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Immunology and inflammation > IMI5: Immune responses against extracellular pathogens > Flashcards

IMI5: Immune responses against extracellular pathogens Flashcards

1
Q

Main mediators of innate immunity are?

A 
barrier functions
complement system
pattern recognition receptors
phagocytes
granulocytes
NK cells
coagulation system
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2
Q

Where do 75% of immune cells reside?

A

mucosal immune system

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3
Q

The commensal flora are collectively known as?

A

The human microbiome

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4
Q

Bacteria can secrete antibiotics or antimicrobial peptides called ________ which can work as a first line defence against an invader

A

bacteriocins

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5
Q

Give two examples of harmless bacteria that can become pathogenic

A

1) The infection by the commensal microorganism Staphylococcus epidermidis after a break in the skin from a cut
2) Pseudomonas aeruginosa, which most of us can fight effectively, can infect the airways, urinary tract and wounds of vulnerable individuals and cause real harm (e.g. by causing pneumonia and in some cases sepsis)

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6
Q

Name 3 life-threatening bacteria that grow in the respiratory tract

A

Streptococcus pneumoniae, Haemophilus influenzae, Bordetella pertussis

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7
Q

What can Streptococcus pneumoniae, Haemophilus influenzae, Bordetella pertussislead to?

A

blood stream infections (when viable bacteria or fungi are found circulating in blood), pneumonia, meningitis and middle ear infections

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8
Q

What are the two immunologically distinct regions of the gut?

A 
Inductive sites
Effector site (makes up most of gut)
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9
Q

What are the inductive sites

A

Regions rich with naive resting immune cells: . These regions drive the education of the immune system of mucosal surfaces

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10
Q

What are the regions responsible for education of the immune system of mucosal surfaces called?

A

Peyer’s patches

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11
Q

What happens in Peyer’s patches?

A

They sample microbes in the lumen of the gut, passing them on to macrophages and B cells to promote IgA responses against these pathogens. In contrast, dendritic cells (DCs) sample other antigens to ensure that immune cells are tolerant of food, and other gut contents that are not hazardous

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12
Q

Where is the effector site?

A

the tissue underlying the epithelium (embedded within the matrix of the peyer’s patch)

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13
Q

What is the effector site made u of and what does it do?

A

It is crammed with activated effector cells: plasma cells that secrete antibodies into the mucus (usually IgA and IgM) and memory B cells, T helper (TH) cells and antigen presenting cells (APCs) - macrophages and dendritic cells.

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14
Q

lymphatics from peyer’s patches and villi drain into where?

A

Mesenteric lymph node

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15
Q

What is the loose connective tissue within the villi called?

A

lamina propria

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16
Q

What cells transport material across epithelial barrier via transcytosis

A

Microfold cells (M cells)

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17
Q

What do dendritic cells within Peyer’s patch do?

A

Extend dendrites between epithelial cells to sample antigens that are the broken down and then used for presenting to lymphocytes

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18
Q

What is tolerogenic activation?

A

Where the immune system initiates and anti-inflammatory response

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19
Q

With their cargo of antigen, what do the dendritic cells within the Peyer’s patch do?

A

Traffic to the T-cells zones. Upon encounter with T-cells, the dendritic cells convert them into regulatory T cells

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20
Q

Defects in the function of what cells causes inflammatory bowel disease?

A

regulatory T cells

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21
Q

Where do the regulator T cells migrate to? How?

A

lamina propia of the villi via the lymphatics

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22
Q

What do regulatory T cells do whenever they get to the lamina propia?

A

Secrete IL-10, which exerts an supressive reaction with the immune cells of the lamina propia and on the epithelial layer itself

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23
Q

What interleukin is critical in maintaining immune quiescence and preventing unnecessary inflammation

A

IL-10

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24
Q

A break down in immune homeostasis can lead to what?

A

gut pathology - over a log period and in an uncontrolled manner this can lead to
inflammatory bowel disease

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25
Q

What are the causes of inflammation in the gut?

A
  • genetic predisposition plus

- chemical, mechanical or pathogenic barrier disruption

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26
Q

When bacteria influxes through the epithelium what do T-regulatory cells do? How are they activated to do this?

A

Down regulate IL-10 secretion, to allow an immune response to proceed.
They are activated by alarm molecules secreted by the epithelium following activation by bacteria

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27
Q

What is released by dendritic cells during a gut immune response?

