Lecture 9 (4b) - Cytokines Flashcards Preview

Basic Immunology > Lecture 9 (4b) - Cytokines > Flashcards

Flashcards in Lecture 9 (4b) - Cytokines Deck (51):
1

Receptors transmit signals

from the cell surface to the nucleus to change gene expression and function
• can work locally, at a distance, at low levels
• signals from - CYTOKINES, chemical messengeres, hormones

2

IL =

interleukin
• called lymphokines
• can sometimes be non-immune cells and target non-immune cells

3

Cytokines in antigen presentation

IL-
1
16
12
18
23
27

4

Cytokines from the gut epithelium to the T cell

IL
7
15

5

Cytokines in costimulation

APC : Tcell
CD40 : CD40L
CX40L : CX40
CD80/86 : CD28

6

Cytokines in inflammation

from T cell
IL
5
13
17
21
22

TNFα IFNγ
--> macrophage
--> TNFα IL-6 IL-1
--> inflammation

(--> Crohn's disease)

7

Cytokines for T cell proliferation

IL
2
21

8

Cytokines are

small proteins secreted by the cells of the innate and adaptive immune systems

9

Cytokine secretion is

brief, self-limited
(transient synthesis)

10

Cytokine are usually not

stored in the cells (except mast cells store it in cells)
• they are synthesized by new gene transcription

11

Transcription of cytokine genes is

a transient process
• cytokine mRNAs are unstable

12

Cytokines, like other polypeptide hormones, mediate their effects by

binding to specific receptors on the surface of target cells
• these receptors are often on many cell types
• immunology is context-specific

13

Cytokines are pleiotrophic

they have many functions
• made by many cell types
• same cytokine made by different cells
• cytokine receptors on many cell types
• have many different effects on different cell types

• many cells make them, many cells respond to them, response depends on what it binds

14

Cytokines produced as a result of activation of the
INNATE IMMUNE SYSTEM

• type 1 interferon
• interleukins
- IL-1
- IL-6
- IL-12
• TNF

15

Cytokines produced as a result of activation of the
ADAPTIVE IMMUNE SYSTEM

• IFNγ
• interleukins
- IL-2
- IL-4
- IL-5
(IL-4 and IL-5 for Th2)

16

Cytokines that stimulate immature leukocyte growth and differentiation

• IL-3
• colony stimulating factors

17

Interleukins vs cytokines

• all interleukins are cytokines
• not all cytokines are interleukins

18

T cells make lots of cytokines when activated

switch on T cell by binding TCR
make nothing -->
activated = lots of transcriptional activation
= mediated by cytokines, lots of different targets

19

IL-2

T cell growth factor

20

IL-3

mast cell growth factor

21

IL-4 and IL-5

B cell growth factor
• made by Th2
• IL-5 = eosinophil growth factor

22

IL-10

• B cell growth factor
• immunosuppressive cytokine

23

IFN- γ

• anti-viral
• activates macrophages

24

IL-2 secretion

cloned as T cell growth factor, does other things:
• induces Th cell, induced by Th cell
• B cell - stimulation of division
• T cell - stimulation of division, IFNγ release (and other mediators)
• NK cell - increase NK cell activity (lymphokine activated killer)
• monocyte activation

25

IFN-γ

made by T cells, important in cell-mediated immunity
• induced by: NK cells, T cells
• endothelial cells - activation
• NK cells - increase in NK cell activity
• many cell types - induction of Class I or Class II MHC
• B cell - differentiation, stops cell division
• T cell - activation
• many cell types - weak anti-viral activity, stops cell division, hematopoiesis stops
• macrophage - activation
• granulocyte - activation

26

Toll-like receptors
(innate immunity)

molecules on the surface of mammalian cells which recognize components of bacteria and viruses to alert the immune system

27

TLR2
+
TLR6 (/ TLRX)

• lipoproteins
• lipopolysaccharides
• PGN (gram-positive)
• zygomosan (yeast)
• GPI anchor (T. cruzi)

28

TLR4
+
MD-2

• LPS (Gram-negative)
• Taxol (plant)
• F protein (RS virus)
• hsp60 (host)
• fibronectin (host)

