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Health.1 > Immunology > Flashcards

Immunology Flashcards

1
Q

cells and molecules of the innate immune system
barriers and consequences of barrier dysfunction
how immune system recognises danger
neutrophils and their manipulation
acute inflammation
Anti-TNF-alpha riska and benefits of manipulating cytokine axes

A
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2
Q

purpose of the immune system 3

A

maintain tissue homeostasis
keep body free from germs, tissue healing
pre infection: minimise risk/impact - public health: sanitisation, vaccination

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3
Q

What are the two branches of the immune system?

A

innate and adaptive immune system

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4
Q

the 2 barriers in immune system?

A

mucus

epithelium

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5
Q

sentinel cells in innate immune system

A

DC
ILC
(transitional)

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6
Q

What are the characteristics of the innate immune system? And 4 parts/components

A

pre programmed
no memory
trigerred within seconds
macrophages, phagocytes, dendritic cells, cytokines

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7
Q

What is the first line defence against microorganisms? 2

A

respiratory system:
pathogen wafted up in mucus along muco-ciliary escalator
cilia produce anti microbial peptides (defensins)

GI system:
Proton pumps on epithelial: K+ in, H+ out
HCl produced to kill pathogens

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8
Q

How are these barriers to pathogens disrupted? (2)

A

physical disruption

  • IV access devices
  • catherers
  • burns
  • skin ulceration (neuropathy/DM/pressure ulcers)

pharmacological disruption
- PPI use: disrupt acidic barrier
- anti-cholingernics: decreased saliva, inc risk of dental caries
can cause urinary retention- inc risk of infection

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9
Q

What molecules compose the innate system?

A
  • cytokines
  • complement
  • CRP
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10
Q

What cells compose the innate system?

A
  • dendritic cells
  • mast cells
  • monocytes
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11
Q

What ‘sensing’ cells compose the innate system?

A

dendritic cells

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12
Q

5 steps to acute phase response?

A 
enter barrier
sentinel cells
inflammation
.. attract granulocytes from blood
acute phase response: CRP, SAA, ferritin
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13
Q

3 types of granulocytes in blood?

A

neutrophils
eosinophils
basophils

increase in infection, inflamm

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14
Q

What cells and special molecules form the adaptive immune system?

A
  • T cells
  • B cells

antibodies

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15
Q

What happens in the case of acute inflammation? 2

A

neutrophils recruited from blood

complement activated

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16
Q

PPI use and CDI (omeprazole, lansoprazole) = pharmacologically disrupt acidic barrier to infection. what may they cause?

A

norovirus

enterobacter infection

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17
Q

how is the adaptive IS different ot innate?

A

highly tailored to infection. It takes 4-6 weeks but is then able to rapidly upregulate on re-exposure. It has memory

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18
Q

What do T and B cells derive from?

A

stem cells in the bone marrow

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19
Q

Where do T and B cells mature?

A

T: in the thymus
B: in bone marrow/ spleen

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20
Q

2 types of T cells?

A
  • CD4

- CD8

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21
Q

steps in innate immunity ( case of inflammation in detail)

how is homeostatic defended?

A 
1. epithelial breach (tight junctions pull apart- cell signal)
bac enter from outside
acute inflamm
neutrophil recruited from blood
complement activated
  • selective against where energy used to defend homeostatic.
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22
Q

What are PAMPs? Where are they

A

immune system is programmed to recognise these - molecular patterns only present on potentially pathogenic organisms (PAMPs)

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23
Q

what is seen with acute inflammation?

A

Dolor
Rubor
Tumor
Calor

(swelling, heat, redness, pain)

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24
Q

what are receptors for PAMPS like?

A

compartmentalised

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25
Q

State the three main types of cells part of the innate immune system.gpd

A

dendritic cells

phagocytes (neutrophils, macrophages)

granulocytes (neutrophils, eosinophils, mast cells)

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26
Q

describe the role of: dendritic cells

in innate immunity

A
  • sentinet, sit below surface and sample environment
  • recognises threats via PAMPs/ DAMPs
  • primes adaptive immune response by travelling to lymph node
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27
Q

describe the role of: phagocytes (neutrophils, macrophages)

in innate immunity

A
  • recognise pathogen (PAMPs, DAMPs, C3b, antibody),
  • phagocytose + destroy pathogen
  • resolve inflammation
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28
Q

describe the role of: granulocytes (neutrophils, eosinophils, mast cells, basophils) in innate immunity

A

recognise pathogen,

granules contain enzymes and peptides to destroy pathogen

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29
Q

How do phagocytes work? 3

A
  1. migration
    to site which chemokines have been produced (site of inflammation)
    e.g. neutrophil migrated blood, down chemokine gradientIL8 interleukins
  2. pathogen recognition
    antibody/complement receptors. receptor interactions
  3. phagocytosis and killing
    internalisation of pathogen, respiratory burst (dependent of free oxygen radicals) trigger
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30
Q

What does an accumulation of dead neutrophils cause?

