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Agents of Infectious Disease > Introduction to Immunology (9-14) > Flashcards

Introduction to Immunology (9-14) Flashcards

1
Q

What are the 5 main pathogens that cause disease?

A

Bacteria
Viruses
Parasites
Fungi
Protozoa

changes in size, location and biochemical composition
→ immune system needs to attack each differently

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2
Q

What is Streptococcus pneumonia?

A

Gram positive bacterium
→ causes acute sinusitis, meningitis, pneumonia…
→ part of the normal upper respiratory tract flora, but can become pathogenic under the right conditions

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3
Q

How does Streptococcus pneumoniae compete with Haemophilus influenzae?

A

S. pneumoniae attacks H. influenzae (a gram -ve bacterium that also causes pneumonia and meningitis) with hydrogen peroxide

→ H. influenzae responds by signalling to our immune system to attack S. pneumoniae so it can thrive itself

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4
Q

What is Clostridium Tetani?

A

Gram positive spore forming bacterium
→ causes tetanus

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5
Q

How does Clostridium Tetani cause tetanus?

A

C. tetani produces potent toxic spores - tetanospasmin toxin
→ when released in a wound, it oxidises and enters circulation
→ reaches end of motor neurones, interfering with neurotransmitter release, causing tetanus

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6
Q

What is sleeping sickness?

A

Caused by Trypanosoma brucei carried by Tsetse flies
→ acquire a dense layer of glycoproteins that continually change, allowing it to avoid the immune system - antibodies don’t work anymore
→ symptoms: sleepiness, insomnia, anxiety, fever, weakness

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7
Q

Why are viruses difficult to fight?

A

Viruses (like smallpox, flu, chickenpox) are difficult to fight
→ always mutating
→ always intracellular - difficult to reach

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8
Q

Why is rapid viral evolution a challenge faced by the immune system?

A

Rapid viral evolution is a virulence strategy
→ pathogens can mutate (HIV) or recombine (flu) to avoid host immune responses
→ the immune system must be able to respond (must be adaptive) - constant evolutionary race

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9
Q

How does HIV rapidly evolve?

A

HIV rapidly evolves by mutation
→ the RNA genome is associated with RNA replicase (reverse trancriptase) with a high mutation rate about 1in10,000 bases
→ the antigentic drift is so rapid that it outpaces development of an effective immune response and confounds attempts to develop vaccines

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10
Q

How does flu rapidly evolve?

A

Flu rapidly evolves through recombination of its RNA segments, giving rise to new flu variants
→ the Spanish flu epidemic was triggered after a bird virus crossed the species barrier - lucky mutation meant it could now infect humans
→ recombination events triggered the Asian and Hong Kong flu epidemics

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11
Q

What is antigenic variation/shift?

A

A virulence strategy where some pathogens can alter their surface proteins to avoid host immune responses

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12
Q

Why is the adaptive immune response of memory important?

A

Re-exposure to pathogens is common
→ the immune response must have a memory
→ improves the secondary response to re-exposure - faster/bigger clears pathogens more efficiently

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13
Q

Why do we reply on our innate immunity during initial exposure to pathogens?

A

Both the primary and secondary adaptive immune responses are slow
→ so we rely on our innate immune system to kick in in the mean time, in the first few critical hours after exposure to a new pathogen
→ bacterial growth is exponential

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14
Q

Does the immune system have tissue specific responses?

A

Yes e.g.
→ lungs have mucus layer skin dry and keratinised

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15
Q

What is the blood brain barrier?

A

The blood brain barrier separates circulating blood from the brain extracellular fluid
→ tight junctions around brain capillaries, which don’t exist in normal circulation - obstacle for adaptive immune system
→ brain almost entirely relies on innate immune response

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16
Q

What’s the difference between the innate and adaptive immune system?

A

Innate
→ first line of defence, rapid
→ no memory, non specific
→ encoded in the germ-line

Adaptive
→ slow to adapt
→ highly specific, has memory
→ somatic gene recombination

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17
Q

What is cell-mediated immunity?

A

Defence provided by specialised cells in blood and tissues
→ e.g. lymphocytes (adaptive), granulocytes (innate)

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18
Q

What is humoural immunity?

A

Soluble-phase defence provided by secreted proteins in body fluids
→ e.g. immunoglobulins (adaptive), complement proteins (innate)

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19
Q

What is the structure of the innate immune system?

A

Humoural arm → barriers, defensins, complement

Cell-mediated arm → phagocytic cells. natural killer cells, toll-like receptors, APC (antigen presenting cells): dendritic cells and macrophages

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20
Q

What is the structure of the adaptive immune system?

