Lecture 4: Innate Immunity Flashcards
(126 cards)
1
Q
The defense mechanisms that respond first to pathogens and dead cells is referred to as what?
A
Innate immune system.
2
Q
What are the other two names for innate immunity?
A
Natural immunity
Native immunity
3
Q
In general; what is the role of the innate immune system?
A
The innate immune system is our first response to pathogens that [prevents, controls and eliminates] infections.
It gets ride of damaged cells via phagocytosis and starts the process to repair damaged tissue.
It also signals the adaptive immune system to respond to intracellular or extracellular pathogens.
4
Q
Tell me about inflammation.
A
Inflammation results from injury or the invasion of a pathogen. It serves to protect us, however it can also damage tissue.
Normally, any damage caused by inflammation is repaired when the inflammation subsites. However, if the infection or damaged-tissue remains, the inflammation can be chronic.q
5
Q
What occurs during inflammation?
A
The blood vessels will become permeable to plasma proteins and immune cells, allowing them to leave the blood go to the site of injury. WBC (leukocytes) attack and release mediators which continue inflammation.
It is these inflammatory mediators that stimulate nerves and cause pain.
The body will then react: chills, fever, muscle aches.
6
Q
What happens when tissue is damaged due to extracellular pathogens?
A
- Damaged tissue will attract mast cells, which release histamine into the blood stream.
- Histamine will cause the vessels to dilate and become leaky; allowing compliment proteins to leave the vessels and attract phagocytes.
- Blood flow to the area increases, producing, warmth, redness and swelling. This increase in blood flow is also accompanied by phagocytes.
- WBC (leukocytes), particularly phagocytes will move from vessel–> infected area and attack.
- At the same time, they release mediators which stimulate nerves and cause pain.
- If severe infection; body will react with chills, fever and muscle aches.
- Histamne and compliment signaling stop and phagocytes are no longer sent to the area.
- Growth factors from WBCs and platelets heal the would
7
Q
Can inflammation protect us against intracellular pathogens?
A
No. Inflammation is only sufficient enough to attack extracellular pathogens.
8
Q
What controls the innate immune response to intracellular pathogens: like viruses?
A
1, Type 1 interferons- blocks viral replication
2. NK cells- kills the virus-infected cells
9
Q
How does the innate immune system recognize self vs non-self cells?
A
PRR (pattern recognition receptors) on cells of the innate immune system recognize PAMPs (pathogen assx molecular patterns), which are displayed on non-self cells.
They are unique to classes of pathogens and needed for the pathogen to survive. Thus, they aren’t hidden well.
10
Q
Do PAMPs have any structural similarity to self antigens?
A
No.
11
Q
What are PRR?
A
PRR (pattern recognition receptors) are located on innate immune system cells that detect PAMPS located on non-self cells.
They are germ-line encoded, meaning that they are found in gamete producing cells; thus, their diversity is limited between people.
12
Q
Binding of PAMP and DAMP ligands to PRRs will induce intracellular signaling in _________ and lead to their _______.
A
Phagocytes
Activation
13
Q
Toll-like receptors (TLR) are a type of _________.
A
Pattern recognition receptor (PRR)
14
Q
TRL description
A
TRL are located on the cell surface (respond to extracellular microbes) and in endosome, responding to pathogens that have been ingested. They recognize PAMPS and activate inflammation.
Endosomal TLRs will only respond to nucleic acids.
15
Q
What TLRs recognize extracellular pathogens?
A
TLR 1, 2, 4, 5, 6
Thus, they’re located on the plasma membrane
16
Q
What TLRs recognize intracellular pathogens?
A
TLR 3, 7, 8, 9
Thus, they’re located in endosomes.
17
Q
What is the PRR that recognized glycans with a TERMINAL mannose?
A
Mannose receptor.
In humans, there are no glycans with a terminal mannose.
