6. Innate Immunity 1 Flashcards
1. The innate immune system is important because it primes immunity. 2. It senses environmental perturbations and releases signals that excite immune cells. 3. Pathogens target innate immunity to try and silence the impact of their presence (77 cards)
1
Q
What is the eternal mission of the immune system?
A
- How do I know who I am?
- How do I know who you are?
- How do I know if you are dangerous?
2
Q
What is innate immunity required for?
A
- Adaptive immunity
- Immune memory
- Long term immune response
3
Q
What is innate immunity at its basic level?
A
A stress response
4
Q
What can trigger the innate immune response?
A
- Infection
- Surgery
- Cancer
- Metabolic dysregulation like diabetes
- Pollution
5
Q
What made it clear that innate immunity is very important?
A
Congenital immunodeficiencies of innate immunity causes children not to live very long.
6
Q
What is the shifting idea of innate immunity?
A
Shifted from a simple idea of barriers to something more active and dynamic
7
Q
What are the 2 main parts of the innate immune system?
A
- Adjuvants that trigger innate immunity
- Inflammation as a response to activation
8
Q
What is inflammation?
A
- A dynamic tissue response to infection or injury.
- Causes Swelling, Redness, and an influx of platelet and leukocytes.
- It is important for expelling pathogens and wound healing
9
Q
What is the framework of innate immunity?
A
- Hard wired specificity that doesn’t change over a person’s life
- Multiple receptor systems with common effector pathways.
- Tightly integrated with adaptive immune responses
- Can be inappropriately activated
10
Q
What is an adjuvant?
A
A substance that enhances the immune system’s response to the presence of an antigen.
11
Q
Why were adjuvants discovered?
A
When vaccinologists were trying to improve vaccines, they found something that was needed to make the adaptive immune response better, but they didn’t know what it was or how it worked.
12
Q
What is Freund’s adjuvant?
A
- An addition to a vaccine needed to trigger an innate response.
- It contains lipids, bits of bacteria and other bits,
- It was needed to for vaccine to be effective but they didn’t understand why.
13
Q
What did vaccinologists discover about adaptive immunity?
A
You can’t have a strong adaptive immune response without an innate response
14
Q
How was adjuvant’s function discovered?
A
- In the development of horse vaccines for diphtheria.
- They needed to purify the diphtheria toxin.
- They did this by precipitating and isolating the toxins from the horse blood using aluminium salts.
- Once the science perfected his technique, he stopped using the aluminium salts and the immune response disappeared.
- This showed the salts were acting as an adjuvant and required to cause the immune response.
15
Q
What types of responses can adjuvants trigger?
A
- inflammation
- NETosis
16
Q
What are vaccine adjuvants?
A
Components that enhance the immunogenicity of vaccines when administered in conjunction with vaccine agents.
17
Q
What are some examples of vaccine adjuvants?
A
- Emulsions
- immunostimulatory complexes
- Proteases
- Bacterial products
- Mineral compounds
18
Q
What is the innate immune system recognising?
A
Foreign/microbial patterns
19
Q
What are the foreign patterns that are recognised by innate immunity?
A
- Something that is conserved across microbe families.
- These patterns are found in multiple microbes but are not specific
- These are things like LPS, RNA, Cell walls
20
Q
What are PAMPs?
A
- Pathogen associated molecular patterns
- Molecules and components of pathogens that are shed during infection and can activate PRR.
21
Q
What are MAMPs?
A
- Microbe associated molecular patterns.
- They are not pathogenic but they do activate the innate immune system.
- They cause low-level inflammation but also have beneficial functions.
22
Q
When are PAMPs and MAMPs normally recognised?
A
When they have ben shed from their pathogen
23
Q
What are DAMPs?
A
- Danger associated molecular patterns.
- They are usually produced from the consequences of PAMPs but they are host molecules.
- DAMPs are released on cell damage or death.
- They are host molecules like DNA, ATP or actin.
24
Q
How do DAMPs activate innate immunity?
A
Innate cells detect DAMPs through PRR and see they are outside of the cells and know something is killing or damaging the cells.
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How is uric acid is a DAMP?
