IMI 1: Sensing Damage, Protecting Our Bodies Flashcards
Observe the learning outcomes for this session
T cells, B cells and NK cells are all lymphoid cells
True or false?
What is the other major class?
- true
- the other major class includes myeloid cells
- such as macrophages (and monocyte which are the precursors), mast cells, dendritic cells, neutrophils, basophils and eosinophils
Only B cells are mediators of immune memory
- false
- both B and T cells mediate immune memory
- they are produced at the same time as effector cells at the time of the first infection, but do not participate in fighting the original infection
Without T cells we would not survive in a non-sterile environment
True or false?
- true
- individuals without T cells cannot fight common infections and often die early in infancy
What do NK cells do?
- involved in innate immunity
- they are large cytotoxic lymphocytes that patrol the blood for virally-infected or damaged cells, which they are able to recognise despite lacking variable receptors like the ones found in B- or T-cells
Cells of the innate immune system detect but cannot recognise what sort of pathogen they encounter
True or false?
- false
- cells of the immune system can both detect pathogens, and recognise certain characteristics of the pathogen so that the appropriate type of immune response is mounted
Observe the diagram of some cytokine receptor complexes, their downstream targets and biological functions
What are cytokines?
Why does γC mutation affect the immune system?
- Cytokines are small polypeptides that are used as messengers in the immune system
- Several cytokines utilise receptor complexes that share the common cytokine receptor γ-chain (γC)
- these cytokines have very different biological functions and it is, therefore, unsurprising that a mutation on the γC can lead to such a catastrophic failure of the immune system
Look at the microbes’ actions below and try to match them with the immune responses that each is likely to elicit
What is the first line of defence in our bodies provided by?
- it is provided by a number of physical barriers
Observe this diagram of the relative sizes of different microbes
Give examples of two physical barriers and compare them
- skin:
- acts as a wall or fence
- 2m2 of body surface
- mucosal membranes:
- 400m2
- make up our digestive, respiratory and reproductive tracts
- mucus helps trap pathogens, making it an additional physical barrier
Describe how secretions, such as mucus, can act as physical barriers
- can neutralise pathogens from:
- their pH
- the production of digestive enzymes
- examples:
- tears in our eyes: have lysozymes with powerful digestive abilities
- stomach or vaginal secretions with extremely low pH
- wax in the ears: thought to have limited anti-bacterial properties but is critical to lubricate and protect the ear canal
Summarise the physical barriers of the body has and their mechanical, chemical and microbiological features
What is the second line of defence against an infection agent after physical barriers are compromised?
Briefly describe it
- the innate immune system
- lacks the specificity of the adaptive immune system
- broad actions
- quick: typically starting minutes after an infection
- can last for days
What is the third line of defence?
Briefly describe it
- the adaptive immune system
- can start within hours or days after the start of infection
- the body will not deploy it unless it is absolutely necessary
- involves an array of new cells and proteins
- so costs a lot of metabolic energy
What are the very first cells pathogens usually encounter after getting through physical barriers?
Describe their functions
- tissue resident macrophages
- these are scavenger cells present in all tissues
- they recognise pathogens
- also recognise old and damaged cells
- gobbling up cells in phagocytosis
- can distinguish harmless vs harmful agents
What does the immune system need to be able to discriminate between?
- something that is part of the body and something foreign: ‘self vs non-self’
- and between something that is harmless and harmful
- otherwise it could lead to immune diseases
How can macrophages distinguish between harmless and harmful agents?
- pathogens have structural features that are essential for their survival and these are not usually found in our cells
- called pathogen-associated molecular patterns (PAMPs)
- damaged cells release intracellular molecules called damage-associated molecular patterns (DAMPs)
- both are able to activate the innate immune system
Do T and B cells react to self-antigens and mount an immune response?
- they do react to self-antigens but they will not activate an immune response
- when an antigen-presenting cell (APC), e.g. a macrophage or dendritic cell, sees a self-antigen, it will present it to a T-cell
- the T-cell will ‘see’ the antigen but will know better and will not mount an immune response
- if the APC sees a foreign antigen on any given pathogen it will activate an immune response
What two signals dictated T-cell activation?