18
Q
TLR1: TLR2 heterdimer
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
A
- Lipopeptides, GPI
- Monocytes, dendritic cells, eosinophils, basophils and mast cells
- Plasma membrane
19
Q
TLR2: TLR6 heteodimers
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
A
- Lipoteichoic acid and zymosan
- Monocytes, dendritic cells, eosinophils, basophils and mast cells
- Plasma membrane
20
Q
TLR 3
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
A
- dsRNA
- NK cells
- Endosomes
21
Q
TLR4: TLR4 Homodimer
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
A
- Lipopolysaccharide
- Macrophages, dendritic cells, eosinphils, mast cells
- Plasma membrane
22
Q
TLR 5
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
A
- Flagellin
- Intestinal epithelium
- Plasma membrane
23
Q
TLR 7
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
A
- ssRNA
- Plasmacytoid dendritic cells, NK cells, eosinophils, B cells
- Endosomes
24
Q
TLR 8
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
A
- ssRNA
- NK cells
- Endosomes
25
TLR 9
1. Recognizes what ligands?
2. What cells carry these receptors?
3. Where are they located?
1. Unemethylated guanine-rich DNA
2. Plasmacytoid dendritic cells, B cells, eosinophils, basophils
3. Endosomes
26
TLR 10 homodimer and heterodimer with TLR1: TLR2
1. Unknown
2. Plasmacytoid dendritic cells, B cells, eosinophils, basophils
3. Unkown
27
For TLR to initiate a response, what must occur?
signaling.
28
TLR 1, 2, 5, 7, 8, 9 undergo what kind of signaling?
MyD88-dependent signaling.
Activates transcription factors [NF-kB] and [IRF] (interferon regulatory factor) via Use [MyD88 adaptor protein].
Thus, they under MyD88-dependent signaling.
29
TLR3 undergoes what kind of signaling?
TRIF dependent signaling.
Activates transcription factors [NF-kB] and [IRF] via TRIF
30
TLR 4 undergoes what kind of signaling?
MyD88/TRIF dependent signaling.
Activates transcription factors [NF-kB] and [IRF] via MyD88 and TRIF.
31
What TLR recognize bacteria?
TLR 1, 2, 4, 5, 9`
32
What TLR recognizes viruses?
TLR 3, 7, 8, 9
33
What TLR recognizes fungi?
TLR 2, 6
34
Activation of transcription factors [NF-kB] and [IRF] via TRL cause what to happen?
Increases the transcription of genes that promote inflammation.
1. Influence the adaptive response of the immune system and call T-cell to initiate cell-mediated immunity (via IL12)
2. Kill bacteria
3. Injure tissue, causing host cells to die and even septic shock.
35
What controls the T-cell immune response?
IL-12
36
Mechanism of TLR-4 Receptor
1. On the surface of a macrophage, [TLR4, MD2, CD14 and LPS] assemble.
2. MyD88 binds and activates [IRAK-4], which will phosphorylate [TRAF6], which then phosphorylated and activates [IKK].
3. IKK phosphorylated [IkB], causing it to degrade and releases NFk-B into the nucleus.
4. NFk-B activates transcription of genes for inflammatory cytokines, which are made in the cytoplasm and secreted via the ER.
37
What is
1. LPS
2. LBP
3. CD14
4. MD2
1. lipopolysaccharide
2. LPS binding protein in the blood
3. receptor for LPS
4. MD2 LPS binding protein that makes a bridge:
CD14-LPS-MD2-TLR4
38
What are DAMPS?
Damage assx molecular patterns
DAMPS are released by tissues undergoing necrosis (cell death via EXTRACELLULAR FACTORS).
Send alarms to activate immune cells, which will then cause inflammation
39
What are examples of DAMP signals sends?
1. HMGB1 (high mobility group box 1), which binds to its receptor RAGE.
2. Uric acid
3. HSPs
These will all activate [NF-kB]
40
What are NOD-like receptors (NLRs)
NLRs (nucleotide oligomerization domain)- like receptors are intracellular, scaffolding proteins use [NF-kB and MAPK] signaling pathways to activate inflammatory caspases.
They respond to PAMPs and DAMPs by forming a signaling complex called the inflammasome. Inflammassomes then activate caspase-1, which produces IL-1B and IL-18, which are inflammatory agents.
41
Where are secreted forms of IL-1B and IL-18 made?
Inflammasome
42
Scavenger receptors are a family of what?
Scavenger receptors are another type of pattern recognition receptors (PRR) that uptake oxidized lipoproteins.
43
What are the 3 types of scavenger receptors?
1. Scavenger receptor class A type I
2. Scavenger receptor class A type II
3. MARCO- macrophage receptor with collagenous structure.
44
What is the structure of scavenger receptors?
Trimeric complex of type II transmembrane polypeptides. They have 3 distinct extracellular structural domains
1. cysteine-rich domain (absent in SR-A-II)
2. collagen-like domain
3. alpha-helical coiled domain (absent in MARCO)
45
What PRRs are expressed on macrophage and help with recognition and phagocytosis of microorganisms?
SR-A and CD-36 (a type of scavenger receptor)
46
What are some receptors for carbohydrates?
Lectin family of PRR.
47
Lectin receptors of PRR
Belong to the ______ lectin family.