1. It is made inside the cell and gets released in diseases like gout.
2. It can cause powerful activation of the inflammasome.
3. Uric acid and other crystals are good DAMPs because they cause powerful activation.
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What are the general properties of adjuvants?
1. They are foreign
2. They are dangerous
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Are PAMPs and DAMPs adjuvants?
yes
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What is the general framework of immune activation?
1. The innate immune priming through transcription factors like NF-kB.
2. This leads to activation of the inflammasome and a full innate response.
3. This triggers a good adaptive response.
4. There is a lot of interaction and feedback loops between all the stages. More like a cycle then linear steps.
29
What is required for a successful adaptive response?
Innate immunity priming and inflammation
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Why does the innate immune response need to be rapid?
1. Due to the fast replication times of bacteria and viruses.
2. A rapid response prevents the bacteria from overgrowing in the tissue
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What time scale does pattern recognition adapt on?
1. An evolutionary timescale.
2. PRR do not recombine in your lifespan
3. They can change through evolution over centuries.
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How can innate immunity be lethal?
If it is activated inappropriately or excessively, it can lead to immunopathology and disease.
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What is the role of the innate immune system in Alzheimer’s?
In the brain of Alzheimer's patients, there is an innate immune response in deposits of amyloid beta that leads to inflammation in the brain.
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How were cytokine storms discovered?
1. Isolated LPS was injected into mice and they all died very quickly.
2. Discovered the LPS was the cause but unsure about how it was doing it in such small amounts.
3. The mice developed fever, shock, swelling and other signs of inflammation.
4. This is a cytokine storm resulting from the innate immune system overacting to the presence of LPS in the blood.
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How did they discover that cytokine storms were caused by the immune system?
1. One of the lines of mice they tested the LPS in didn't die or produce a cytokine response.
2. This showed cytokine storms were down to the innate response and genetics not the LPS
3. These were C3H/HeJ mice that couldn't detect the lPS.
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What are C3H/HeJ mice?
A line of inbred mice with a mutation in TLR4
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How do we know cytokine storms are due to inflammatory cytokines?
When an anti-TNF antibody was introduced to the mice alongside the LPS, all mice survived.
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How was the receptor for LPS discovered?
1. Flies were irradiated to cause many mutations and were isolated into fly lines with single mutations.
2. The flies were infected with fungus and their different reactions were observed.
3. A fly that was overrun with the fungus had a specific mutation in the Toll gene.
4. They looked for genes in humans with the same structure as the fly gene. This was identified as the TLR4 gene.
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What is TLR4?
1. A pattern recognition receptor.
2. Has an extracellular domain and a transmembrane domain.
3. A coreceptor MD-2 that binds the circulating LPS and then the MD-2 LPS complex binds to the TLR and trigger signalling.
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What is the innate immune system activation pathway?
1. A PAMP like LPS is recognised by a PRR like TLR4.
2 This activated a signalling cascade via transcription factors like MyD88 and NF-kB
3. This causes the transcription and production of TNF and other cytokines.
41
What are the uses of preventing innate immunity activation?
1. Pathogens do this to block the response to escape immunity.
2. We can use this in medicine to suppress the inflammatory cascade.
3. Anti-TNF antibodies in rheumatoid arthritis work well to reduce damage and inflammation.
42
What is TLR4?
1. It was the first TLR found in mice than humans
2. It detects LPS and gram negative bacteria
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What do all TLRs have?
1. An extracellular Leucine Rich Repeat domain.
2. An intracellular Toll/IL-1 (TIR) domain which is heavily conserved and important for signalling.
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How many TLRs are there in humans?
11
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What was the first type of immune response?
innate immunity
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What do animals without adaptive immunity do?
1. Boney fish were the 1st animals with adaptive immunity.
2. Other animals without adaptive immunity have much more developed innate immune systems with expanded PRR and TLR repertories.
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What does TLR2 recognise?
Gram positive bacteria through lipids in the cell wall.
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What does TLR3 recognise?
dsRNA
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What does TLR7 recognise?
ssRNA
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What does TLR9 recognise?
CpG DNA
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What does TLR5/11/12 recognise?
