Innate Immune Mechanisms Flashcards
1
Q
What are the 5 innate immune mechanisms?
A
- inflammation
- cellular recruitment
- phagocytosis
- oxidative burst
- NETs
2
Q
What are the 4-5 signs of inflammation?
A
- heat
- redness
- swelling
- pain
- sometimes loss of function
3
Q
What is inflammation?
A
- innate, non-specific immune response
4
Q
What is involved during inflammation?
A
- vascular permeability
- cellular recruitment (increases swelling and pain)
- cellular proliferation and metabolism/activity (increased metabolism brings heat)
5
Q
What does inflammation bring to the site of infection?
A
- white blood cells
- leukocytes
- plasma proteins
6
Q
Define vascular dilation
A
increased blood flow
7
Q
Define vascular permeability
A
- there’s increased cells and plasma proteins entering the tissue
- leads to increased lymph drainage
- leads to increased trafficking of DC to LN
8
Q
What does the increase in cells and plasma proteins lead to?
A
- leakiness
- more fluid
9
Q
What happens to infectious debris?
A
- the increased number of cells and plasma proteins carry it to the lymphatic system to drain
10
Q
What controls inflammation?
A
- cytokines
- chemokines
- plus other soluble mediators
11
Q
What are cytokines?
A
- small proteins released by the cell in response to a stimulus that induces a response in a target cell
- does so by binding to an appropriate cytokine receptor
12
Q
How are cytokines and chemokines classified?
A
into cytokine/ chemokine families
13
Q
What are the cytokine families?
A
- interleukins
- hematopoietins
- tumor-necrosis factor
- interferons
14
Q
What are some examples of interleukins?
A
IL-4, IL-10, IL-13, etc
15
Q
What are some examples of hematopoietins?
A
G-CSF, M-CSF
16
Q
What are some examples of tumor-necrosis factor?
A
TNF-a (alpha), FAS-L
17
Q
What are some examples of interferons?
A
IFN-a (alpha), IFN- B (beta), IFN-y (gamma)
18
Q
What are some responses cytokines can start?
A
- activation
- repression
- inflammation
- anti-inflammatory responses
- etc
19
Q
T or F: cytokines usually work alone
A
false, they usually work with something else
20
Q
What are chemokines?
A
- chemoattractant cytokines
- cytokines that induce cellular adhesion or directional cell migration in response to a gradient of the chemokine
21
Q
What’s a metaphor for chemokines?
A
- a trail of bread crumbs for cells that tells them where to go and activates them
22
Q
How are chemokines classified?
A
- into families based on the location of 2 conserved cystine (C) residues
- grouped by structure
23
Q
What are the chemokine families?
A
- CCL
- CXCL
- CX3CL
24
Q
What are some examples of the CCL family?
A
- CCL2
- CCL3
etc
25
What are some examples of the CXCL family?
- CXCL2
- CXCL3
etc
26
What's an example of the CX3CL family?
- CX3CL1
27
What does the X in the chemokine families stand for?
amino acids
28
How are chemokines recognized?
- they're recognized by specific receptors that all belong to a conserved class of 7-transmembrane G- protein coupled receptors
29
What are the sepcific receptors that recognize chemokines?
- CCR1-10
- CXCR1-7
- CX3CR1
30
What are the cytokine and chemokine receptors?
- homodimeric receptors
- heterodimeric recpetors with a common chain
- heterodimeric receptors with no common chain
- TNF receptor family
- chemokine receptor family
31
What are homodimeric recptors?
- receptors for erythropoietin and growth hormone
32
What are heterodimeric receptors with a common B chain?
- receptors for IL-3, IL-5, GM-CSF
| - all share a common chain known as CD 131 or Bc (common B chain)
33
What are heterodimeric receptors with a common y chain?
- receptors for IL-2, IL-4, IL-7, IL-9 and IL-15
| - all share a common chain known as CD132 or yc (common y chain)
34
What's special about the IL-2 receptor?
- has a third chain
| - a high affinity subunit IL-2Ra (CD25)
35
What are heterdimeric receptors with no common chain?
- receptors for IL-13, IFN-a, IFN-B, IFN-y, IL-10
36
What are TNF receptor family?
- TNF recpetors I and II CD40, Fas (Apo1, CD95_, CD30, CD27, nerve growth factor response
* has three receptor chains
37
what are the chemokine receptor family?