Have domains that recognize ______, ______, ______
Bind what kind of lectins?
Role:
These receptors belong to the C-type lectin family because they bind carbs. They have domains that recognize carbs such as
[microbial mannose, N-acetylglucosamine and B-glucans].
The lectins that bind to lectin receptors can be soluble and found in the blood or ECF or they can be integral membrane proteins found on macrophages and DCs.
Role:
Phagocytosis
Secrete cytokines to promote the adaptive immune response.
48
What is soluble mannose-binding lectin (MBL)
a protein that is involved in complement activation via the lectin pathway.
49
What are the three components of innate immunity?
1. Physical barriers
2. Phagocytes- fixed and free macrophages, neutrophils, eosinophils and monocytes
3. Immunological surveillance (NK cells; destroy abnormal cells)
50
Epithelial barriers will make anti-microbial substances like ______, ______ and ______ that will kill pathogens.
Produce anti-microbial substances, such as defensins and cathelicidins, and lymphocytes to kill pathogens.
51
What are defensins?
Defensins are small cationic peptides that have cationic and hydrophobic regions.
They are made by epithelial cells on mucous surfaces and granulocytes like neutrophils, NK cells and CTLs.
When a pathogen enters, they insert in it and fuck up the membrane. They also activate immune cells involved in inflammatory response.
52
What stimulates the synthesis of defensins?
Cytokines and microbial products via PRRs.
53
What are Cathelicidins?
Antimicrobial peptides that are located on the skin, GI tract and respiratory tract.
Cytokines and pathogens promote their synthesis from neutrophils.
They do many things:
1. direct toxicity
2. Activate leukocytes
3. Bind and neutralize LPS
4. Have an anti-inflammatory role by blocking inflammasome rxn.
54
AMP are also called
anti-microbial peptides
55
How does the innate immune system provide natural immunity?
1. Phagocytosis
2. Recruitment of inflammatory cells
3. Presents antigens
56
What are leukocytes?
Neutrophils
Monocytes
Tissue macrophages
Eosinophils
57
What are lymphocytes?
NK cells
58
What cells are the first to arrive at the site of tissue damage?
Neutrophils
59
Activation of neutrophils results in what?
Respiratory bursts and the release of granuals to prevent bacteria from growing.
60
What engulfs pathogens and releases inflammatory mediators?
Macrophages
61
What have cationic granules that figt helminthes and other parasites?
Eosinophils
62
What kill infected cells by releasing perforin and granzymes?
NK cells
63
PRR-triggered responses in neutrophils and macrophages
How can phagocytes distinguish self-nonself?
Phagocytes can distinguish self vs. non-self attacking proteins with fMet (N-formylmethionyl peptides).
f-Met is only located on prokaryotes.
64
Maturation of mononuclear phagocytes
In the steady state in adults, and during in inflammatory reactions, precursors in the bone marrow give rise to circulating monocytes, which enter peripheral tissues, mature to form macrophages, and are activated locally. In early development, as in fetal life, precursors in the yolk sac and fetal liver give rise to cells that seed tissues to generate specialized tissue-resident macrophages
65
PRR primary function is what?
Phagocytosis via: macrophage activation
66
What are the types of dendritic cells
1. Myeloid DCs (derived from monocytes)
2. Classical DC's (derived directly from stem cells and located in tissue)
3. Plasmacytoid DCs (derived directly from stem cells and located in tissue)
4 . Langerhan cell (derived from stem cells and located in skin)
67
What type of cell is a langerhan cell?
Dendritic cell
68
How do DC acquire antigens?
1. Phagocytosis
2. Receptor-mediated endocytosis
3. Pinocytosis
They have receptors that recognize antigens made by microbes, NOT mamillian cells.
69
Do DC's secrete cytokines?
Yes.
70
What are the differences between classical DCs and plasmacytoid DCs?
Classical DCs live in skin, mucous and organ parenchyma. When activated, they go to the LN and they present antigens to t-cells.
Plasmacytoids DC's are early responders to viral infection. When nucleic acids of intracellular viruses are recognized, they produce soluble interferons (IFN-alpha/B), which have antiviral activities. `
71
Mast cells
Mast cells are first defenders of the innate immune cells that develop from CD34+ HSC in the bone marrow. They circulate in the blood and do not mature until they establish a home in a target tissue.
The homes they establish are located in: skin, gut, respitratory and urinary tract. They are also close to BV, which allow them to exacerbate inflammation and help with angiogenesis.
72
How are mast cells activated?
Mast cells do not mature and differentiate until they reach their target tissue.