A

IL-6, IL-12, IL-23

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28
Q

What do effector T cells do in the gut during an immune response?

A

They up-regulate the immune response by secreting: tumor necrosis factor, interferon gamma, IL-17

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29
Q

Following effector T cell arrival in the gut, what comes next?

A

Neutrophils
- netosis (NET)
causes collateral damage to tissues

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30
Q

What happens to the remaining neutrophils, once the immune response has won?

A

They die by apoptosis and are cleared by macrophages

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31
Q

How are the damaged epithelial cells replaced

A

By new cells from the intestinal crypts of Lieburkuhn

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32
Q

How do M cells act?

A

Passive immunity
Transport substances
stimulate production of IgA
uptake antigens viaendocytoisis, phagocytosis and transcytosis

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33
Q

What is the role of DCs in the Peyer’s patch?

A
  • Sampling proteins from the gut lumen
  • Presenting antigens to T cells
  • Producing T regulatory cells
  • Inducing tolerance to an antigen
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34
Q

Describe gram positive bacteria

A

They have a single membrane surrounded by a thick wall made of peptidoglycan, a polymer of sugars and amino-acids

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35
Q

Describe gram negative bacteria

A

have an inner membrane, a thin peptidoglycan wall and then an outer membrane, whose lipids are studded with sugars

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36
Q

Do gram positive or gram negative bacteria have lipopolysaccharides

A

Only gram-negative bacteria

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37
Q

What are the three key players of the complement system?

A
  • Opsonisation
  • Lysis of pathogens
  • Tagging (attracting immune cells)
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38
Q

What are the three main initiators of complement activation, and which pathways do they initiate?

A
  • Antibody initiates classical pathway;
  • Bacterial cell wall components / PMAPs, initiate the lectin pathway
  • Spontaneous hydrolysis of C3b that joins it to surfaces initiates the alternative pathway
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39
Q

What structure is IgA and IgM secreted in?

A

IgA: dimer
IgM: pentamer

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40
Q

In what case are antibodies required for innate immunity?

A

Antibodies involved in the activation of the classical complement pathway

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41
Q

How could low affinity antibodies activate the classical complement pathway?

A

IgM has 10 complementary determining regions (CDR) these can all bind with a low affinity to multiple antigens on pathogen’s surface (in a repeating pattern such as bacterial wall of virus capsid) - making its avidity 10x its affinity. Thus activating the classical complement pathway

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42
Q

What binds to the boundIgM molecules to initiate the classical complement pathway?

A

C1q

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43
Q

In what bacteria can the MAC components not reach the inner membrane?

A

Gram positive

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44
Q

What can the MAC components attack?

A

MAC is able to penetrate both of the membranes of gram-negative bacteria and those of enveloped viruses

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45
Q

Since gram positive bacteria cannot be attacked by MAC, how can they be targeted?

A

It can be efficiently opsonised by complement, and trigger the release of the anaphylotoxins that recruit and activate phagocytes

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46
Q

What two bacteria are able to prevent complement recognition? How?

A

1) Haemophilus influenzae excretes a protease enzyme able to accelerate breakdown of complement proteins;
2) Staphylococcus aureus makes capsules that make the bacterium more resistant to opsonisation by complement, and can also secrete a bacterial protein that stimulates the production of C3b-fibrinogen complexes to make an opsonised decoy

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47
Q

What are known to lead to susceptibility to extracellular pathogens, particularly to pyogenic bacteria, which cause purulent (better known as pus-forming) inflammation (e.g. Streptococcus pneumoniae)?

A

Deficiencies in early components of the alternative pathway (e.g. Factor D, Factor P or C3)

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48
Q

What are deficiencies in the Lectin pathway associated with?

A

Early childhood susceptibility to infections

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49
Q

MAC deficiencies can lead to what?

A

Infection and susceptibility to Neisseria gonorrhoeae species

50
Q

What molecule do pathogens typically target to evade complement?

A

C3b since this is critical to complement signalling cascades and the strongest opsonin

51
Q

Which PRRs would be best suited to sensing bacteria outside the cell?

A

TLR1, 2 and 4 detect bacterial cell walls, while TLR5 can detect bacterial flagellin. Some CLRs can also sense some bacteria (although they are more critical for sensing fungi). MBP is also a PRR that initiates the complement cascade. However, NOD-like receptors sense bacterial peptidoglycans inside the cell.

52
Q

Can you recall from previous sessions mechanisms which phagocytic cells can use to kill microbial cells?

