Lecture 22

Question 1

How do persistent pathogens affect macrophages

Answer 1

1) Inhibit fusion of phagosome and lysosome
2) Prevent acidification–>lysosomal proteases can’t activate

Question 2

How does TH1 affect macrophages

Answer 2

1) Increases antimicrobial activity
2) Increase production of TNF-alpha
from the macrophage

Question 3

Function of TNFalpha secretion from macrophage

Answer 3

Autocrine signaling that sends survival signal to same macrophage

Question 4

CD40L binding effect on macrophages

Answer 4

1) Activates macrophages (M1)
2) Increases IL-12 expression
(IFN-gamma from effector CTL can also activate M1 macrophages)

Question 5

Effect of secretion of BOTH TNFalpha and IFN-gamma on macrophages

Answer 5

Further activates TH1 cells (positive feedback) by
Increasing expression of MHC class 1 and 2, CD40, B7 molecules, and IL-12

Question 6

How do TH1 cell stimulate increased differentiation of monocytes in bone marrow

Answer 6

TH1 cells secrete IL-3 and GM-CSF–>circulate in blood–>act on precursors in bone marrow (endocrine effect)

Question 7

How do TH1 cells recruit macrophages through chemotaxis

Answer 7

TH1 cells secrete chemokine CCL2 that attracts macrophages to site of infection

Question 8

What is in the core of a Granuloma

Answer 8

Infected macrophages
Center often becomes necrotic due to lack of oxygen and cytotoxic effect of activated macrophages

Question 9

What does the surrounding layer of granulomas consist of

Answer 9

Activated macrophages and then a layer of TH1 cells

Question 10

What is the associated TH2 cytokine for signal 3

Answer 10

IL-4

Question 11

What are the effector cytokines associated with TH2

Answer 11

IL-4, IL-5, IL-13

Question 12

What is the master transcriptional regulator for TH2

Answer 12

GATA-3

Question 13

Main action of TH2 in response to helminths (parasites)

Answer 13

TH2 activates eosinophils, mast cells, basophils, and macrophages

Question 14

What are involved with allergies (TH2)

Answer 14

Dysregulated TH2 responses

Question 15

What transcription factor does TH2 signal 3 activates?

Answer 15

STAT 6 protein gets activated by IL-4 (TH2 signal 3)

Question 16

TH2 transcriptional pathway

Answer 16

TH2–>IL-4 (signal 3)–>STAT 6 (transcriptional factor)–>GATA-3 (master transcriptional regulator)–>IL-4, IL-5, IL-13 secretion

Question 17

TH2 functions

Answer 17

1) Secrete IL-4, IL-5, IL-13
2) Targets eosinophils, basophils, mast cells, and macrophages
3) Helps in killing of helminth parasites

Question 18

What are parasitic helminths

Answer 18

Multicellular worms
Colonize in gut of animals and humans
Cause chronic infection

Question 19

What does TH2 do to clear helminths

Answer 19

1) Can clear pathogen (except when chronic infection)
2) Reduce worm burden with weep and sweep
weep–>increase mucous production
sweep–>increase worm expulsion
3) Facilitate tissue repair
4) IgE antibodies (to mount an immune response against helminths)

Question 20

Effect function of TH2

Answer 20

1) Promote cell turnover and mucous production
2) Enhance worm expulsion
3) Recruit and activate M2 macrophages
4) Eosinophil activation
5) Mast cell activation

Question 21

How does TH2 promote cell turnover and mucous production

Answer 21

By signaling release of IL-13 cytokine–>increases mucous production by goblet cells and increase epithelial tissue turnover
WEEP in weep and sweep

Question 22

How does TH2 enhance worm expulsion

Answer 22

By signaling release of IL-13–>stimulate contraction of smooth muscle cells–>lead to worm expulsion
SWEEP in weep and sweep

Question 23

How does TH2 recruit and activate M2 macrophages

Answer 23

By signaling IL-4 and IL-13 release
M2 macrophages–>alternative activated macrophages

Question 24

Function of M2 macrophages

Answer 24

Alternatively activated macrophages
1) Help in tissues repair and participate in worm killing and expulsion (by increasing smooth muscle contraction)
2) Form granulomas to entrap worms
3) Release toxic mediators directly onto the worm by antibody dependent cell mediated cytotoxicity (ADCC)

Question 25

How does TH2 activate eosinophils

Answer 25

IL-5 activates eosinophils

Question 26

How do eosinophils kill parasites

Answer 26

1) MBP (major basic protein) that is within eosinophil granules
2) IgE antibodies that bind antigens on parasite, eosinophils express receptors that recognize the Fc portion of IgE–>eosinophils can specifically target pathogen and degranulate to kill in

Question 27

Consequence of Histamine release

Answer 27

1) Increase vascular permeability
2) Increase intestinal motility
3) Increase recruitment of inflammatory cells

Question 28

How does TH2 activate Mast cells

Answer 28

Cytokines activate mast cells, mast cell granules contain histamine
Mast cells also express receptors that recognize the Fc portion of IgE (ADCC)