They are activated when IgE binds, temperature or pressure increases or cell-cell contacts; causing effector molecules of histamine, serotonin, tryptase, chymase and other things to be secreted.
73
What is special about NK cells?
They are generated from a lymphoid progenitor but they function as innate immune cells.
74
What is the fx of NK cells?
NK cells recognize ligands on infected cells, kill them and eliminate the reservoirs, releasing the intracellular pathogens so that they can be phagocytozed.
To call on the macrophages, they secrete macrophage- activating cytokine IFN-γ.
75
How are NK cells activated and inhibited>
NK cells have both activating receptors (called killer cell immunoglobins) and inhibiting receptors.
If the inhibitory receptor binds a [class 1 MHC molecule], it will release protein tyrosine phosphotase and inhibit activation signal.
If there is no MHC, but an agonist binds to the activator R, it will release protein tyrosine kinases and kills it.
76
If reduced expression of class 1 MHC is detected, how to NK cells rxt?
Signal to destroy.
77
How will NK cells kill infected cells?
1. NK cells release perforins, which create holes in virus-infected cells
2. Granzymes from the NK then enter the hole and induce apoptosis of the virus-infected cell.
3. IFN-y is released and macrophage comes in to ingest the dying cells.
78
What is the most powerful activator of macrophages to kill phagocytized microbes?
IFN-y, which is secreted by natural killer cells.
79
What is the compliment system?
A system of 3 pathways, made up of about 30 proteins that lead to the production of C3b.
C3b will then activate C5 and create holes in plasma membranes to kill pathogens
80
3 pathways in the compliment pathway
1. Classical pathway
2. Lectin pathway
3. Alternative pathway
81
All pathways of compliment lead to _____
production of C3b
82
C3b will initiate the activation of what?
C5 component.
83
What are acute phase proteins?
Acute phase proteins are plasma proteins that increase rapidly after infection.
They are made by hepatocytes, where production is regulated by cytokines (mainly IL-6)
84
Name 2 acute phase proteins and what are their roles.
1. C-reactive protein
2. Mannose binding protein
They both fix complement and opsonize (coat cells and make them more susceptible to phagocytosis)
85
What is opsinization?
Coat cells and make them more susceptible to opsonization.
86
What are cytokines?
Small proteins that are secreted and control [inflammation, immunity and hematopoiesis].
They can work over long distance (endocrine), short distance (paracrine) or on the cells that produce them (autocrine)
Cytokines responsible for innate immunity are divided into 2 kinds:
1. Pro-inflammatory cytokines
2. Anti-inflammatory cytokines
87
What are the two types of cytokines in innate immunity?
1. Pro-inflammatory cytokines
| 2. Anti-inflammatory cytokines
88
What are chemokines?
Chemoattractants that direct immune cells to infection
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What are the anti-inflammatory cytokines
1. Interleukin-10 (IL-10)
| 2. TGF-B
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What are the pro-inflammatory cytokines?
1. TNF
2. IL-1
3. IL-6
4. IL-15
5. IL-18
6. ChemokinesI
7. Interferon-y
8. Type 1 IFNs
91
What pro-inflammatory cytokines ACTIVATES macrophages?
Interferon-y
All other pro-inflammatory agents are secreted by macrophages but do not act on them.
92
What are interleukins?
Cytokines that are produced by leukocytes and act on leukocytes.
93
Upon sensing antigens, macrophages secrete many kinds of pro-inflammatory cytokines. Which can produce system effects?
IL-1B
TNF-alpha
IL-6
94
What does IL-12 do?
Goes to NK and T cells and produces IFN-y
95
How do immune cells go to tissues?
A. Neutrophils and monocytes
If an infection breaches the epithelium, neutrophils and macrophages recognize and respond by making cytokines (TNF and IL-1). These cytokines act on the site of infection and cause leukocytes to migrate.
1. Endothelial cells that are inflamed have increased amount of ES (e-selectin) and PS (P-selectin) adhesion molecules due to activated mast cells and macrophages.
2. Neutrophils have ligands for ES and PS, allowing them slow and roll along the ES and PS.
3. Leukocytes have integrins called LFA-1 (adhesion molcules on neutrophils) , which often have a low affinity. In order to increase the affinity of these, we need to activate them
4. Chemokine receptors on the LEUKOCYTE bind to chemokines and ACTIVATE the LFA-1, causing them to increase their affinity.