A

A phagosome that fuses with a lysosome can:

  • Generate reactive oxygen species (ROS)
  • Generate nitric oxide (NO)
  • Digest bacteria with antimicrobial molecules (e.g. lysozyme, proteolytic and hydrolytic enzymes, defensins)
53
Q

When does the formation of NETs take place?

A

Within 1-2 hours of neutrophil activation

54
Q

What does deficiency of the number or function of phagocytes lead to?

A

severe immunodeficiency

55
Q

What does the failure of the removal of NETs may lead to?

A

Yes, it may lead to the formation of auto-antibodies directed against NET components. This, in turn, can result in the development of autoimmune diseases (e.g. rheumatoid arthritis)

56
Q

What are the lethal microbial components of NETs

A
  • myloperoxidases
  • neutrophil elastase
  • defensins
    The net captures athogens and anything in the net is killed
57
Q

When a neutrophil encounters a pathogen, what enzyme does it activate?

A

PAD4

58
Q

What does PAD4 do?

A

unpackage the tightly coiled DNA to loose strands of sticky web like material thats ejected from the cell

59
Q

How is the toxic NET deactivated and destroyed?

A

serum? nucleases chop the NET DNA into small fragments that can be ingested by macrophages

60
Q

An extracellular pathogen penetrates the skin barrier and infiltrates into the underlying tissue, explain what happens next

A

The complement system is activated by MBP/lectin and amplified by the alternate pathway, which opsonises the pathogen and releases anaphylotoxins to attract immune cells.

61
Q

After anaphylotoxins attract immune cells what happens?

A

It induces degranulation of mast cells and, along with sensing of bacterial PAMPs by TLRs on immune and epithelial cells, this triggers the release of potent cytokines and chemokines that signal to other immune cells so that reinforcements are sent to the site of infection soon.

62
Q

An acute inflammatory response increases the vascular permeability and induces what to migrate from the blood into the tissue?

A

Neutrophils

63
Q

Following the complement cascade induces lysis of Gram-negative pathogens what happens?

A

Activated tissue macrophages can then devour the opsonised bacteria, and neutrophils can form NETs to contain the bacteria locally and stop the spread of the infection to neighbouring cells and blood vessels.

64
Q

Which cells belong to the adaptive immune system?

A
  • Cytotoxic T cells
  • B cells
  • Memory B cells
  • Memory T cells
  • T helper 17 cell types
65
Q

Extracellular antigens are presented by antigen presenting cells (APCs) to T cells by?

A

MHC class II

66
Q

Where is MHC I expressed?

A

On all cells, but MHC II is only constitutively expressed on APCs

67
Q

High levels of what interferon made activated immune cells can force other cell types (eg epithelia) to produce MHC class II on their cell surface - turning them into ‘non-professional APCs’ at the site of infection

A

Interferon gamma

68
Q

Generally, what are MHC I and MHC II for?

A

MHC class II is for presenting extracellular antigens, while MHC class I is for intracellular antigens

69
Q

Which cells sense loaded MHC class II?

A

CD4 T

70
Q

The invariant chain blocks the peptide binding groove while the MHC class II is being assembled. What role does the invariant chain play?

A

Preventing self-peptides from loading onto the MHC class II in the endoplasmic reticulum

71
Q

What are the similarities and differences between the structure of MHC I and MHC II

A

S: ‘cleft’ or ‘groove’ made of α helices, and a ‘floor’ made of β sheets. The peptide is bound in this groove.

  • MHC class II the peptide binding site is made half each from the α and β chains.
  • MHC class I, the α chain makes all of the peptide binding region. In contrast, the beta chain (beta 2 macroglobulin) does not. Therefore there are many MHC Class I α chain genes, but only one β 2 macroglobulin gene.
72
Q

How does the pathogen’s antigen bind to the MHC class II molecule?

A

The amino-acid side chains from both the B sheet floor and the a-helices sides of the cleft contribute to binding the peptide

73
Q

T cell receptors will only recognise antigens when?

A

If these are attached to MHC molecules

74
Q

How many amino acids long are peptides that bind to MHC I and MHC II molecules?

A 
MHC class I-bound peptides:  7 to 11 amino acids long
MHC Class II-bound peptides are longer – around 14 to 24 amino acids.
75
Q

How do the several MHC gene clusters that we have in our genomes vary? What is the purpose of this variation

A

The different genes have variations in the amino acids at the bottom and sides of the cleft. These different MHC variants bind best to peptides with different characteristics. Thus having a variety of MHC molecules allows the immune system to present a wide range of peptides

76
Q

How many different MHC versions are there?