A

Cell mediated arm → APC (antigen presenting cells): dendritic cells and macrophages, T cells, B cells

Humoural arm → antibodies

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21
Q

How do barriers of the innate immune system defend against pathogens?

A

Physical + chemical - stop pathogens entering blood stream
→ e.g. thick layer of keratinised dead cells - skin
→ tight junctions between epithelial cells
→ acid stomach pH
→ mucus layers

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22
Q

What are mucus layers?

A

Made up of secreted mucins and other glycoproteins
→ slippery - hard for pathogens to attach to mucus-coated epithelia
→ found on moist epithelial surfaces - epithelial cells often have beating cilia which facilitate clearance of pathogens
→ contain defensins - wide antimicrobial activity

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23
Q

What are defensins?

A

Small positively-charged antimicrobial peptides
→ hydrophobic or amphipathic helical domains
→ can kill or inactivate: gram +/-ve bacteria, fungi, parasites (inc. protozoa and nematodes), enveloped viruses (HIV)
→ although non specific different types of defensins work better on different pathogens

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24
Q

How do defensins work?

A

Their hydrophobic domains or amphipathic helice4s may enter into the core of the lipid membrane of the pathogen and destabilise it → cell lysis

Following membrane disruption, the positive charges may interact with (negatively-charged) nucleic acids in the pathogen

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25
Q

How do defensins lyse pathogens, but not our own epithelial surfaces?

A

Defensins are much more active on membranes that don’t contain cholesterol
→ our membranes contain cholesterol

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26
Q

How does the innate immune system recognise pathogens as ‘non-self’?

A

The innate immune system recognises pathogen-associated molecular patterns (PAMPs) that are common to many pathogens
→ PAMPs are absent in the host
→ e.g. N-formyl methionine (fMet), peptidoglycans from bacterial cell walls, bacterial flagellae, LPS from gram -ve bacteria, mannans, glucans, chitin from fungi, ‘CpG’ motifs in bacterial or viral DNA

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27
Q

How are PAMPs recognised?

A

PAMPs are recognised by soluble receptors in the blood and by cellular receptors: Pattern Recognition Receptors (PRRs)

Blood receptors recognise peptidoglycans, mannans, chitin→ complement system → direct killing + aid phagocytosis

Cell receptors recognise LPS, ‘CpG’ motifs, flagellae → toll-like receptors → an alarm system

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28
Q

What is the complement system?

A

Complement activation targets pathogens for lysis
→ complement: about 20 soluble proteins that are activated sequentially upon infection

  1. early complement components - proenzymes that activated the next member by cleavage → amplified proteolytic cascade
  2. pivotal proteolysis - cleaves C3 into C3a & C3b
  3. C3a → calls for help - attracts phagocytes, lymphocytes stimulating inflammation
  4. C3b → binds covalently to pathogen’s plasma membrane
  5. Pathogen-bound C3b stimulates local cascade (reactions C5-C8)
  6. C9 is inserted into the membrane
  7. A C9 pore breaches the membrane - form a membrane-attack complex
  8. pathogen lysis
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29
Q

What are toll-like receptors (TLRs)

A

An alarm system
→ on the cell membrane of epithelial cells and macrophages, dendritic cells and neutrophils
→ looks out for PAMPs, signals to the nucleus, gene expression changes - promotes inflammation

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30
Q

How does Neisseria Gonorrhoeae evade the innate immune system?

A

The capsule of N. gonorrhoea lacks LPS, instead contains lipoligiosaccharide (LOS)
→ N. gonorrhoea can add sialic acid from host to its LOS
→ human cells display sialylates glycoproteins - allows to mask as a human cell evading the innate immune system

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31
Q

What are phagocytes?

A

Phagocytes seek, engulf and destroy pathogens
→ 3 major classes: neutrophil, eosinophil, macrophage
→ contain numerous lysosomes and secretory vesicles (or granules)

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32
Q

What are neutrophils?

A

Most common type of granulocyte, have multilobes nucleus
→ phagocytose and destroy microorganisms, mainly bacteria - have a key role in innate immunity to bacterial infection
→ short-lived cells, abundant in blood, not present in normal healthy tissues
→ rapidly recruited by: activated macrophages, peptide fragments of cleaved complement proteins, PAMPs

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33
Q

What are macrophages?

A

Larger and longer-lived than neutrophils
→ recognise and remove senescent, dead, and damaged cells in many tissues
→ able to ingest large microorganisms like protozoa

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34
Q

What are eosinophils?

A

Team players, they help to:
→ destroy parasites
→ modulate allergic inflammatory responses
→ have double lobed nucleus

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35
Q

How to phagocytes engulf their targets?