5. The high affinity integrin now binds to ICAM and VCAM tightly.
4. Diapedsis- neutrophils transmigrate through the endothelium of post-capilly venules into the tissue.
5. Chemoattractants (IL-8) directs them where to go.
6. They then eliminate pathogens, clear dead tissues and repair the damage.
* They do not, however, go to parenchymal tissues (liver, lungs and kidneys)
96
Which leukocytes express [integrin LFA-1]?
ALL.
They usually have low-affinity, though.
97
Integrin LFA-1 on leukocytes are activated how?
Normally, integrins have low affinity. When leukocytes roll, chemokines on the surface of the endothelium bind chemokine receptors on the leukocyte. Signaling will then activate integrins and increase their affinity.
98
When are P and E selections expression activated?
Upon inflammation produced by activated [mast cells and macrophages.
99
Bent ribbon confirmations of integrin have low/high affinity?
Low.
100
Extended ribbon confirmation of integrin have low/high affinity?
High.
101
MPC is a chemoattractant for which type of blood cells?
Monocytes
102
Which cells express integrins?
All cells.
Normally, they have low affinity.
103
Which cells express integrin?
Damaged ENDOthelial cells
104
Which molecules regulate chemotaxis?
1. Chemokines
2. C3a
3. C5a
4. Leukotrienes.
105
How is the transmigration of monocytes different than before neutrophils and macrophages?
Rolling, firm adhesion and diadepesis are the same.
However, the chemicoattractants are macrophage inflammatory protein-1alpha and 1-beta (MIP-1a and MIP-1B).
When they enter the tissue, they mature into tissue macrophages.
106
What are the phagocytocic cells that destroy extracellular pathogens?
1. Neutrophils
| 2. macrophages
107
What are examples of pattern recognition receptors in phagocytosis?
Phagocytes have PRR that bind pathogens for phagocytosis (Mac-1 integrin, scavenger receptor and mannose receptors are examples).
Phagocyte membrane engulfs pathogen and it is ingested.
The phagosome then fuses with the lysosome and can be killed by [lysosomal enzymes in the phagolysosome] or ROS and NO.
108
How do we create the NO?
iNOS converts arginine to NO.
109
How do we defend against viruses?
Type I interferons (IFN-alpha and IFN-beta) inhibit viral replication, and create an antiviral state, in which cells become resistant to infection.
110
What is the mechanism by which IFN-1A and IFN-1B protect against viruses?
Type 1 IFN binds to IFN receptor and
1. activates RNaseL (latent nuclease), which degrades viral RNA.
2. activates PKR (protein-kinase-RNA-activated), prevents guanine diphosphate from being recycled, which blocks viral RNA translation.
3. Activates NK cells to kill the virus
111
Where are ICAM and VCAM expressed?
On activated ENDOthelial tissues. They bind to integrin receptor (integrin-LFA-1).
112
Which organism is resistant to phagocytosis?
Pneumococci
Capsular polysaccharide inhibits it.
113
Which organism is resisteant to ROS intermediates in phagocytes?
Staphylococci
114
What organism is resistant to compliment activation (alternative pathways)
Strep and neiseseria menginitidis
115
What organism is resistant to antimicrobial antibiotics?
Pseudomonas
116
Lymphocytes fx in adaptive immunity, which is stimulated by innate immunity. What signals are needed for this to happen?
1. Antigen
| 2. Substance made during the innate immune response to the pathogen.
117
What is the major second signal for T-cells?
Costimulators because they work with antigens to activate T-cells.
118
How can we link innate and adaptive responses?
Recognizing pathogens via PRR is important to bridge innate and adaptive immunity.
This activates and causes maturation of APC.
The processed antigen is then presented to the naive T cell and cytokines help to mature the T-cell.
119
Cells of the innate/adaptive immune system display PRRs
Innate only
120
What is inflammation?
A response iniatiated by the innate immune system.
It involves the activation of leukocytes and the release of inflammatory mediators.
121
What PRR are expressed macrophages and help to recognize and phagocytoze pathogens?
SR-A and CD36
122
How do SRs decide what to bind?
They bind bind bacteria based on if the have a NEGATIVE (-) charge.
123
What happened to SR knockout mice
They are more susceptible to infection
124
What is the most studied membrane C-lectin R?
What does it bind?
Mannose receptor
Binds
1. Terminal D-mannose
2. L-Fructose
3. N-acetyl-D-glucosamine
125
The most important function of PRRs is what?
TO ACTIVATE MACROPHAGES!
126
What are the 3 functions of compliment in host defense?
1. Lysis of the cell or bacteria via MAC complex.
2. Opsonization and phagocytosis (C3b)
3. Chemotactis anaphlaxis (C3a, C4a, C5a)
