Innate immunity Flashcards
LO
- Explain the differences between innate and adaptive immunity
- Identify the key cell types and receptors involved in an innate immune response
- Describe the mediators of an innate immune response and how it links to adaptive immunity
The following things are important to understand in innate immunity
Examples of common pathogens, you dont have to learn the table, just something to be aware of
Compare the time of response for the innate vs. adaptive immune system
Compare the specificity of the innate vs adaptive immune system
Compare the diversity of the innate vs adaptive immune system
Compare the memory of the innate vs adaptive immune system
Compare the self/non-self of the innate and adaptive immune system
Compare the soluble mediators of the innate vs adaptive immune system
Compare the major cell types of the innate vs adaptive immune system
What immunity is the first one to response and is it almost immediate?
The innate immunity is the first response and is almost instant
What cells have been shown to possibly have memory in the innate immunity?
The NK cells (will come onto this in a later lecture)
What is the main function of innate immunity?
What things does this involve?
The funciton of innate immunity is to eliminate invaders
for instance:
- infection (pathogens)
- Cancer
During innate immunity when pathogens are being eliminated, what are the two key events to identify whether its an infection or cancer to eliminate?
- Pathogen recognition
- Pathogen elimination
What does pathogen recognition involve?
What does pathogen elimination involve?
Once the immune system is activated, what can then go on to be activated?
The adaptive immune system
Tell me the different cells of the immune system and where there may be some overlap
What are NK T cells?
NK T cells as look like NK cells but express a T cell receptor. This T cells receptor is invariant and only has one or two receptors, whereas cytotoxic T cells have loads
What are the soluble mediators of the innate immune system?
- Antimicrobial peptides
- Interferons
- Natural antibody
- Pro-inflammatory cytokines
Give an examples of a antimicrobial peptide
Defensins
How do defensins work?
- Kill by disrupting microbial membrane and other mechanisms such as inhibition of synthesis of DNA, RNA, and protein
- Act against viruses as well
Tell me the following about interferons type I and II (innate response)
- What do they provide defence against
- What do they produce
- What do they prevent
- What do they stimulate
Interferons type I and II (innate response)
- Defence against viral infections
- Cytokines produced & released by host cells invaded by viruses
- Prevents viruses from infecting healthy cell
- Stimulates uninfected cells to produce antiviral proteins- makes the area harder for the virus to infect
Out of the following interferons (IFN) which ones are type I and type II?
IFN alpha
IFN beta
IFN gamma
IFN alpha/beta is Type I
IFN gamma is Type II
Tell me about IFN α/β functions (type I)
Activation of endoribonuclease and destruction of viral mRNA
Inhibition of protein synthesis (via EF-2 phosphorylation) through expression of protein kinase
Tell me about IFN-g functions (type II)
IFN-g functions (type II)
- Works on the innate and adaptive response
- Upregulation of MHC class I
- Enhancement of cytotoxic T cell activity- acts on CD8 also?
- Activation of Natural Killer (NK) cells- makes it a potent IFN
What are natural antibodies an important mediator of?
Innate immunity
What is the first antibody to appear at the first exposure to the antigen
Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antigen.
Whats the structure of an antibody?
Tell me about the IgM antibody
- specificity?
- How they work
- what do they bind to
- Typically, IgM form of antibody
Other classes such as IgA
- Not specific
- Work in the same way as antibodies produced in adaptive immune response
- Bind to bacteria or viral particles themselves and identify to phagocytes via opsonisation or form a complex to stop the bacteria or viral particle infecting the host cell
Table showing innate and adaptive cytokines
Again don’t need to remember it all, just be aware and hvae a basic understanding
Tell me about dendritic cells
What form do they exist in?
How do they differentiate and develop?
- Exist in an immature form
- Once receive a particular stimulus, they become activated and mature
Compare some of the roles of immature vs mature dendritic cells
How are mature dendritic cells different to immature ones?
State some roles of dendritic cells
- Take up antigen by phagocytosis
- pinocytosis
- receptor mediated uptake
- Process antigen for presentation
- Present antigen to T cells in the form of MHC-peptide complexes
- Secrete inflammatory cytokines (IL-12, TNF-a, IL-6)
Name the dendritic cell subsets and what area of the body they are present in
Tell me the dendritic subsets in humans
What si the only cell which can directly activate and prime naive T cells?
Dendritic cells
What are some of the methods in which pathogens are eliminated?
- Phagocytes: macrophages (differentiate from blood monocytes) and neutrophils
- Complement
- NK cells
How do phagocytes kill the pathogen?