A

Phagocytes display cell-surface receptors for PAMPs and chemicals produced by the immune system (TLRs, antibodies, complement C3b protein)
Binding activates them -
→ enhances killing power
→ causes release of cytokines to attract more white blood cells
→ induces actin polymerisation: the phagocyte’s plasma membrane surround pathogen and engulfs in phagosome

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36
Q

What are granules?

A

Dense membrane-bound lysosomal derivatives
→ fuse with the phagosome membrane and release their contents (lysozyme acid hydrolases) inn an attempt to digest pathogen cell wall
→ contain defensins - destabilise pathogen’s membranes

37
Q

What do NADPH oxidase complexes on the phago-lysosomal membrane do?

A

A respiratory burst (a transient increase in O2 consumption) by the phagocyte allows the NADPH oxidase complexes to produce highly toxic oxygen-derived compounds
→ e.g. superoxide O2-, hypochlorite HOCL, hydrogen peroxide H2O2

38
Q

Can neutrophils survive the chemicals of a killing frenzy?

A

No - most macrophages can
→ neutrophils appear to be suicide squads - will use own DNA to trap bacteria preventing escape
→ dead neutrophils/pathogens = pus (can be green due to release of copper-containing compounds)

39
Q

How can pathogens survive a killing frenzy?

A

→ addition of sialic acid to capsule components avoids complement attack and subsequent engulfment (Neisseria gonorrhoeae)
→ some survive and replicate inside neutrophils - express virulence factors that protect against respiratory burst, until neutrophils die (Neisseria gonorrhoeae)
→ neutralise actin polymerisation and therefore phagocytosis, inject a toxin that disrupts assembly of the actin cytoskeleton (Yersinia pestis)
→ survive inside macrophages, which usually survive the killing frenzy (Salmonella)

40
Q

How does inflammation aid in a killing frenzy?

A

Inflammation (good when controlled/acute) - blood vessels dilate, local swelling, accumulation of components of the complement cascade
→ activation of TLRs in epithelia and activated macrophages contribute to inflammation
→ macrophages secrete cytokines, including chemokines that attract neutrophils

41
Q

What can go wrong with inflammation?

A

Systemic release of inflammatory cytokines can lead to excessive blood vessel dilation, resulting in sudden lowering of blood pressure (shock)
→ if widespread inflammation, swelling and blood clotting occurs - septic shock
→ significant decrease in BP, blood supply to vital organs is reduced - organ failure

42
Q

What are interferons?

A

Interfere with viral infection
→ most important cytokines in virology
→ produced by cells in response to viral dsRNA

→ induce changes in the infected cell - autocrine action
→ induce changes in neighbouring cells - paracrine action

43
Q

How do interferons limit viral replication?

A
  1. make virally-infected cells and neighbours into much less efficient factories - warn neighbouring cells of infections to induce expression of other cytokines, activate a ssRNA nuclease and other mechanisms that shut down host cell synthesis
  2. limit viral spread by promoting apoptosis of infected cells
  3. upregulate display or viral peptides - signals for recognition by activated T cells
  4. stimulate expression of the immunoproteasome to process and destroy viral proteins
  5. call for help: attract natural killer cells, activate macrophages
  6. fight cancers
44
Q

What are natural killer cells?

A

Viruses and cancers down-regulate expression of immune system recognition molecules - unusually low expression likely to be infected or transformed
→ NK cells recognise their targets by monitoring the level of expression of these molecules
→ NK cells are attracted to virally-infected cells by INFs
→ NK cells persuade cells to die by apoptosis

45
Q

What is the adaptive immune system?

A

Destroys invading organisms and toxins they produce
→ highly specific to a particular pathogen
→ long-lasting protection (immunological memory)
→ recruited and trained by the innate immune system

46
Q

What are antigens?

A

(ANTIbody GENerators)
Any substance capable of generating an adaptive immune response

47
Q

How do immunisations help understand the adaptive immune system?

A
  1. an antigen is injected into a mouse in the form of a suspension containing adjuvant
  2. adjuvant activates innate immunity responses, contains:
    → immunological stimulants - inactivated mycobacterial proteins
    → irritants - aluminium hydroxide
  3. the activated innate response also responds to the antigen in the vaccine
  4. the innate immune response trains the adaptive immune response - very specific
48
Q

What are the benefits and problems of immunisations?

A

benefits → reduces reported cases due to immunological memory
problems → anti-vax movements causing increase in cases (e.g. false link with MMR vaccine and autism)

49
Q

What are lymphocytes?