A

Roughly 700

77
Q

What is the key difference between MHC class I and MHC class II?

A

Their source of antigens

78
Q

A portion of the invariant chain binds where on MHC II? What is the purpose of this?

A

To the peptide binding groove of the MHC class II molecule: this prevents peptides or unfolded proteins present in the ER from binding

79
Q

What does the invariant chain do other than block binding?

A

It guides the transport of the MHC II molecule out of the ER, through the golgi apparatus and into a vesicle, that becomes part of the endocytic pathway

80
Q

What occurs in the endocytic pathway?

A

Pathogens and foreign proteins are taken into the cell

81
Q

Progressive acidification of the endocytic vesicle containing MHC II leads to what?

A

It activates proteases: that cleave in invariant chain in two places leaving a small peptide (CLIP) bound to the class II molecule

82
Q

What does CLIP stand for?

A

The Class II invariant chain peptide

83
Q

Why can engulfed pathogens and their proteins, also degraded by acid activated proteases into peptides, not immediately bind to the MHC II?

A

CLIP peptide is still bound to the peptide binding groove

84
Q

What removes the CLIP molecule? How?

A

HLADM, present in the vesicle
- Functioning as a catalyst, coordinating both the release of the CLIP peptide and the binding of pathogen derived peptides
(In the endoplasmic reticulum)

85
Q

In the endocytic pathway, once HLADM has functioned, where does the MHC class II peptide complex go?

A

It is transported to the cell surface where it can be recognised by the antigen receptors of CD4 T cells

86
Q

What can antigens be made of that B cells can present?

A

Peptides or glycoproteins

87
Q

Which APCs can activate DC, macrophages or B cells? (CD4+ cells)

A

TH1 - DC
TH2 - Macrophage
TH1&2 - B cell
Any APC with MHC class II can activate any T cell with the right T cell receptor. It is the co-receptors or cytokines that accompany the MHC-TCR interaction that are disease type-specific and that will dictate whether a TH1 or TH2 response is required

88
Q

Where do peptides for MHC Class I presentation come from?

A

Intracellular (cytoplasmic) proteins
- Most of these peptides are produced from proteins as they are being synthesised (translated). This comprises both cellular and viral proteins.

89
Q

What can produce peptides for MHC Class I from digested intracellular pathogens, like bacteria and protozoa?

A

Immunoproteasome

90
Q

For MHC I and II is there discrimination between self and non-self peptides?

A

No

91
Q

Why must clonal selection in the thymus, rigorously delete T cells whose receptors can bind to self peptides on MHC molecules?

A

MHC Class I presents a lot of self-peptides

MHC I and II cannot distinguish between self and non-self peptides

92
Q

How can some exogenous pathogens avoid being detected by MHC class II presentation pathway?

A

A) Activate inflammatory responses
B) They might produce two forms of toxin:
1) Endotoxin - usually a component on the pathogen’s surface
2) Exotoxin – secreted form of toxic molecules

93
Q

What do gram-positive bacteria secrete?

A

soluble proteins called exogenous superantigens (exotoxin)

94
Q

What do superantigens secreted by gram-positive bacteria do?

A

Staphylococcal enterotoxins, toxic shock syndrome (TSS) toxin, and exfoliative dermatitis toxin

95
Q

How do superantigens work?

A

override the antigen presentation process. The superantigen binds directly to the outside of MHC class II and joins it to the variable domain (Vβ) of the T cell receptor, regardless of what peptide is in the binding groove

96
Q

The super antigen binding to the MHC class II causes what to happen?

A

Allows coreceptors to crosslink, and signal to the T cell that it has found its enemy: causing activation independent of the peptide. This means there will be indiscriminate activation of non-specific T cells, helping the bacterium to overwhelm any specific responses there might be, with irrelevant responses.

97
Q

Following activation of T cells by super antigens, what occurs?

A

The widespread activation that follows the cross-linking by a superantigen results in overproduction of pro-inflammatory cytokines, (such as TNF-α and IL-2) by T helper (TH) cells, which can lead to systemic toxicity (toxicity throughout the blood). Thus, the food poisoning induced by the toxic shock syndrome (TSS) is a consequence of cytokine overproduction induced by superantigens. It is also part of what happens during sepsis.

98
Q

What is sepsis?