- Best phagocytic cell is the macrophage
- The macrophage engulfs the bacteria into a vesicle known as a phagosome
- It then degrades the bacteria by enzymes (lysosomes) breaking up the invader
- This vesicle is known a phagolysosome
- Then the broken-up pieces of the invader are released outside of the cell
- But some becomes APC
Name the tissue macrophages like phagocytes in the following locations of the body…
- Liver
- Brain
- Lung
- Bone
- Liver= Kupffer cells
- Brain= microglial cells
- Lung= Alveolar macrophages
- Bone= osteoclasts
Tell me about tumour-infiltrating lymphocytes and their role in cancer…
- Tumour associated macrophages (TAMs)
- Want M1 macrophages in cancer
- Cancer will create an anti-inflammatory response which leads to M2 macrophages being present which are a type of immunosuppressant and helps protect the tumour
Tell me about neutrophils
- Phagocytes
- Most abundant cell in the blood
- Type of phagocytes and do the same as macrophages just not as effectively
What are the three types of complement system and what are each of the systems triggered by?
- Classical pathway initiated by: Antigen-antibody complexes
- Lectin pathway initiated by: Binding of mannan-binding lectins to cell surface
- Alternative pathway initiated by: binding of C3b to cell surfaces (regulatory proteins protect host cell surface)
What do all three complement system pathways converge to?
C3
Where does the C3 protein reside and over time what does it degrade to?
What enzyme is this facilitated by?
C3 resides in tissues and liver and over time degrades into C3b and C3a
This is facilitated by the C3 convertase
What happens in the complement system once C3b is made?
C3b acts an an oxidising agent (a substance that has the ability to oxidize other substances — in other words to accept their electrons)
C3b can bind with Factor B and form a complex known as C3bB
What happens to C3bB in the presence of Factor D?
C3bB in the presence of factor D gets degraded into C3 Convertase (c3bBb)
What does C3 convertase catalyse?
C3 convertase catalyses the conversion of C3 into C3a and C3b which is an amplification step
Whats formed when C3b interacts with C3 convertase (C3bBb)?
C5 convertase (C3bBb3b)
During the formation of C5 convertase, what is C5 converted into?
C5 –> C5b + C5a
What does C5a go on to do?
C5a will then bind with C6-C9 to form the membrane attack complex. Which forms pores in the membrane of bacteria which makes it hard for bacteria to regulate integrity causing them to die
Important system for killing bacteria, stopping their invasion and phagocytosis
What part of the complement system is involved in opsonisation?
C3b
What part of the complement system is involved in inflammation?
C3a and C5
Overview of the complement system
What is an important link between the innate and adaptive immunity?
NK cells
How are pathogens recognised?
Pattern recognition receptors (PRR) or pattern recognition proteins (PRP)
Tell me about PRRs and PRPs
- Cell surface receptors on immune cells (mostly as part of the innate immune system)
- Cytoplasmic sensors for nucleic acids and PAMPs/DAMPs
- Secreted soluble proteins that circulate in the blood and lymph
- Also found in cytoplasm and intracellular vesicles called endosomes as well as on the cell surface
Tell me about Pathogen associated molecular patterns (PAMPs)
- What are they expressed by?
- Where are they found?
- What type of molecules are they?
- Expressed by external pathogens
- Intrinsic molecules found on surface of bacteria which differentiate them from mammalian cells
- As intrinsic to molecules they are hard to remove by the pathogens
- Can be glycoproteins on the cells external surface, the way the viral genome is stored e.g., ssDNA or dsRNA
Where are sugar PAMPs found?
Where are they not present?
When is their expression high?
- Found on the surface of bacteria
- Not present in the host own body
- Found at higher level expression on bacteria or fungi
Give some examples of sugar PAMPs
- High mannose
- Fucose
- Xylose
- b-glucans (polysaccharide portion of LPS)
Are PRRs and PRPs germ line or somatic receptors?
Where are they expressed?
They are germ-line encoded receptors which means that they are present in all cells
They are expressed on the surface of innate cells
What are some of the families of receptors that the PRRs and PRPs go into?
Toll-like receptors
Mannose and glucan receptors- found in high levels in fungi and bacteria
Complement receptor- identify complement going round which is only activated in the presence of an immune response
Are PRRs and PRPs specific?
They have a broad binding profile which means they recognise many different pathogens
What are some secreted soluble proteins that circulate in the blood and lymph?
- Mannose binding lectin (MBL)
- C-reactive protein (CRP)- key was to diagnose autoimmune diseases like lupus.
- LPS-binding protein- binds to Lipopolysaccharides, a component of gram -ve bacteria
- Complement proteins e.g., C3b etc.