A

pus formation

too many macrophages to clear

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31
Q

What are you at risk of if you have neutropenia?

When does neutropenia occur?

A

SEPSIS

failure of neutrophils to adequately patrol mucosal barriers
undetectable, neutropenic

neutropenia usually occurs day 7-14 after high dose chemotherapy

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32
Q

What drives neutrophil production?

A

G-CSF

recombinant

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33
Q

What are the molecules of the innate immune system that cause dolor, tumor, rubor and calor?

A

mediators (susbstance P) - dolor (pain)

histamine, bradykinin, NO - local vasodilation and fluid leak - tumor (swelling, rubor (redness)

cytokines IL-1, IL-6 - calor (heat)

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34
Q

what drive RBC prodn?

A

EPO (erythropoetin)

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35
Q

basophil, neutrophil, eosinophil, monocyte (-> macrophage) are all types of what cell?

A

myeloblast

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36
Q

what drives neutrophil prodn?

A

G-CSF

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37
Q

what does common lymphoid progenitor differentiate into?

A

natural killer cell

small lymphocyte -> T and B lymph -> plasma cell

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38
Q

What is histamine?

Produced by and role

A

produced by mast cells
cause vasodilation and endothelial junction widening (increased permeability)
around perivasculature

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39
Q

What are cytokines and 3 examples? When increased

A

(IL-1, TNF-alpha, IL-6)

small mols
messengers to drive systemic response
increased DC activation

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40
Q

What is C3a and C5b? Roles?

A

complements:
C3a - acute inflammation - drives histamine release
C5b - acute inflammation - neutrophil chemoattractant

both = opsonin + enzyme

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41
Q

6 categories of acute inflammatory response? from macrophages

A
  • neutrophil influx (IL-8, C5a)
  • cytokines: IL-1, TNF-alpha, IL-6
  • lipid metabolites (prostaglanding, leukotrienes)
  • complement: C3, C5
  • fluid leak oedema
  • histamine (mast cells)
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42
Q

role of lipid metabolites (prostaglanding, leukotienes) involved in acute inflamm response?
And derived from what

A

derived from arachidonic acid

prolong oedema, cause vasodilation and bronchoconstriction

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43
Q

effect of complement in acute inflamm response?

A

chemotaxis and vasodilation

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44
Q

systemic inflamm response: what do cytokines affect? (4)

A
  • hypothalamus: IL-6, IL-1
  • liver: TNF-alpha, IL-6, IL-1
  • bone marrow
  • fat and muscle
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45
Q

systemic inflamm response: affect of cytokines on hypothalamus
(3)

A

program:

  • fever
  • rigors
  • anorexia
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46
Q

systemic inflamm response: affect of cytokines on liver?

A

acute phase proteins!

CRP, complement, transferrin, fibrinogen, SAA

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47
Q

systemic inflamm response: affect of cytokines on bone marrow?

A

increase mobilisation!

neut- bact
leuk - viral
eosin - parasite

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48
Q

systemic inflamm response: affect of cytokines on fat and muscle?

A

metabolism change: protein breakdown, cahexia

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49
Q

how is acute phase response monitored?

How’s this inhibited

A

through acute phase proteins (produced by liver)
inc in response to infection, inflamm stimuli

blocking cytokines can inhibit normal characteristics of this reponse

e.g. tocilizumab (anti-IL-6R) infections w/o fever and CRP rise

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50
Q

Complement cascade

3 pathways possible to lead to C3, C5, TCC release

A

classical pathway (antibody)
mannose binding lectin pathway
alternative pathway

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51
Q

What is the terminal complement complex?

A

C5b - C9

membrane attack complex- punches holes through cell membranes killing them

regulatory proteins stop lysis of human cells

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52
Q

Describe congenital and acquired complement deficiency.

A

congenital: deficiency in C5/6/7/8/9
acquired: eculizumab blocks C5

= membrane attack complex cant assemble properly
= susceptibility to recurrent meningococcal meningitis

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53
Q

how to prevent/treat congenital and acquired complement deficiency

A

vaccination and prophylactic antibiotics

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54
Q

characteristics of the complement cascade?
And how many arms
What can deficiency lead to

A

complex,highly regulated proteolytic cascade (C1-C9)
has 3 arms: classical, alternatice, MBL

typically a component is cleaved into a soluble fragment (a) and a bound fragment (b)

consumption of complement - associated with disease which can be measures (e..g SLE)

deficiency of complement/ regulatory proteins can -> infections, angiodema, aHUS

v expensive drugs being used now to target

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55
Q

What are the 5 ways to pharmacologically inhibit the cytokine axes?