- CCR1-10, CXCR1-5, XCR1, CX3CR1
| * all chamokines use this 7 chain
38
What happens in a local inflammation response?
- bacteria triggers macrophages to release cytokines and chemokines
- vasodilation and increased vascular permeability cause redness, heat and swelling (aka it gets leaky)
- inflammatory cells migrate into the tissue, releasing inflammatory mediators that cause pain
39
What is IL-1B's response when secreted by an activated macrophage?
- activates vascular endothelium
- activates lympocytes
- local tissue destruction
- increases access of effector cells
40
What is TNF-a's response when screted by an activated macrophage?
- activates vascular endothelium and increases vascular permeability
- this leads to increased entry of IgG, complement and cells to tissues and increased fluid drainage to lymph nodes
41
What's IL-6's response when secreted by an activated macrophage?
- lymphocyte activation
| - increased antibody production
42
What's CSCL8's response when secreted by an activated macrophage?
- chemotactic factor recruits neutrophils, basophils and T-cells to the site of infection
43
What's IL-12's response when secreted by an activated macrophage?
- activates NK cells
| - induces the differentiation of CD4 T cells into T(H)1 cells
44
Where do most mediators of inflammation act on during a local response?
- on the local blood vessels
45
What are the 4 changes to the vasculature that occur during a local inflammatory response?
1) vascular dilation
2) endothelium expression of adhesion molecules
3) vascular leakage
4) clotting
46
What is vascular dilation?
- increased blood flow
| - results in heat and redness
47
What does the endothelium expression of adhesion molecules allow to occur?
- the recruitment of leukocytes
48
What is vascular leakage?
- fluid and plasma proteins like comlpement and antibodies, enter the tissue
results in swelling and pain
49
What happens during clotting?
- blocks the vessels, preventing the pathogen from spreading
| - if this didn't occur the pathogen would use the blood vessel to get away and infect other cells
50
How is a local inflammarory response mediated?
- mostly from lipid mediators released from macrophages and neutrophils
- lipid mediators like prostaglandins, leukotrienes, and platelet-activated factor (PAF)
51
What's the process of a local inflammatory response?
1) cytokines produced by macrophages cause dilation pf local small blood vessels
2) leukocytes move the periphery of the blood vessel as a result of increased expression of adhesion molecules by the endothelium
3) Leukocytes extravasate at the site of infection
4) Blood clotting occurs in the microvessels
52
Why is a local response acted put by soluble mediators?
- because they can move around
53
What are some examples of mediators acting systemically to modulate the immune response on the level of the whole organism?
- fever (1C more can kill bacteria/viruses completely)
- increased cellular proliferation and mobilization from the bone marrow
- increased plasma protein production by the liver
- mobilization of energy stores
54
What's the response of the liver during a systemic response activated by a mixture of cytokines?
- acute-phase proteins (c-reactive protein, mannose-binding lectin)
- this leads to activation of complement and opsonization
55
What's the response of the bone marrow epithelium during a systemic response activated by a mixture of cytokines?
- neutrophil mobilization
| - this leads to phagocytosis
56
What's the response of the hypothalamus during a systemic response activated by a mixture of cytokines?
- increase body temperature
- this leads to:
- decreased viral and bacterial replication
- increased antigen processing
- increased specific immune response
57
What's the response of fat and muscle during a systemic response activated by a mixture of cytokines?
- protein and energy mobilization to allow increased body temperature
- this leads to:
- decreased viral and bacterial replication
- increased antigen processing
- increased specific immune response
58
What's the response of the dendritic cells during a systemic response activated by a mixture of cytokines?
- TNF-a stimulates migration to lymph nodes and maturation
| - this leads to initiation of adaptive immune response
59
T/F: all inflammation is good
False, not all inflammation is good
60
Why is too much inflammation bad?
- can lead to organ failure and death of the host
61
What is sepsis?
- when the body is reacting like its infected everywhere in the body
62
Why is sepsis bad?
- it's hard for the body to maintain blood pressure
- reduces blood flow to organs
- the brain can swell
- fluid can get into lungs
- lots of clots especially near heart and brain could kill you
63
Why is too much inflammation hard to treat?
- to stop clotting you have to give patient anti-coagulates which will lead to bleeding all over body
- can't do surgery
64
What is cellular recruitment?