A

White blood cells (T or B) that perform adaptive responses
→ develop in central or primary lymphoid organs - bone marrow, thymus
→ migrate to peripheral or secondary lymphoid organs - adenoids, tonsils, lymph nodes, spleen, skin, respiratory tract
→ highly concentrated in blood and lymph

50
Q

How did experiments from the 1950s confirm that lymphocytes are responsible for adaptive immune response?

A

Mice were heavily irradiated
→ unable to produce apatite immune responses, could still do innate

Lymphocytes transferred into these mice restored adaptive immunity

51
Q

What are dendritic cells?

A

Type of phagocyte and APC
Display wide variety of TLR and pattern receptors
→ activated by binding of pathogen to any of these receptors
→ activated DC phagocytose and degrade invading microbes
→ peptides from degrade organisms are displayed on their cell surface
→ migrate to lymphoid organ to activate adaptive immune responses (training to recognise displayed peptide fragments)

52
Q

How do dendritic cells (DC) find T cells?

A

innate immune response activates DC → digests pathogen → mature into APC → migrate to lymphoid organ → find T cells

53
Q

How to T cells develop?

A

T cells develop in thymus tissue from thymocytes derived from common lymphoid progenitor cells derived from a haemopoietic stem cell (liver - foetuses, bone marrow - adults)

54
Q

How do dendritic cells (DC) activate T cells?

A
  1. DC present peptides to T cells in lymphoid organs
  2. T cell TCR recognises ‘self’ antigen - no action taken
  3. T cell TCR recognises no antigen - no action taken
  4. T cell TCR recognises ‘non-self antigen’ - clonal expansion of specific T cells
55
Q

Why do APCs only present to T cells?

A

highly specific 2 step recognition to stop groove proteins wrongly activating non T cells
→ co-stimulatory molecules on APC dock with T-cell specific co-stimulatory molecules
→ peptide held in groove of APC presenting protein and scanned by the TCR

no recognition - no activation, cells undock
recognition - T cells activated - migrate to site of infection

56
Q

What are the 3 types of T cell?

A

T regulatory (or supressor)
T cytotoxic
T helper

57
Q

What are T helper cells?

A

Activated macrophages (phagocytes), dendritic cells, B cells (lymphocytes) and maintain cytotoxic T cell activity by secreting variety of cytokines

58
Q

What are T regulatory cells?

A

Inhibit the function of helper T cells, cytotoxic T cells and dendritic cells
→ regulate inflammation, prevent too many cytokines released

59
Q

What are cytotoxic T cells?

A

Kill infected host cells by persuading them to undergo apoptosis
→ recognise the antigens that activated it, binds specifically to target cell forming an immunological synapse

60
Q

How do cytotoxic T cells kill target cells?

A
  1. secrete perforins, assemble and form channel in target cell wall
    → T cell secretes specific proteases which enter target and activate caspases (effector proteins of apoptosis)
  2. bind to receptors on target cell that send a signal that activates caspases → apoptosis
61
Q

Why is T cell activation an amplifying process?

A

The apoptotic bodies (causes by cytotoxic T cells) are phagoctyosed by antigen-presenting cells - can therefore retrain T cells
→ why T regulatory cells are needed

62
Q

What is the difference between T cells and B cells?

A

Both derived from common lymphoid progenitor cells, which are derived from haemopoietic stem cells but,

T cells → develop the thymus, recognise antigens from dendritic cells
B cells → develop in bone marrow, recognise antigens as soluble proteins

63
Q

How to B cells recognise their antigens?

A
  1. soluble antigens in blood or lymph
  2. B cell receptor (BCR) recognises ‘self’ antigen - no action taken
  3. BCR recognises no antigen - no action taken
  4. BCR recognises ‘non-self’ antigen - activation, mitosis and clonal expansion of specific B cells
64
Q

How do resting B cells differentiate?

A

Differentiate into effector B cells (plasma cell)
→ increase in ER, can secrete lot of antibodies
→ specific to antigen that activated in lymphoid organ

65
Q

What is the structure of an antibody?

A

Tetrametric - Y shae
→ 4 polypeptide chais, 2 identical heavy chains and 2 identical light chains
→ held together by covalent disulphide binds at the hinge between H and L chains

66
Q

How many antigens can one antibody tetramer bind?

A

2 identical antigens

67
Q

What can occur if an antigen has two identical antigenic determinants?

A

Antibodies can cross-link the antigens making small cyclic complexes or linear complexes
→ antibody cross-linking can generate lattices
→ antibodies with different specificity can co-operate

68
Q

How do antigens make it easier for phagocytes to engulf pathogens?