A
  1. monoclonal antibody to block cytokine
  2. soluble (decoy) cytokine receptor
  3. monoclonal antibody to block receptor/s
  4. mimics of natural antagonist to receptor
  5. small mol inhibitors of signaling mols (inside)

cytokine receptor -> signalling mols inside -> gene expression

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56
Q

Anti-TNF-alpha benefits and consequecnes?

A

RA
nail infection
joint deformity and swelling
thin, aged skin

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57
Q

what are anti-TNF-alpha used in treatment of?

A

rheumatoid arthritis (RA)
plaque psoriasis,
ankylosing spondylitis,
ulcerative colitis (UC)

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58
Q

How does TNF-alpha work for rheumatoid arthritis? (summary of all)

A

causes endothelila activations: inc inflammation

+ve feedback on inflamm cytokine cascades

systemic effects (sarcopenia, malaise, lipid profiles, atheroma)

causes cartilage destructions via MMPs

causes bone erosion by priming osteoclasts

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59
Q

TNF-alpha inhibition drugs

A

infliximab (mAb targeted against TNF- alpha)
adalimumab
golimumab

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60
Q

What is a risk for patients on anti TNF?

A

infections:
TB common and difficult to clear entirely
latent: common with TB containes within granulomas (in macrophages)
- reactivation of latent TB

TNF-alpha = critical in maintaining control over latent infection

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61
Q

whats TNF-alpha critical in?

A

maintaining control over latent infection

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62
Q

what must all patients starting anti-TNF have to be screened for? 4

A
  1. latent TB
  2. Hep B
  3. Hep C
  4. HIV-1
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63
Q 
what can (latent) TB reactivation by TNF-alpha, form macrophages lead to?
(symptoms of TB reactivation) 4
A

malaise
weight loss
cough
haemoptysis (coughing of blood)

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64
Q

Part 2: adaptive immunity

  • function of immunoglobulin (antibodies)
  • therap uses of immunoglobulin - prophylactic, replacement, immunomodulatory
  • prodn of monoclonal antibodies and naming
A
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65
Q

What is the name of the receptor of a B cell?

A

B cell receptor, antibody or immunoglobulin

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66
Q

There are 2 types of T cells. One type is subdivided. What is this subdivision based on, and what are these subdivisions?

A
  • CD4 is subdivided (CD8 is not)
  • based on the cytokines they produce
  • Th1, Th2, Th17
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67
Q

CD8 T cells role?

A

cytotoxic killer lymphocytes.

kill virally infected cells + undertake immune surveillance

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68
Q

How does the innate immune system prime the adaptive response?

A

innate detects danger signals
antigen presenting cells sends instructions to B and T cells
CD4 T cells produce cytokines
CD8 T cells - cytotoxic
B cells produce antibodies
B cells feedback - complement, ADCC, opsonisation

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69
Q

What do B cells differentiate into?

A

plasma cells

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70
Q

What do B cells produce? (name the exact names)

A

antibodies: Ig: M, A, G, E, A

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71
Q

How does the number of human cells compare to the number of bacterial cells in our body?

A

10 trillion in a human, 100 trillion in bacteria

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72
Q

Describe the T cell receptor.

A

a and B chain

constant region and Fab (highly reactive)

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73
Q

Describe the B cell receptor

A

heavy and light chain on outside

constant region and variable region

attaches to antigen

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74
Q

What cells of the innate immune system recognise danger signals? What are these danger signals?

A
  • neutrophils
  • macrophages
  • dendritic cells
  • these danger signals are PAMPs and DAMPs
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75
Q

whats X-linked agammaglobulinaemia?

A 
no immunoglobulin
occurred in boys
recurrent bacterial:
- pneumonia,
- sinus infection
- ear infections
  • enterovirus meningitis
  • > resp failure

no B cells so cant produce antibodies!

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76
Q

Once the innate immune cells have recognised the danger signals (PAMPs, DAMPs), what cells of the adaptive system do they communicate to?

A

first antigen presenting cells have role,…. then

adaptive:T cells and B cells

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77
Q

What do the the B cells do in response to instructions from dendritic cells?

A

produce antibodies- more specific response to pathogen

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78
Q

What types of innate immune cells can recognise PAMPs?