Bacterial flagella
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What are the 2 main signalling pathways used by TLRs?
1. NF-kB for triggering inflammatory cytokines like TNFa
2. IRF3/7 for triggering the production of type 1 interferons that induce an antiviral state - IFNa/b
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How is TLR signalling done?
Through highly conversed transcription factors and signalling pathways
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TLRs summary
1. A family of PRR molecules that recognise many ligands
2. Co-receptors play a key role
3. Recognise molecular patterns associated with pathogens
4. Induce innate and later adaptive immune responses against microbial infection
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What does dectin-1/2 recognise?
C-type lectin binding on ß-(1,3)-glucans for a response to fungal pathogens
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What do mannose binding lectin recognise?
Mannose on the pathogen surface and triggers the complement
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What do invariant chain TCRs recognise?
Use non-classical MHC molecules to recognise a rang of antigens including lipid antigens found on mycobacteria
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What does NOD2 recognise?
Muramyl dipeptide binding intracellular protein
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What does RIG-I recognise?
RNA viruses to induces type 1 interferons
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What is cell autonomous sensing?
One cell can detect the foreign antigen through TLRs and is triggered. But this leads to a systemic activation.
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What transcription factors and cytokines cause the systemic activation of innate immunity?
1. The transcription factor NF-kB activated TNF and IL-6 signalling to trigger inflammation
2. IL-1ß causes the recruitment of neutrophils
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How do we know both innate and adaptive immunity are essential for an effective immune response?
1. If you infect wild type mice with an infection they mostly survive and return to a healthy state.
2. If you knock out the innate response, all the mice die, and they die quickly.
3. If you knock out the adaptive response, the mice die but much slower.
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What is the overlap in molecular recognition pathways?
PRR recognise both pathogen-produced PAMPs and self-produced DAMPs.
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What is the result of the innate/adjuvant response?
inflammation
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What is sterile inflammation?
Inflammation without the presence of an infection
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What causes sterile inflammation?
1. Cutting tissue releases DAMPs
2. Reperfusion injury
3. Stress
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Innate immune cells overview: Mast cells
1. Tissue resident
2. Found everywhere exposed to the environment like nose skin and mucus membranes.
3. Releases histamine and heparin to cause vasodilation and bronchoconstriction.
4. Recruit macrophages and neutrophils
5. Similar to basophils
68
Innate immune cells overview: Basophils
1. Circulate in the bloodstream
2. defence against big parasites like worms and ticks
3. Allergy
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Innate immune cells overview: Eosinophils
1. Circulate in the blood
2. Defence against parasites and allergy
3. Trigger the Th2 response
70
Innate immune cells overview: macrophages
1. Phagocyte
2. Stimulates other immune cells
3. Antigen presenting
4. Long lived
71
Innate immune cells overview: NK cells
1. Circulate in the blood
2. Rare
3. Specialised in detecting intracellular pathogens
4. Kill using granzymes and perforin
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Innate immune cells overview: Dendritic cells
1. Tissue resident where there is exposure to the environment
2. Mainly in epithelial tissues
3. specialised antigen presentation
4. Very mobile cells to quickly move to the lymph node.
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Innate immune cells overview: Monocytes
1. Very abundant cells
2. Circulate in the blood and stored in the spleen
3. When activated they move to the tissues and differentiate into macrophages or dendritic cells in response to inflammation
4. They are very good at producing cytokines
74
What are the granulocytes?
1. Neutrophils
2. Basophils
3. Eosinophils
75
What is the Red Queen hypothesis?
1. All immunity and all pathogens are constantly evolving.
2. Therefore you have to evolve to stay in the same place you were before.
3. This is a stalemate.
4. Named for the scene in Alice in Wonderland where the Red Queen is chasing Alice but neither are moving.
76
What, other than killing, is the immune system getting better at?
Tolerance
77
Why is the immune system improving tolerance?
1. You are always in contact with foreign antigens and don't want to overreact or always have an active response.
2. Pathogens are evolving to be less virulent to prevent killing the host, as this is a dead end for them.
3. You can have bacteria or parasites in your body, and if they are not causing damage, you will not have a response and remain healthy.
