IMI 1: Sensing Damage, Protecting Our Bodies Flashcards

1
Q

Observe the learning outcomes for this session

A
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2
Q

T cells, B cells and NK cells are all lymphoid cells

True or false?

What is the other major class?

A
  • 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
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3
Q

Only B cells are mediators of immune memory

A
  • 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
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4
Q

Without T cells we would not survive in a non-sterile environment

True or false?

A
  • true
  • individuals without T cells cannot fight common infections and often die early in infancy
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5
Q

What do NK cells do?

A
  • 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
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6
Q

Cells of the innate immune system detect but cannot recognise what sort of pathogen they encounter

True or false?

A
  • 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
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7
Q

Observe the diagram of some cytokine receptor complexes, their downstream targets and biological functions

A
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8
Q

What are cytokines?

Why does γC mutation affect the immune system?

A
  • 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
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9
Q

Look at the microbes’ actions below and try to match them with the immune responses that each is likely to elicit

A
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10
Q

What is the first line of defence in our bodies provided by?

A
  • it is provided by a number of physical barriers
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11
Q

Observe this diagram of the relative sizes of different microbes

A
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12
Q

Give examples of two physical barriers and compare them

A
  • 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
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13
Q

Describe how secretions, such as mucus, can act as physical barriers

A
  • 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
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14
Q

Summarise the physical barriers of the body has and their mechanical, chemical and microbiological features

A
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15
Q

What is the second line of defence against an infection agent after physical barriers are compromised?

Briefly describe it

A
  • 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
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16
Q

What is the third line of defence?

Briefly describe it

A
  • 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
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17
Q

What are the very first cells pathogens usually encounter after getting through physical barriers?

Describe their functions

A
  • 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
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18
Q

What does the immune system need to be able to discriminate between?

A
  • 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
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19
Q

How can macrophages distinguish between harmless and harmful agents?

A
  • 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
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20
Q

Do T and B cells react to self-antigens and mount an immune response?

A
  • 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
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21
Q

What two signals dictated T-cell activation?

A
  1. The antigen presented by major histocompatability molecules (MHC)
  2. 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
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22
Q

How are molecules on the APC triggered?

A
  • 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
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23
Q

What do PAMPs look like?

A
  • 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
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24
Q

What are DAMPs?

A
  • 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
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25
Q

Observe some examples of different PAMPs and DAMPs

A
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26
Q

Name some PAMPs from bacteria, viruses, parasites and yeast

A
  • bacteria:
  • LTA
  • PGN
  • lipoproteins
  • DNA
  • flagellin
  • LPS
  • virus:
  • ssRNA
  • dsRNA
  • DNA
  • coat proteins
  • parasite:
  • Glycosylphosphatidylinisotol (gpi)-anchored proteins
  • yeast:
  • zymosan
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27
Q

Describe some key differences between innate and adaptive immune systems

A
  • 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
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28
Q

What are some other innate receptors other than PRRs?

A
  • other are mainly phagocytic receptors
  • complement receptors
  • scavenger proteins
  • lipopolysaccharide (LPS) receptrs
  • some types of lectins
29
Q

What are the five families of PRRs that lead to the induction of an antiviral response or inflammation?

A
  • toll-like receptors (TLRs)
  • C-type lectin receptors (CTLRs)
  • nucleotide-binding oligomerization domain-like receptors (NLRs)
  • RIG-I like receptors (RLRs)
  • cytoplasmic DNA sensors (CDSs)
30
Q

Observe this image to see where 4 of the PRR classes are localised in the cell

note that CLRs are not depicted here

A
31
Q

Describe TLRs

  • where in the cell are they found
  • what do they sense
A
  • found on:
  • cell surface
  • in endosomes
  • signal intracellularly via the TIR domains
  • they can sense:
  • triacyl lipopeptides (TR 1/2)
  • diacyl lipopeptides
  • lipoteichoic acid
    (TLR2/6)
  • lipoproteins
  • peptidoglycan
  • lipoarabinomannan
  • porins
  • envelope glycoproteins
  • GPI-mucin
  • phospholipomannan
  • zymosan
  • ß-Glycan (TLR2)
  • dsRNA (TLR3)
  • LPS
  • envelope glycoproteins
  • glycoinositolphospholipids
  • Mannan
  • HSP70 (TLR4)
  • Flagellin (TLR5)
  • sSRNA (TLR7,8)
  • CpG DNA (TLR9)
32
Q

Describe RLRs

Where are they in the cell?

What is their function?