A
  • macrophages
  • neutrophils
  • dendritic cells
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79
Q

What do CD4 T cells do in response to dendritic cell instruction- from innate danger signals?

A

release and coordinate cytokines

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80
Q

What do CD8 T cells do in response to dendritic cell instruction?

A

they’re activated - cytotoxic lymphocytes

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81
Q

What are the two regions of a T cell receptor?

A
  • constant

- variable (Fab)

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82
Q

Of the two regions of a T cell receptor, the constant region is composed of two what? What are these each called?

A
  • composed of two chains
  • one is called alpha
  • one is called beta
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83
Q

What is another name for a B cell receptor?

A

antibody/immunoglobulin

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84
Q

What is the region of antigen called that is recognised by both T cells and B cells?

A

epitope

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85
Q

How does the epitope recognised by B cells differ from that recognised by T cells? Sketch the difference between the two.

A
  • T cells recognise a linear epitope (9-15 amino acids)

- B cells recognise a soluble, conformational 3D epitope

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86
Q

Where exactly on a T cell receptor must the epitope of antigen have to bind in order to achieve a T cell response?

A

on MHC (major histocompatibility complex)

group of genes that code for proteins found or surface of cells to help immune system recognise foreign substances

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87
Q

In response to epitope binding on a T cell receptor, what are the T cell responses? 5

A
  • T cell proliferation
  • cytokine production
  • macrophage activation
  • help to B cells/ macrophages
  • cytotoxicity
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88
Q

In response to antigen binding to B cell receptor, what are the B cell responses?

A
  • antibody production

- antigen presentation

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89
Q

What must the epitope to B cell be in order to trigger the specific B cell response?

A

must be able to fit B cell receptor site

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90
Q

How are the variable regions of T and B cell receptors created?

A

through the shuffling of multiple genes

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91
Q

The variable regions of T/B cell receptors have are very diverse. What are the 3 letters describing the 3 regions of this region, and what do they each stand for?

A

V (variable)

D (diversity)

J (joining)

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92
Q

Of the variable region, how many genes are there to choose from?

A

approx 40

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93
Q

Of the diversity region, how many genes are there to choose from?

A

23

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94
Q

Of the joining region, how many genes are there to choose from?

A

6

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95
Q

Outline a typical immune response. Make sure you include the following cells: dendritic, T cells, B cells.

A
  • pathogen has PAMPs that trigger activation of dendritic cell
  • dendritic cell phagocytoses pathogen, and expresses pathogen peptide on MHC groove
  • PAMP also leads to release of costimulatory factors from dendritic cell
  • dendritic cell travels to lymph node and presents peptide to T cell
  • T cell with receptor that fits peptide is activated
  • if CD4 T cell activated, proliferations and releases cytokines (+ costin)
  • if CD8 T cell activated, travels to viral infected cells to kill them
  • soluble antigen from phagocytosis of pathogen also travels to lymph node to B cell
  • B cell that fits antigen is activated
  • B cell then communicates w T cell to produce antibody
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96
Q

Summarise a typical immune response. (alternative narrative)

A

barrier breached - pathogen enters

PAMPs detected - dendritic cells activated - takes them to lymph node

DC travels to lymph nodes, meets T cells

CD8 (cytotoxicity) and CD4 activation (cytokines produced)

in this time, soluble antigens have travelled to lmph node and B cell recognition has occured

B cells present antigen to T cells in MHC II = full activation = high affinity antibodies produced

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97
Q

What are the two molecules that can be used to present pathogen peptide to T cells?

A
  • MHC I for CD8

- MHC II for CD4

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98
Q

Where do CD4 T cells act and what do they do?

A

MHC II - peptide from pathogen held in place

different cytokines produced

  • Th1 - releases IFN-gamma
    activates macrophages against intracellular bactera
  • Th2 - releases IL-4/5
    activates eosinophils against worms and parasites
  • Th17 - releases IL-17
    uses neutrophils to target extracellular bacteria
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99
Q

Why is it useful that MHC I + peptide is recognised by CD8 T cell?

A
  • MHC I is expressed on every nucleated cell

- therefore if viral infected, CD8 can detect and kill this cell

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100
Q

What are the two things a B cell can do, once its receptor is engaged by antigen?

A
  • produce IgM antibodies
  • interact with T cells to undergo antibody class switch to more higher affinity antibodies

essentially
1. B cell receptor engaged by antigen
2. IgM production (rapid but low affinity)
AND
B cell presents antigen in MHC II to T cells (CD4)
switch to high affinity antibodies (IgG, IgA, IgE)

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101
Q

How do B cells interact with T cells? What type of T cell interacts and why?