A

Ability to cross-link antigens + flexible hinge region
→ soluble antigens and viruses can be trapped in large cross-linked networks that often precipitate

69
Q

What are the classes of antibody?

A

Collective name for antibodies is immunoglobulin (Ig)

IgM - μ heavy chain
IgD - δ heavy chain
IgG - γ heavy chain
IgA - α heavy chain
IgE - ε heavy chain

70
Q

What are IgMs?

A

The most primitive immunoglobulins
→ the first antibodies B cells will make
→ expressed my immature B cells in bone marrow
→ once B cell has IgM and IgD can respond to antigens
→ T helper cells aid clonal expansion

71
Q

How can IgMs cause inflammation?

A

IgMs bound to targets can activate the complement pathway (classical pathway)

72
Q

Why is IgM efficient at activating complement?

A

Phagocytic cells don’t have a receptor for IgM
→ ineffective at assisting phagocytosis

but IgM is very efficient at activating complement - considered opsonin
→ targets antigens for phagocytosis

→ IgM is part of humoural arm of adaptive immune system

73
Q

What are the functions of IgG?

A

→ toxic neutralisation
→ binding to micro-organisms and opsonisation by coating pathogen + activating complement - phagocytosis
→ provision of passive immunity to foetuses (pinocytosis) and newborns (maternal milk)

74
Q

What is IgA?

A

A dimer of two tetrameric structures held together by a J chain and S chain which allows secretion into
→ saliva, tears, milk and mucus

75
Q

How do plasma cells switch the class of immunoglobulin secretion?

A

Heavy chain changes only
→ specificity stays the same

IgM can switch to: IgG, IgA, IgE

76
Q

What is IgE?

A

Standard tetrametric structure
→ same specificity as IgM
→ bound IgE acts as receptors for the particular antigens
→ triggers mast cell/basophil degranulation
→ results in histamine release - pro inflammatory mediator
→ uncontrolled IgE - hay fever, asthma

77
Q

What is the antigen binding site made from?

A

The n-terminal domains of both heavy and light chains are called variable (V) domains
→ the antigen binding site is made from V light and V heavy domain interactions

78
Q

What are the functions of the different constant domains?

A

Cy1, Cy2 - bind complement components
Cy2, Cy3 - bind Fc receptors on neutrophils
Cy3 - binds Fc receptors on macrophages and NK

79
Q

Do heavy chain structures differ considerably?

A

Yes

80
Q

What cells does class switching occur in?

A

Mature B cells
→ can switch classes from IgM to other Ig classes
→ whilst maintaining the same specificity for antigens
→ required same variable chains and different heavy chains

81
Q

How is the H chain gene segmented?

A

There is one antibody H chain gene
→ Ig H gene encodes a variable (VH) domain and all the H chain constant regions separated by non-coding regions

82
Q

How do mature B cells class switch?

A

Somatic recombination of DNA
→ cuts out small segments of DNA to allows expression of variable heavy chain with different constant components

83
Q

Summarise class switching:

A

Primary response
→ antigen stimulates clonal expansion of B and T cells, that already have receptors that already recognise the antigen
→ mature B cells produce IgM
→ can switch antibody heavy chain classes by somatic recombination, maintaining their variable domains and specificity

84
Q

What is the clonal selection theory?

A

Following infection an antigen activates only lymphocytes committed to respond to it
→ they display cell surface recptors that specifically recognise the antigen
→ upon encountering the antigen lymphocytes undergo clonal expansion and differentiation

85
Q

How are there so many antibodies that recognise different antigens?

A

To do with variable domains that encode specificity
1. there are only 3 antibody genes → two classes of light chains which increases diversity and possible binding sites
2. there are multiples gene segments encoding V domains that can be combined with C domains by somatic recombination
3. the somatic recombination used to select V gene segment is complex → link V domain with constant domains at protein level creating 10^14 proteins with unique potential antigen binding sites

86
Q

What is affinity maturation?

A

Over time antibodies made by B cells improve in affinity and become more specific
→ due to accumulation of point mutations in the V domains
→ occurs in the lymph nodes
→ evolution of a high affinty antibody

87
Q

What is the antibody secondary response?

A

Second exposure results in a greater and more efficient secondary response with a short lag period
→ immune system has memory
→ greater and more specific as it made up of class-switched antibodies that have undergo somatic hypermutation

88
Q

How is immunological memory generated?

A

After clonal expansion T and B effector cells produced
→ some antigen-stimulated cells multiple and differentiate into memory cells
→ memory cells can be induces to become effectors by antigenic stimulation
→ most effectors die after an immune response, memory cells do not

Agents of Infectious Disease (4 decks)

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