29

TLR5

flagellin

30

TLR9

CpG DNA

31

When bacteria interact with macrophages through TLRs, macrophages release large amounts of cytokines

IL-1
TNFα
IL-6
IL-8
nitric oxide
IL-12*******
MMPS

32

Actions of IL-12
NK cells

increased cytosolic activity

and

stimulate IFN-γ
--> IFN-γ
--> macrophage activation, killing of phagocytosed microbes

33

Action of IL-12
CD8+ T cell

stimulation of IFN-γ secretion
--> IFN-γ
--> macrophage activation, killing of phagocytosed microbes

34

Action of IL-12
Naive CD4+ T cell

Th1 cell
--> stimulate IFN-γ secretion
--> macrophage activation, killing of phagocytosed microbes

35

Bacteria in skin, Lagerhans recognize via TLR

macrophage makes TNFα and IL-1
--> endothelial cells, makes them sticky
--> neutrophils (in blood) stick to surface and go through
• localize phagocytes where bugs are

36

Cytokines are important in mobilizing inflammatory cells into tissues

inflammation
--> cytokines increased on endothelial cells (eg ICAM and selectin)
--> neutrophil finds these because it has receptors (LFA1)
--> neutrophil rolls, slows down and anchored by LFA1-ICAM
--> stops
==> through endothelial into tissue

37

Septic shock

• most common cause of death in ICUs in the US
• dissemination of infections into the vasculature
• caused by systemic microbial infection, most often by gram-negative infection (endotoxic shock) but can also occur with gram-positive and fungal infections
• infection from site into blood

38

How - septic shock

Cell envelope of gram-negative bacteria
--> endotoxin (CLPs)
--> TLR4
--> macrophage releases cytokines
--> local inflamation
--> septic shock

39

Disseminated intravascular coagulation in small vessels

little clots in small vessels
--> punch holes in sides
--> vessels so sticky can't get through
(disseminated intravascular coagulation in small vessels)
• lack of oxygen to the extremities because blood vessels are blocked --> tissue dies
• • cytokines here are bad

40

Chemokine

• a small subgroup or superfamily of cytokines that are released during the initial phase of cell response to injury, antigens, and invading microorganisms
• selectively attract leukocytes to inflammatory foci during both cell migration and activation
(hemotatic - draw cells into body)

41

Neutrophils move by

chemotaxis
• move up chemokine concentration gradient

42

There are lots of chemokines, often

binding to the same receptor
• redundancy
• knock out 1 chemokine and another does its function

43

IL-8
(CXCL8)

a chemokine that attracts neutrophils into tissues
• macrophage in lung making IL-8, binds CXCR1/2, chemotaxes it through into tissue and causes damage (CXCR1/2 causes damage)

44

Chemokines in extravasation

1. capture
2. activation
3. adhesion
4. transmigration
• ICAM-LFA1
• ICAM2 brings cells through

45

Anti-inflammatory cytokines

• IL-10 made by T cells, B cells, macrophages
• TNF, IL-1, IL-6 - pro-inflammatory

• transforming growth factor TGFβ (--> Treg)
- inhibits T cell activation
- inhibits antigen presentation

46

Damaging cytokines vs inhibitor cytokines

damaging - TNF, IL-1, IL-6

inhibitory - IL-10, TGFβ

• balance is anti-inflammatory usually

47

Cytokine storm

positive feedback loop between cytokines and immune cells --> elevated levels of cytokines
• TGN1412 (anti-CD28) activated all T cells --> cytokine storm
• antibodies to Cd28 usually activating for T cells
• TGN1412 (anti-CD28) meant to induce unresponsiveness in T cells
• given to patient with T cell disease, would switch T cells off
• cytokine storm same as septic shock

48

Anti-TNFα antibodies

• rheumatoid
• IBD
• asthma
• psoriasis

49

Anti IL-15 antibodies

rheumatoid

50

Soluble IL-1R

• rheumatoid
• psoriasis

51

Summary

• cytokines are critical for immunity
• complex, redundant, wide-ranging
• can kill you in excess