A
  • through MHC II + peptide

- CD4’s TCR as this is the type that recognises MHC II

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102
Q

What are the characteristics of IgM? (produced initially in response to antigen engaging BCR)

A
  • released rapidly
  • large
  • low specificity
  • able to agglutinate multiple antigens at once
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103
Q

How do T cells help B cells with their function?

A
  • release cytokines

- these help B cells produce IgG, IgE and IgA antibodies

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104
Q

What are the 2 distinct chains found on antibodies?

A
  • light chain

- heavy chain

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105
Q

What are the two light chain (Fc) types?

A

kappa or lambda

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106
Q

what do the light chains do?

A

Fc- IgM, A, G, D, E

binds receptors and determines function

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107
Q

What are the functions of antibodies?

A
  • neutralise toxins
  • opsonise pathogens
  • aid in antibody-dependent cellular cytotoxicity
  • agglutinate antigens
  • activate/fix complement
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108
Q

What joins the 2 chains of an antibody?

A

a disulphide bridge

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109
Q

What part of an antibody tells you what class of antibody it is? (F… region) Which chains are these?

A
  • the Fc region

- heavy chains

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110
Q

What is an example of a toxin-producing genus?

A

Clostridium

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111
Q

How is antibodies opsonising pathogens beneficial?

A

allows for macrophages to phagocytose pathogens

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112
Q

Which antibody classes are able to activate/fix complement?

A

IgG1, IgG3, IgM

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113
Q

How do antibodies help NK cells?

A

sticks to target and facilitates cytotoxicity from NK cells

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114
Q

How do antibodies block viral entry?

A

blocks receptor-dependent viral entry

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115
Q

What are the different classes of antibody?

A

IgG - most abundant
IgA - mucosal, lung/gut
IgM - low affinity
IgE - mast cell affinity, anaphylaxis

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116
Q

why do antibodies agglutinatae to pathogens?

A

stick to them, stick them together to make immune complexes

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117
Q

What can IgE antibodies drive? Why?

A
  • anaphylaxis

- mast cells have high affinity IgE receptors

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118
Q

What can be appreciated about the different subclasses of antibodies?

A

they all have different functions

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119
Q

What fragment changes to change antibody class?

A

Fc fragment

Fab stays the same (antigen binding site)

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120
Q

What is the default immunoglobulin class?

A

IgM

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121
Q

What is the shape/structure of IgM?

A

pentameric

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122
Q

what antibody present in

  • early B cell response
  • later B cell response?
A
  • IgM

- Fc gramnet changes to IgG/ IgE/ IgA

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123
Q

How does IgM act as a link?

A
  • activates/fixes complement

- links adaptive and innate immune system

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124
Q

When an IgM antibody undergoes a class switch, what happens to each region of antibody?

A
  • constant region (Fc) changes class to refine antibody response
  • variable region (Fab) - antigen bindig. stays the same
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125
Q

Why is the adaptive system said to be highly specific?

A

T cell receptor/B cell antibody is highly specific to a pathogen’s protein

  • made clone of T cells with a receptor (or B cell with antibody)
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126
Q

Why is the adaptive system said to have memory?

A

can form memory cells from T cells (pathogen specific clones) which live long and rapidly upregulate the immune response to re-exposure

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127
Q

What are the two types of antibody/immunoglobulin?

A
  • polyclonal (diff B cells, diff specificities)

- monoclonal (same B cell, same specificity- target+func)

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128
Q

What are the 2 in vivo uses of monoclonal antibodies?

A
  • myeloma

- LPD

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129
Q

What is the ex vivo use monoclonal antibodies?

A
  • therapeutic

- diagnostic

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130
Q

What are 3 medicinal uses of monoclonal antibodies according to the region of the antibody?

A
  • conjugatation - drugs, fluorochromes
  • Fab region: target specific proteins
  • Fc region: generate specific immune functions
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131
Q

What are examples of protein targets for monoclonal antibodies? 4

A
  • cytokines
  • cytokine receptors
  • surface markers of immune cells
  • cellular growth receptors
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132
Q

What immune functions can be generated using monoclonal antibodies?

A
  • cellular depletion via ADCC - IgG1

- target blockade - IgG 4

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133
Q

How are antibodies made?

polyclonal and monoclonal?

A

antigen we want an antibody against injected into mouse…

a) spleen cells extracted
- cells fused with myeloma to form hybridoma
- monoclonal antibodies selected with best specificity

b) isolate serum
= polyclonal serum with all antibodies in

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134
Q

What is a hybridoma?

A

a fused myeloma and antibody extracted from the spleen of a mouse

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135
Q

What are two examples of monoclonal antibody blockbuster drugs?