- The antigen presented by major histocompatability molecules (MHC)
- Molecules on the APC called CD80 (or B7-1) and CD86 (B7-2)
- these are receptors in the immunoglobin superfamily
- so their structure comprises domains similar to those in antibody molecules
How are molecules on the APC triggered?
- by Pattern Recognition Receptors
- Janeway hypothesised the existence of a new family of receptors that are evolutionarily ancient and present in both vertebrate and invertebrate organisms
- these would directly recognise common microbial patterns in pathogens (the PAMPs) and control the activation of signal 2 (CD80/CD86)
- these receptors would be called Pattern Recognition Receptors
- the first PRR is now known as Toll-like receptor 4 (TLR4)
- in invertebrates, PRR does not just control the innate arm of the immune system but they can also modulate adaptive immune responses
What do PAMPs look like?
- bacterial proteins such as flagellin (important for bacteria to swim using flagellum)
- sugar or lipid structures not found in verterbrates
- nucleic acids (ssRNA/ssDNA/dsRNA/dsDNA) present in forms and/or locations that are not usually found in healthy vertebrate cells
What are DAMPs?
- DAMPs are molecules that are produced by our cells and released upon damage or cell death
- they can still be released from damaged cells following infection, but they are often released from cells that have been damaged by ‘sterile stimuli’
- e.g. by trauma, radiation, burns or chemical toxins
Observe some examples of different PAMPs and DAMPs
Name some PAMPs from bacteria, viruses, parasites and yeast
- bacteria:
- LTA
- PGN
- lipoproteins
- DNA
- flagellin
- LPS
- virus:
- ssRNA
- dsRNA
- DNA
- coat proteins
- parasite:
- Glycosylphosphatidylinisotol (gpi)-anchored proteins
- yeast:
- zymosan
Describe some key differences between innate and adaptive immune systems
- the speed with which they respond to damage or pathogens
- each innate immune cell expresses several different innate receptors capable of recognising different types of pathogens
- the expression of these innate receptors is not restricted to innate immune cells and many are found in other cell types
- e.g. epithelial cells, keratinocytes or even B and T cells
- some innate receptors are not expressed on the cell surface but rather on internal cell membranes
- e.g. those of the endosomal system or in soluble parts of the cytosol
Observe this image to see where 4 of the PRR classes are localised in the cell
note that CLRs are not depicted here
Describe RLRs
Where are they in the cell?
What is their function?
- location:
- in the cytoplasm
- function:
- have helices domains: which unwind nucleic acids
- involved in transducing caspase recruitment domain (CARD)-dependent signalling after being activated by:
- dsRNA (short)
- 5-triphosphate RNA (RIG-I)
- dsRNA (long) (MDA5)
Describe NLRs
- location
- function
- location:
- in the cytoplasm
- function:
- has a central NOD domain and a c-terminal LRR that recognises:
- diaminopimelic acid (NOD1)
- MDP (NOD2 and NLP1)
- ATP
- uric acid crystals (NALP3)
- they signal via CARD domains
Describe CDSs
- location
- function
- location:
- cytoplasm
- function:
- CDSs, such as DAI, AIM2, cGAS, are all activated by DNA
Summarise some of the key characteristics of the innate response receptors
- cellular location
- ligands
- functions
- icon
Observe this diagram to see how PAMPs are recognised and how that leads to cell lysis and the production of cytokines
How do tissue damaged cells activate the immune cells if they are ‘self’ cells?
- their compromised cell membranes become leaky, so molecules that are not usually exposed to other cells become exposed
- these molecules function as flags signalling that these cells need to be taken care of
- the PRRs can be found associated with membranes or free in the cytoplasm and other organelles
- they can be extracellular or intracellular
- this helps the cell to understand where the infection is located and what type of infection it is
Describe cytokines
- structure
- function
- biological response after cytokine signalling
- they are like the hormones of the immune system
- they are soluble molecules that travel small distances in our bodies
- can act in an autocrine, paracrine or endocrine manner
- they have pleiotropic functions: so they behave differently in different cell types and can have many different functions
- biological responses (in order from the diagram):
- cell contraction, more cytokine secretion
- macrophage cell activation
- dendritic cell differentiation
- phagocytic cell migration
How is inflammation the neutrophils’ key to the infection site?