PRRs- activation of Toll-like receptors (TLRs) by microbial products
Tell me about the human toll-like receptor family and the location of the expression of different types of TLRs
- 12-13 TLR in humans
- Diagram shows the most common expressed TLR in innate cells
- Generally found on cell surface
- Not all TLR on cell surface, some are found inside the cell e.g., TLR 3/7/8/9 which are found on the lumen of the endosome. These are also involved in the innate immune response
- mRNA should never be found in endosome. So, if identified there (genome of pathogen) then it would activate it
Tell me about the structure of toll-like receptors
- Highly conserved
- First characterised in drosophila
- Two major domains; intracellular (TIR domain) and extracellular (LRR domain)
- extracellular domains have Leucine repeat which is found in all cell types
- Clear domain or Toll/IL-1 in intracellular domain
- Toll-like as like toll gene found in drosophila
Tell me about the TLR signalling pathway
- MyD88 is used by most TLR
- TRIF only used by TLR3 and 4
- TIRAP forms a complex with MyD88
- Tram –> TRIF –> cascade to drive expression of type 1 IFN
- TIRAP + MyD88 –> cascade to drive expression of pro-inflammatory cytokines
What can PAMPs be used as and what is this?
PAMPs can be used as adjuvants
Adjuvants are compounds in vaccines that stimulate the innate immune system to facilitate the induction of an adaptive immune response to antigen
Tell me some toll-like receptor agonists, what TLR they are agonists for and what theyre used for
TLR8 (ssRNA) is different to other types of TLR, why?
Its a Vita-pump receptor
TLR8 has the unique ability to differentiate whether themicroorganism its interacting with is alive or dead…
Expressed at high levels in human monocytes and can differentiate life and dead bacteria through recognition of its RNA (can sense viral RNA also)
Whats the potential problem with vaccines the the presence of the TLR8 receptor?
Potential problem with vaccines that use killed bacteria- won’t be able to invoke TLR8 and hence innate response so important other TLR are engages so response can be as strong as it can be
What does TLR8 induce?
Induces high levels of IL-12 and TNF-a and maturation of monocytes critical for activation of CD4+ T cells including follicular CD4+ T cells.
What are the cytoplamic sensors of nucleic acids?
What nucleic acid do they detect and why do they do this?
The things these sensors sense should never be found in cytoplasm
Molecules have been evolved to recognition of nucleic acids in cytoplasm e.g., MDA5 and RIG-1
MDA5 – dsRNA
RIG-I – capped ssRNA
Signal in a similar way to TLR except it involved a molecule called ‘sting’ which is important in cancer therapy
What are the cytosolic pathways for sensing DNA?
cyclic-GMP-AMP synthase (cGAS)
trigger’s reaction of GTP and ATP to form cyclic GMP-AMP (cGAMP)
With PRRs and PRPs what are the secreted soluble proteins that circulate in the blood and lymph?
- Mannose binding lectin (MBL)
- C-reactive protein (CRP)
- LPS-binding protein
Tell me about Mannose-binding lectin, how can it recognise mannose in normal and abnormal conditions?
Recognise mannose
- Will only bind if mannose residues are correctly spaced i.e., more abundant (diagram on right)
Can identify between normal and abnormal via mannose levels. abundance of mannose allows it to cross-link with activates MBL whereas under normal circumstances it can’t do this
During innate immunity, how is abnormal self sensed?
TLR receptors can recognise self-ligand
- In infection when tissue damage occurs – ‘DANGER’ signal
- In presence of ‘danger signals’ you will get an immune response
- Some TLR can bind to self-ligands
- Danger signals and DNA in right place at wrong time allows you to create an immune response
Damage-associated molecular patterns (DAMPs)
Other innate receptors can also recognise DAMPs
Tell me about damage-associated molecular patterns
Whats secreted when a cell dies and what cascade happens after that?
Damage-associated molecular patterns (DAMPs)
- HMGB1- secreted when a cell dies e.g., via apoptosis or necrosis
HMGB1
- HMGB1 is recognised by RAGE and TLR4 (overlap in specificity)
- RAGE used different pathway to TLR
- Engage transcription factors which leads to the production of inflammatory cytokines via a signal cascade as shown on right
HMGB1…
Damage-associated molecular patterns (DAMPs)
PAMPs and DAMPs
Dont need to learn this flow diagram just have an appreciation for it
Tell me about DAMPs involvement in cancer
- Activation of DAMPs can be used to induce anti-cancer T cell responses
- Need dendritic cell for specificity
- Important pathway that is being examined for future cancer therapies
e. g., STING and its activation
* DAMPS are more complex than we believe not just specific to HMGB1 (as shown in flow diagram above)
Cancer agents are central for vaccinating against cancer
What ways can vaccination be done?
Tell me about plasmid DNA vaccines and how inflammatory cytokines are invoked
Tell me about SARS-CoV2 recognition by TLRs
Tell me about Subversion of TLR signalling and interferon responses