A
  • infliximab

- etanercept

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136
Q

What conditions can anti-TNF alpha drugs be used in?

A
  • rheumatoid arthritis
  • ankylosing spondylitis
  • psoriasis
  • ulcerative colitis
  • Crohn’s disease
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137
Q

What 4 conditions can anti-CD20 B cell depletion drugs be used?

A
  • vasculitis
  • rheumatoid arthritis
  • lymphoma/leukaemia
  • multiple sclerosis
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138
Q

What is recent NHS push with a lot of monoclonal antibody drugs?

A

to move patients to less expensive, biosimilar non-patent drugs

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139
Q

What drug/monoclonal antibody targets B cells and how does it do this?

A
  • rituximab

- Fab domains target CD20 on B cells

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140
Q

What is expressed on all B cells? How long until?

A
  • CD20

- until it becomes a mature plasma cell

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141
Q

What does the Fab domain of rituximab target?

A

CD20

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142
Q

What does the Fc domain of rituximab do once Fab is bound to CD20?

A
  • interacts with Fc receptors
  • can directly kill cells expressing CD20
  • induces ADCC
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143
Q

What does ADCC stand for?

A

antibody dependent cellular cytotoxicity

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144
Q

Which store of B cells does rituximab rapidly deplete:

haemopoetic stem cells (bone marrow),
peripheral B cells (spleen/LN)
plasma cells (bone marrow)?

A

peripheral B cells (spleen/LN)

restored by stem cell pool

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145
Q

In what conditions is the rapid depletion of peripheral B cells by rituximab beneficial?

A
  • lymphoma/leukaemias

- autoantibody producing

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146
Q

What is the dangerous side effect of rituximab?

A
  • due to B cells depletion, body becomes unable to make antibodies
  • e.g. for SaRS-CoV-2, patients were unable to make antibodies against virus
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147
Q

What molecule of the adaptive immune system can be used therapeutically?

A

immunoglobulins

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148
Q

Where is therapeutic immunoglobulin obtained from?

A

the plasma of blood donors

  • expensive
  • limited resource
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149
Q

What happens to the plasma in order to obtain therapeutic immunoglobulin?

A

it’s fractionated, nanofiltered + pasteurised then IgG is isolated

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150
Q

What is the main antibody class found within therapeutic immunoglobulin?

A

IgG

no IgM, v little IgA

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151
Q

immunoglobulin products are not G_ and largely i_?

A

NOT generic

largely interchangeable.

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152
Q

What is there a theoretical risk of with immunoglobulin products?

A

BBV transmission

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153
Q

How can immunoglobulin be administered?

A
  • IV
  • IM
  • SC
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154
Q

Why is it difficult to obtain immunoglobulin products in the UK?

A
  • it’s not produced from UK blood donors due to new variant Creutzfelt-Jakob disease (nvCJD)
  • supply issues in the UK

subject to strict evidence-based guidelines

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155
Q

clinical uses of immunoglobulin (IVIG)

What is the use of immunoglobulin products when in the context of e.g. chickenpox?

A
  • prophylaxis (passive immunity)

- e.g. used as post-exposure prophylaxis (VZIG) against chickenpox

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156
Q

How are immunoglobulin products obtained for prophylactic use?

A
  • a population’s blood donors are taken
  • out of the blood donor, an individual has high % of IgG antibody against pathogen
  • this is purified
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157
Q

How are immunoglobulin products used in the context of mothers planning to become pregnant?

A

(anti-Rhesus D) used prophylactically to prevent Rhesus negative mother from making antibodies to Rhesus positive antigens on baby’s RBC surface

stop risk of haemolysis in subsequent pregnancy

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158
Q

What is the most common use of immunoglobulin products?

A

as replacement therapy for those with antibody deficiencies

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159
Q

What is the dose of immunoglobulins as a replacement therapy?

A

0.4-0.6g/kg/m

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160
Q

How are immunoglobulins for replacement use obtained?

A
  • general population will be exposed to lots of pathogens
  • a pool of polyclonal immunoglobulin will be obtained
  • this will be supplied to antibody-deficient individual = get passive protection against pathogens
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161
Q

Why are those needing antibody replacement on lifelong treatment?

A

the pool of polyclonal antibody mainly contains IgG, (no IgM/A) which has a short half-life (6 weeks)

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162
Q

What are the two forms of antibody deficiency?

A
  • primary

- secondary

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163
Q

What is the cause of primary antibody deficiency?

who does it mainly affect?

A

usually genetic

  • no B cells
  • failure of T cell help
  • failure to class switch

affects young people

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164
Q

Which antibody deficiency is more common and who does it affect?

