cytokine) that, among other things, induced cachexia.
When they had its sequence, they found it was identical to TNF

15

Cardinal signs of inflammation

heat
swelling
redness
pain
tissue damage

16

What causes the cardinal signs of inflammation?

biological action of inflammatory cytokines (IL-1, IL-6, TNF…) on the vascular endothelium, or through production of prostaglandins or chemokines.

17

Inflammation

Macrophages encountering bacteria in the tissues are triggered to release cytokines that increase the permeability of blood vessels, allowing fluid and proteins to pass into the tissues.
They produce chemokines that direct the migration of neutrophils to the site of infection.
The stickiness of the endothelial cells of the blood vessels is also changed, so that cells adhere to the blood vessel wall and are able to crawl through it; first neutrophils and then monocytes are shown entering the tissue from a blood vessel.

The accumulation of fluid and cells at the site of infection causes the redness, swelling, heat, and pain, known collectively as inflammation. Neutrophils and macrophages are the principal inflammatory cells. Later in an immune response, activated lymphocytes may also contribute to inflammation.

18

TNF-mediated diseases

1-Septic shock
2-Multiple organ failure
3-Respiratory distress syndrome
4-Rheumatoid arthritis
5-Inflammatory bowel disease
6-Graft-versus-host rejection
7-Diabetes
8-Pulmonary fibrosis

(where TNF is a pathogenic mediator and where inhibition of TNF is protective in animal models)

19

Which cytokines are involved in allergy?

While Th1 cytokines are important in inflammatory diseases, Th2 cytokines are important in allergic diseases

The Th1/Th2 differentiation
is often viewed as a balance

20

TH1 cytokines from CD4

IFN-gamma, IL-12, IL23

21

TH2 cytokines from CD4

IL4

22

TH1 cytokines

IFN-gamma -> inflammation

23

TH2 cytokines

IL4, IL5, 9 and 13
allergy
anti-inflammation

24

TH17 cytokines

IL17 -> inflammation

25

Treg cytokines

IL-10, inhibit activity of other T cells
anti-inflammation

26

Chemokines

Chemotaxis
Discovered originally by neutrophils chasing bacteria

Then to explain infiltration of leukocytes

Important in the homing and migration of cells of the immune system (= role in development)

27

Examples of some chemokines

MCP-1/CCL-2

IL-8

28

CCL2 effect

causes macrophages to accumulate at site of infection - by chemotaxis

29

Therapeutic use of interferons

IFN-gamma Macrophage activation
IFN-beta (MS) "immunomodulation"

30

Host defence therapeutic uses

Host defense
IL-2 (melanoma, renal cell carcinoma)

IFN-alpha (hairy cell leukemia, Kaposi, viral hepatitis)