What does it lead to?
- it causes:
- local redness and swelling
- increased blood flow (after momentary constriction of blood vessels)
- vascular permeability (leaky blood vessels)
- these combine to allow the exit of neutrophils and other leukocytes from the blood
- and the subsequent proliferation of NK cells
Learn the different types of PAMPs TLRs can recognise
and their haematopoietic cellular distribution
Looking at these TLRs, what statement is true?
- they work as homodimers
- TLRs have repetitive motifs called LRRs
- all TLRs recognise PAMPs on the extracellular side of the plasma membrane
- TLRs have repetitive motifs called LRRs
- ligands bind to TLRs on the leucine-rich repeats domain
- the TLRs signal as homodimers, except for TLR2 which can heterodimerise with TLR1 or TLR6, and TLR10 which can signal as a homodimer or heterodimerise with TL1 or TLR2.
Look at this statement and determine what is not true
- not true: TLRs are only found in mammalian cells
- TLRs are located on the plasma membrane and in membranes of lysosomes and endosomes
- TLR signalling leads to the activation of phosphorylation cascades which involve key adapter proteins (such as MyD88, TRIF) and kinases (such as TAK1, TBK, IKK, IRAK)
Observe the TLR pathways
- location
- PAMP recognized
- signalling pathways
- Transmembrane proteins localized either at the plasma membrane or in endosomes (see two diagrams)
- Broad range of specificities recognizing proteins, nucleic acids, glycans etc…
- Activate: MAP kinase, NF-kB and IRF pathways
- Example: TLR4 recognizes lipopolysaccharide (LPS), a component of the gram bacteria cell wall; TLR3 for dsRNA
Observe the CLR signalling pathway
- location
- PAMP recognized
- signalling pathways
- Trans membrane proteins localized at the plasma membrane
- Recognize glycans from the wall of fungi and some bacteria
- Activate kinase syk and CARD9/MALT1/Bcl-10 adaptor complex
- Example: Dectin-1/CLEC7A recognizes B-1/3-glucans of the cell wall of various fungi species.
- figure legend: CLR bind carbohydrates on the cell membranes of extracellular pathogens
Observe the NLR signalling pathway
- location
- PAMP recognized
- signalling pathways
- Cytoplasmic sensors
- Multiple subfamilies:
- NLPRs recognize bacterial, viral, parasitic and fungal PAMPs
- AIM2 detects viral and bacterial DNA
- Form multiprotein signalling complexes known as inflammasomes
- Activates caspase-1-mediated processing and activation of pro-interleukins IL-1B and IL-18
- Example: NOD1, NLRP3
- Figure legend: they bind PAMPs for cytosolic pathogens
Observe the RLR signalling pathway
- location
- PAMP recognized
- signalling pathways
- Cytoplasmic sensors of viral RNA, which are RNA helicases
- Signal via the mitochondrial adaptor protein MAVS
- Activate IRFs and NF-kB
- Trigger antiviral responses including the production of type I interferon
- Examples: RIG-I, MDA5
- Figure legend: RLRs bind to cytosolic viral RNA
Observe the cGAS and STING signalling pathway
- location
- PAMP recognized
- signalling pathways
- Cytosolic sensors of DNA & dinucleotides
- signal via cGAMP from GTP and ATP
- Activate IRF-3 and NF-kB, leading to the synthesis of type I IFNs and cytokines
- Examples: cGAS, STING
- Figure legend: cGAS and STING are activated by cytosolic DNA and dinucleotides
- note location of STING (stimulator of IFN genes) on the ER
Recap the innate initiation of adaptive response
Summarise the three lines of defence
- which immune system
- function
- examples
Observe this diagram of the cellular locations of receptors of the innate immune system
Observe this figure for the signalling functions of toll-like receptors
Compare the specificity of receptors of innate and adaptive immunity
