Lecture 22 Flashcards
How do persistent pathogens affect macrophages
1) Inhibit fusion of phagosome and lysosome
2) Prevent acidification–>lysosomal proteases can’t activate
How does TH1 affect macrophages
1) Increases antimicrobial activity
2) Increase production of TNF-alpha
from the macrophage
Function of TNFalpha secretion from macrophage
Autocrine signaling that sends survival signal to same macrophage
CD40L binding effect on macrophages
1) Activates macrophages (M1)
2) Increases IL-12 expression
(IFN-gamma from effector CTL can also activate M1 macrophages)
Effect of secretion of BOTH TNFalpha and IFN-gamma on macrophages
Further activates TH1 cells (positive feedback) by
Increasing expression of MHC class 1 and 2, CD40, B7 molecules, and IL-12
How do TH1 cell stimulate increased differentiation of monocytes in bone marrow
TH1 cells secrete IL-3 and GM-CSF–>circulate in blood–>act on precursors in bone marrow (endocrine effect)
How do TH1 cells recruit macrophages through chemotaxis
TH1 cells secrete chemokine CCL2 that attracts macrophages to site of infection
What is in the core of a Granuloma
Infected macrophages
Center often becomes necrotic due to lack of oxygen and cytotoxic effect of activated macrophages
What does the surrounding layer of granulomas consist of
Activated macrophages and then a layer of TH1 cells
What is the associated TH2 cytokine for signal 3
IL-4
What are the effector cytokines associated with TH2
IL-4, IL-5, IL-13
What is the master transcriptional regulator for TH2
GATA-3
Main action of TH2 in response to helminths (parasites)
TH2 activates eosinophils, mast cells, basophils, and macrophages
What are involved with allergies (TH2)
Dysregulated TH2 responses
What transcription factor does TH2 signal 3 activates?
STAT 6 protein gets activated by IL-4 (TH2 signal 3)
TH2 transcriptional pathway
TH2–>IL-4 (signal 3)–>STAT 6 (transcriptional factor)–>GATA-3 (master transcriptional regulator)–>IL-4, IL-5, IL-13 secretion
TH2 functions
1) Secrete IL-4, IL-5, IL-13
2) Targets eosinophils, basophils, mast cells, and macrophages
3) Helps in killing of helminth parasites
What are parasitic helminths
Multicellular worms
Colonize in gut of animals and humans
Cause chronic infection
What does TH2 do to clear helminths
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)
Effect function of TH2
1) Promote cell turnover and mucous production
2) Enhance worm expulsion
3) Recruit and activate M2 macrophages
4) Eosinophil activation
5) Mast cell activation
How does TH2 promote cell turnover and mucous production
By signaling release of IL-13 cytokine–>increases mucous production by goblet cells and increase epithelial tissue turnover
WEEP in weep and sweep
How does TH2 enhance worm expulsion
By signaling release of IL-13–>stimulate contraction of smooth muscle cells–>lead to worm expulsion
SWEEP in weep and sweep
How does TH2 recruit and activate M2 macrophages
By signaling IL-4 and IL-13 release
M2 macrophages–>alternative activated macrophages
Function of M2 macrophages
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)
How does TH2 activate eosinophils
IL-5 activates eosinophils
How do eosinophils kill parasites
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
Consequence of Histamine release
1) Increase vascular permeability
2) Increase intestinal motility
3) Increase recruitment of inflammatory cells
How does TH2 activate Mast cells
Cytokines activate mast cells, mast cell granules contain histamine
Mast cells also express receptors that recognize the Fc portion of IgE (ADCC)