A

a reaction to an infection that can lead to failure of major organs and can thus be life-threatening. The rate of mortality varies depending on severity and in patients with severe septic shock it is as high as 80%. For patients that survive sepsis, recovery can be a long process with as many as 50% of patients suffering from post-sepsis syndrome (PSS)

99
Q

What are the symptoms of Sepsis?

A

very low body temperature; reduced need to urinate; rapid pulse; rapid and shallow breathing; nausea and vomiting, diarrhoea

100
Q

What is another advantage of the bacterial strategy to produce superantigens?

A

the organism has less chance of developing an effective T cell memory response: even if the immune system does make some memory T cells, they are likely to be a mixed in with a much larger number of non-specific T cells

101
Q

How can superantigens make T-cells exhausted?

A

crosslink and overstimulate existing memory T cells, causing them to become ‘exhausted’ (the state of anergy) and thus ineffective, or even tolerant for their target.

102
Q

which classes of T cells recognise MHC Class II-bound peptide?

A

CD4 TH1 and CD4 TH2

103
Q

CD8+ T cells (cytotoxic T cells) (CTLs) recognise what?

A

MHC Class I

104
Q

What is a super antigen?

A

Class of antigen that causes non-specific activation of T-cells

105
Q

What is ancient jawless fishes’ method of preventing reinfection of a pathogen

A

VLRs still undergo somatic hypermutation with cytidine deaminases to generate diversity, resembing toll-like receptors

106
Q

By what method are soluable molecules internalised by antibodies mounted on B cells, before presentation on MHC II?

A

receptor-mediated endocytosis

107
Q

T or F, has a naive B cell has recognised an antigen with its BCR?

A

False

108
Q

T or F, A naive B cell has undergone class switch recombination of its antibody gene?

A

True

109
Q

Has a naive B cell undergone somatic hypermutation?

A

Yes

110
Q

The interaction of naïve B cells with antigen-specific CD4+ T cells (T-helper, TH, cells), causes what?

A

Their differentiation and proliferation

111
Q

What do TH2 cells promote and secrete?

A

Antibody formation and secrete IL-4, IL-5 and IL-10

112
Q

Following selection of B cells in the germinal centre, what are the two types of cells produced? Describe them

A

1) plasma cells which can secrete antibodies from the lymph node into the humoral fluids of the body
2) activated high affinity B cells, which settle down to become memory B cells.

113
Q

Give an example where B cell response does not require T cell help

A

If certain stimuli such as T-independent antigen are sent to the B cells: highly repetitive structures with a weak affinity for antibody – like bacterial (in particular) or viral (sometimes) surfaces. If enough antibodies bind to the antigen, then the B cell can become activated without T cell help

114
Q

What are the main modes of action of high affinity secreted antibodies?

A

1) opsonisation
2) neutralisation
3) complement classical pathway activation.

115
Q

How can a microbe evade surveillance from the immune system?

A

antigenic variation
- Altering its antigens once an antibody response has been established against the surface (usually) of an infectious agent

116
Q

What has streptococcus pneumoniae evolved to protect itself from antibodies generated against other strains?

A

it scapsule polysaccharide: the capsule is visible as the white halo around each bacterium - An infection with S. Pneumoniae of one capsule-type leads to a capsule-specific immunity in the infected host. This means that despite being immunised with this type of capsular antigen, you will not be protected from S. Pneumoniae infection inflicted by a bacterium that carries any of the other 89 capsule types

117
Q

What does salmonella do to evade the immune system?

A

Change their flagellin protein mid-infection

118
Q

How does Salmonella change its flagellin mid-infection?

A

When the bacterium receives signals indicating that the flagellum is not working (e.g. if it has become coated with IgA in the gut mucus) it can trigger a part of the bacterial genomic DNA to flip (an example of DNA rearrangement) switching to a new flagellin gene.

119
Q

How does neisseria gonorrhoeae use DNA arrangement to escape immune detection?

A

variation of the surface pilin protein (responsible for adherence epithelial cells)

120
Q

What is molecular mimicry?

A

critical antigens of the infectious agent have evolved to so closely resemble proteins of the host that the host doesn’t detect them as invaders but rather self-antigens. If the immune system does not manage to recognise them, this poses a major problem since it may be liable to attack the mimicked host protein, causing autoimmunity

121
Q

What are biofilms

A

Bacteria creates a matrix to protect themselves from antibiotics

Immunology and inflammation (11 decks)

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