- the process to get a specific cell to a specific area in the tissue
65
What are the four fundamental problems with getting innate immune cells to a site of infection?
1) cells circulate throughout the body and need to find the specific site of infection
2) cells are flying past any given spot, carried by blood flow making it hard to stop them
3) cells need to get out of the blood vessels and into the tissue
4) once in the tissue leukocytes need to be able to hone-in on the pathogen
66
What happens when resident sentinel cells, such as macrophages and DC, detect pathogens or damage?
- cytokines and chemokines are produced
- these activate the cells in the endothelium
- activated endothelium expressed different molecules like adhesion molecules and more chemokines
- plus the activated endpthelium serves as a landing pad for leukocyte recruitment
67
What is the general difficulty of cellular activation?
- it's a intricate ballet involving cellular activation, cytokines, chemokines and adhesion molecules expressed by both the vascular endothelium and the leukocyte
68
What are the 5 major steps to leukocyte recruitment cascade?
- tethering
- rolling
- activation
- firm adhesion
- transmigration
69
What is the weakest interaction throughout the leukocyte recruitment cascade?
- tethering
70
What is involved with tethering?
- brief molecular interactions which facilitate bringing the leukocyte into close contact with the endothelium
71
How is tethering mediated?
- by selectins binding to their ligands (likek Chinese finger traps that only work if trying to pull apart
- also by mucin like cell adhesion molecules (mucin CAMs) which contain sialyl-Lewis^x residues
72
What is the optimal condition for tethering?
- flow conditions because you need the sheer force of blood flow to stabilize these interactions
73
What are catch-bonds?
- interactions that optimally occur under flow conditions because the sheer force of the blood flow is needed to stabilize the interactions
74
Why are selectins and their ligands able to constantly let go and reform?
- because they have relatively weak interactions
75
How is the cell able to move along?
- blood flow is able to continuously push the cell
| when one end of the cell releases the other end can come in contact with the endothelium
76
Why is rolling important?
- it serves to slow down the cell which is necessary for the cell to collect information
77
What happens when the cell is rolling slow enough?
- it has time to sample molecules on the surface of the endothelium, including chemokines
78
What happens when the leukocyte and chemokine bind?
- the chemokine further activates the leukocyte after they have started binding to the 7-chain receptor
- this induces a change in the integrins
79
What happens in integrins in leukocyte recruitment cascade?
- under basal conditions integrins are in a low affinity conformation but when activated they switch to high affinity conformation
80
When is the cell firmly adhered to the endothelium?
- after chemokine-mediated activation of the leukocyte integrins
- integrins are able to bind their ligands located on the endothelium (these ligands are Ig-superfamily CAMs)
81
How does firm adhesion affect the leukocyte?
- causes it to flatten out and crawl along the endothelium, looking for a way out of the vessel
82
How do the adherent leukocytes enter the tissue below them?
- they squeeze between or pass directly through (transcytosis) endothelial cells
83
T/F: the process of transmigration during the leukocyte recruitment cascade is tightly regulated
- true
- it doesn't have holes to let the leukocytes through but instead the vessel reseals immediately when the cell passes through so there is absolutely no leakage
84
What happens when leukocytes are outside the of the vessel?
- they continue to follow the initial chemokine gradient made by the sentinel cells to find the site o finfection
85
What's another term for leukocyte?
- white blood cell
86
Why don't all leukocytes get recruited to a site of infection?
- differential expression of adhesion molecules (cells are specific, so even if they're sticky they will only stick to what they are programmed to)
- differential expression chemokine receptors (it will roll past unless it notices the specific cell it's supposed to be with)
87
T/F: cells can be specifically activated while other are not
True, the specific receptors on different cells prevents other cells from being activated
88
Summarize tethering
- by selectins under flow conditions, brings the leukocyte into close physical association with the endothelium
89
Summarize rolling
- initiated by the binding of selectins, found on the inflamed vascular endothelium to mucin-like ligands on the leukocyte
90
Summarize activation
- initiated by integrin binding of Ig-superfamily CAMS found on the surface of stimulated endothelial cells
- allows for the tight adhesion of the leukocyte to the endothelium
91
Summarize transendothelial migration
- leukocytes passage through the interendothelial unctions and across the endothelium cells of the blood vessel