A
  • 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)
33
Q

Describe NLRs

  • location
  • function
A
  • 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
34
Q

Describe CDSs

  • location
  • function
A
  • location:
  • cytoplasm
  • function:
  • CDSs, such as DAI, AIM2, cGAS, are all activated by DNA
35
Q

Summarise some of the key characteristics of the innate response receptors

  • cellular location
  • ligands
  • functions
  • icon
A
36
Q

What sort of immune response can be triggered when PAMPs and PRRs interact?

A
  • pathogen can be killed directly by lysis
  • pathogen can be made more attractive to phagocytes by a process of opsonisation
  • direct phagocytosis by interaction with a membrane-bound PRR
  • increase of phagocytic cell functions
  • increase in the levels of antimicrobial molecules
  • induction of cytokines and chemokines
  • differentiation of effector cells
37
Q

Observe this diagram to see how PAMPs are recognised and how that leads to cell lysis and the production of cytokines

A
38
Q

What does tissue damage often induce?

A
  • it often induce necrosis (programmed cell death)
  • leads to the release of damage signals: alarmins or DAMPs
  • will also activate the immune system
39
Q

How do tissue damaged cells activate the immune cells if they are ‘self’ cells?

A
  • 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
40
Q

How does the innate immune system know the location and type of infection?

A
  • there are more than 100 different innate receptors, but each cell type expresses just a few types
  • each individual effector cells of a certain functional immune cell type can express different combinations of PRRs
  • this is cellular heterogeneity and it increases the cell’s ability to identify non-self or damage
  • PRRs do not just exist in immune cells but also other cell types where they trigger an alert state and ensure that the non-immune cells also remain microbe or damage free
41
Q

What type of receptor do macrophages express

What can they not do?

A
  • phagocytic receptors:
  • e.g. complement receptors and scavenger receptors
  • these lead to the dismissal of the pathogen
  • but unlike PRRs, they do not signal further downstream
42
Q

What does signalling downstream of PRRs involve?

What does it lead to?

A
  • signalling downstream of PRRs involved many kinases and adapter molecules
  • eventually leads to gene transcription
43
Q

What two key types of immune responses do the signalling downstream of PRRs lead to?

Briefly describe what happens

A
  1. antiviral response
  2. inflammatory response
    - it increases the effector functions of the cells carrying PRRs
    - i.e. macrophages increase their ability to phagocytose or produce antimicrobial proteins
    - it leads to the production of soluble messenger proteins, most notably cytokines
    - it can also induce the differentiation of cells such as dendritic cells (DCs), which acquire more specialised functions
44
Q

What are some different types of cytokines?

A
  • interleukins (ILs) : more than 40
  • chemotactic chemokines
  • antiviral interferons (IFNs)
  • these shape and determine the magnitude of immune responses
45
Q

Describe cytokines

  • structure
  • function
  • biological response after cytokine signalling
A
  • 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
46
Q

What type of cytokines are induced upon infection?

A
  • pro-inflammatory cytokines:
  • e.g. IL-1β , IL-6, IL-12, CXCL8 and TNF-α

-

47
Q

Why are pro-inflammatory cytokines needed to resolve an infection?

A
  • unlike most immune cells that have some access to tissues, neutrophils are generally barred access since they have the greatest potential to cause collateral damage
  • Neutrophils, however, have a way to get access to our damaged tissues.
48
Q

How is inflammation the neutrophils’ key to the infection site?

What does it lead to?

A
  • 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
49
Q

Why is cytokine production so important?

A
  • cytokines trigger signal transduction pathways that lead to the activation of immune cells for effector functions
  • the specific production of specific cytokines and chemokines leads to the recruit of certain specific sets of immune cells
  • determining the sort of adaptive response best suited to deal with the invader
  • the recognition and categorisation of the threat is key to kick start the immune system down the line
50
Q

Learn the different types of PAMPs TLRs can recognise

and their haematopoietic cellular distribution

A
51
Q

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
A
  • 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.
52
Q