A

secondary

any age, most likely old

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165
Q

What are the causes of secondary antibody deficiency? Which is the most common?

A
  • B cell depletion (due to e.g. drugs) COMMON
  • GI loss of IgG
  • Renal loss of IgG
  • lymphoid malignancy
  • immunosuppression
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166
Q

What infections are common for those who have antibody deficiencies?

A
  • sinus infections
  • ear infections
  • pneumonia
  • conjunctivitis
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167
Q

Which therapeutic use of immunoglobulin is subject to strict DoH guidelines?

A

immunoglobulin as an immunomodulatory product

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168
Q

What are the 3 therapeutic uses of immunoglobulins?

A
  • prophylaxis
  • immunoglobulin replacement
  • immunomodulation
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169
Q

What is the dosage of an immunoglobulin used as an immunomodulatory product?

A

1-2g/kg

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170
Q

How do immunoglobulins used as immunomodulatory products work?

A
  • activate inhibitory Fc receptors
  • induce T regulatory cells
  • modulates inflammatory cytokines
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171
Q

The immune system is programmed to recognise PAMPs. What are these?

A

pathogen-associated molecular patterns - certain features associated with pathogens found nowhere else in nature so the human immune system recognises these as a threat

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172
Q

Where are the receptors for PAMPs located? Why?

A
  • compartmentalised beneath the epithelial surface (so form 2nd line of defence)
  • prevents overstimulation
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173
Q

What does TLR5 recognise?

A

(toll-like receptor 5 detects) flagellin, a polymer found within the flagellum - a structure enabling bacteria to move

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174
Q

What does TLR4 recognise?

A

lipopolysaccharide (LPS) - a sugar found in Gram-negative bacteria cell wall

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175
Q

What does MBL recognise?

A

(mannose binding lectin) detects unshielded mannose residues found in the cell wall of some bacteria

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176
Q

What does TLR9 recognise?

A

CpG motives - cytosine followed by an unmethylated guanine, a pattern more characteristic of pathogenic nucleic acid than human

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177
Q

What are the roles of dendritic cells?

A
  • sentinel cells: recognise threats

- prime adaptive response by travelling to lymph node

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178
Q

How do dendritic cells recognise threats?

A

via their receptors, which will bind to PAMPs or D(damage)AMPs

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179
Q

What trigger phagocyte migration?

A
  • a pathogen that has breached an epithelial surface may have complement (C3b) or an antibody attached to its surface
  • its breach will cause acute inflammation, which will trigger the release of the chemokine IL8
  • the phagocyte will then migrate down the chemokine gradient
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180
Q

How will a phagocyte recognise a pathogen?

A

it will bind to either complement (C3b) or antibody attached to the pathogen’s surface

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181
Q

How does a phagocyte phagocytose a pathogen and kill it?

A

it will internalise it, then kill it which is triggered by respiratory burst (dependent on the generation of free O radicals)

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182
Q

What is neutropenia?

A

low neutrophil count

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183
Q

What is the purpose of titrating a blood cancer chemotherapy regimen?

A
  • to induce neutropenia

- theory is that by killing sufficient neutrophils, you’ve also killed sufficient cancer cells

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184
Q

What is neutrophil production boosted with following an induced neutropenia?

A

G-CSF

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185
Q

What cards are chemotherapy patients given? Why?

A
  • warning cards
  • indicate that if patient gets a fever, need immediate antibiotic treatment
  • due to the induced neutropenia
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186
Q

What are the common types of infections neutropenic individuals will acquire?

A
  • invasive extracellular bacterial infections
  • invasive fungal infections
  • these are due to lack of surveillance at the mucosal barrier
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187
Q

How does G-CSF work?

A

it’s a recombinant exogenous cytokine that will boost the differentiation of neutrophils from the bone marrow

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188
Q

What substance is released that causes the pain (dolor) of inflammation?

A

substance P - a neuropeptide that induces pain (can be released by hitting yourself on accident too)

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189
Q

What substances are released that cause the swelling (tumor) and redness (rubor) of inflammation?

A
  • bradykinin
  • histamine
  • NO
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190
Q

What molecules do macrophages release during the acute inflammatory response?

A
  • cytokines

- lipid metabolites

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191
Q

What cells are involved in the acute inflammatory response?

A
  • macrophages
  • neutrophils
  • mast cells
  • complement molecules
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192
Q

What do the cytokines released by macrophages during the acute inflammatory response do locally?

A
  • IL-8

- causes neutrophil influx

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193
Q

What do the cytokines released by macrophages during the acute inflammatory response do systemically?