Describe TLRs

  • structure
  • types of TLRs and what they do
A
  • Toll-like receptors are composed of multiple leucine-rich repeats that are useful for recognizing various PAMPs
  • they are membrane-associated proteins:
  • some are located on the surface of the cell
  • others are located on endocytic vesicles: where they survey the degraded contents of pathogens taken up by endocytosis
  • Each member of the TLR family recognizes different kinds of PAMPs e.g.:
  • TLR5: recognizes flagellin, which is a highly conserved constituent of the bacterial flagellum.
  • TLR9: Bacterial genomes contain unmethylated CpG oligonucleotide motifs, which are recognized by TLR9 once the genome has been degraded in the lysosome
  • TLR6 and TLR2 dimer: that recognize diacyl lipopeptides
  • TLR1 and TLR2: are a dimer that recognize triacyl lipopeptides
  • TLR4 recognizes lipopolysaccharide (LPS), a component of gram-negative bacteria
  • TLR3 and TLR7 are located on endocytic vesicles, and recognize double-stranded RNA (dsRNA) and single-stranded RNA (ssRNA), respectively
  • When any TLR is activated, it sends a signal to the nucleus by activating transcription factors

https://vimeo.com/garlandscience30308032/review/248932214/a27d098728

53
Q

Describe NLRs

  • location
  • signalling pathways
A
  • the NOD2 protein, which is located in the cytosol, can detect bacterial proteoglycans of intracellular bacteria
  • When the NOD2 protein recognizes its ligand, the muramyl dipeptide, it sends a signal to the nucleus to activate transcription.

https://vimeo.com/garlandscience30308032/review/248932214/a27d098728

54
Q

Describe RLRs

  • structure
  • signalling pathway
A
  • there is a class of intracellular receptor proteins that contain an RNA helicase domain and two caspase recruitment domains, or CARD domains
  • One member of this family, RIG-I, recognizes dsRNAs that are components in the life cycle of many RNA viruses
  • This class of proteins also sends a signal to the nucleus, but unlike TLRs and NODs, it activates the production of type I Interferons (IFNs)

https://vimeo.com/garlandscience30308032/review/248932214/a27d098728

55
Q

Look at this statement and determine what is not true

A
  • 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)
56
Q

What does the signalling downstream of TLRs activate?

A
  • activates kinase IKK
  • which phosphorylates IκB, an inhibitor of NF-κB
  • When IκB is phosphorylated it gets targeted for degradation thereby releasing NF-κB
  • NF-κB, a key transcription factor that regulates inflammation, is now free to be transcriptionally active.
  • TLRs also lead to the activation of other transcription factors such as IRFs, which also help provide specificity.
57
Q

Observe the TLR pathways

  • location
  • PAMP recognized
  • signalling pathways
A
  • 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
58
Q

Observe the CLR signalling pathway

  • location
  • PAMP recognized
  • signalling pathways
A
  • 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
59
Q

Observe the NLR signalling pathway

  • location
  • PAMP recognized
  • signalling pathways
A
  • 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
60
Q

Observe the RLR signalling pathway

  • location
  • PAMP recognized
  • signalling pathways
A
  • 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
61
Q

Observe the cGAS and STING signalling pathway

  • location
  • PAMP recognized
  • signalling pathways
A
  • 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
62
Q

Observe the ALR signalling pathway

  • location
  • PAMP recognized
  • signalling pathways
A
  • AIM2-like receptors (ALRs)
  • Activated by long dsDNAs from cytosolic pathogens (viruses, bacteria)
  • Their activation leads to the formation of a multiprotein complex called inflammasome that leads to inflammation and, in some cases, IFNs
  • Examples: AIM2, IFI16
63
Q

Recap the innate initiation of adaptive response

A
64
Q

Summarise the three lines of defence

  • which immune system
  • function
  • examples
A
65
Q

Remember these points

A
  • Once a pathogen breaches our firewalls, pathogens carrying characteristic PAMPs are recognised by an army of PRRs and subsequently destroyed.
  • PRRs also detect damaged cells which express DAMPs and are similarly destroyed.
  • PRRs recognise structural features that are present in many different microbes and thus are not specific for just one pathogen, but can define a type of pathogen.
  • These molecular bar codes are so important to the microbes that they are not easily susceptible to random mutations that might otherwise enable immune evasion.
  • The PAMP/DAMP-PRR interaction leads to the production of cytokines which in turn help to destroy the bugs and activate the adaptive immune response.
66
Q

What are the two classes of receptors that can detect pathogens in the cytosol and why?

A
  • Not all pathogens, however, live in the extracellular space or are phagocytosed
  • Some pathogens, such as viruses, exist and replicate in the cytosol
  • There are at least two classes of receptors that can detect pathogens in the cytosol and signal their presence to the immune system:
  • nucleotide oligomerisation domain family, or NOD proteins
  • retinoic acid-inducible gene-I (RIG-I)-like receptor
67
Q

Observe this diagram of the cellular locations of receptors of the innate immune system

A
68
Q

Observe this figure for the signalling functions of toll-like receptors

A
69
Q

Compare the specificity of receptors of innate and adaptive immunity

A