A
  • drive the systemic response to inflammation

- increase dendritic cell activation

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194
Q

What do the lipid metabolites released by macrophages during the acute inflammatory response do?

A
  • prostaglandins, leukotrienes derived from arachidonic acid
  • prolong oedema
  • cause vasodilation
  • cause bronchoconstriction
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195
Q

What does the histamine released by mast cells during the acute inflammatory response do?

A
  • causes vasodilation

- causes endothelial cell-junctional widening leading to increased permeability

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196
Q

What systemic inflammatory cytokines are released to the liver and what do they do?

A
  • IL-6, IL-1, TNF-alpha
  • cause acute phase response proteins to be released to contain infection in liver
  • acute phase proteins include: transferrin, fibrinogen, CRP
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197
Q

What do systemic inflammatory cytokines released to the bone marrow do?

A
  • increase mobilisation of cells to site of infection
  • neutrophils: bacterial
  • leukotrienes: viral
  • eosinophils: parasitic
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198
Q

What do systemic inflammatory cytokines to the fat and muscle do?

A
  • increase muscle breakdown in state of cachexia

- change metabolic programme

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199
Q

During infection, what liver proteins decrease?

A
  • transferrin
  • albumin
  • this is because the liver is dedicated to producing other proteins
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200
Q

What can we do therapeutically to interfere with the changes in liver protein levels during infection/inflammation? What is an example?

A
  • block cytokines
  • this will inhibit the normal response
  • tocilizumab blocks cytokine IL-6, so no CRP rise or fever (can block the signs of infection)
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201
Q

What do C3b and C5b act as?

A

opsonins and enzymes

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202
Q

What do all 3 complement pathways descend on? What complement molecules compose this?

A

the terminal complement complex (TCC) (ring shaped molecule) - composed by C5b-C9

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203
Q

What does the TCC do?

A

punches holes through cell membranes killing the cell (complement-mediated lysis)

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204
Q

What bacteria are susceptible to the TCC?

A

Neisseria menigitidis

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205
Q

How are human cells protected from the TCC?

A

regulatory proteins stop lysis of human cells

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206
Q

What are 2 types of complement deficiency?

A
  • congenital

- acquired

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207
Q

What does complement deficiency make you susceptible to?

A

meningococcal meningitis

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208
Q

What 2 fragments are complement molecules cleaved into?

A

a soluble fragment (a) and a bound fragment (b)

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209
Q

Which cytokine was discovered to be an important one in driving the pathology of rheumatoid arthritis?

A

TNF-alpha

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210
Q

How does TNF-alpha affect bone in rheumatoid arthritis?

A

primes osteoclasts to cause bone erosion

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211
Q

How does TNF-alpha affect endothelium in rheumatoid arthritis?

A

increases endothelial activations, leading to inflammation

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212
Q

How does TNF-alpha affect cartilage in rheumatoid arthritis?

A

causes joint lining to produce proteases that break down cartilage

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213
Q

How does TNF-alpha affect cytokines in rheumatoid arthritis?

A

have positive feedback on the inflammatory cytokine cascades

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214
Q

What was the first anti-TNF alpha drug produced?

A

Infliximab (Remicade) - chimeric (mouse/human) antibody

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215
Q

What are examples of fully humanised anti-TNF drugs?

A

adalimumab (Humira) and golimumab (Simponi)

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216
Q

What anti-TNF drug is a soluble receptor protein?

A

etanercept (Embrel)

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217
Q

What were the 2 positive outcomes of the clinical trial of an anti-TNF drug?

A
  • decrease in the number of swollen joints

- CRP decreased and stayed down for week 8. inflammation reduced

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218
Q

What are latent tuberculosis (TB) infections?

A

where the tuberculosis infection is kept within macrophages within granulomas in the lungs - TNF-alpha plays a role in maintaining this

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219
Q

Patients who were treated with anti-TNF were followed up for 20 years and some developed active tuberculosis infections. Why is this?

A
  • they may have had latent TB infections
  • the anti-TNF drug would have removed the TNF that was containing the TB infection within the granuloma of the lungs
  • this would lead to reactivation of the latent TB
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220
Q

Part3: vaccination
Overview of immunological memory
How vaccination can exploit immunological memory to generate long lasting protection
Different types of vaccines - their advantages and disadvantages
Role of the pharmacist in vaccination

A
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221
Q

4 roles of pharmacist in vaccination

A

clinical advice

  • who can/cant have vaccine
  • who not to give to and when

demand management/prioritis
- e.g. Hep B vaccine shortage

public health + commun
- why you should have it

service delivery and saftey monitoring

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222
Q

Vaccination involves the administration of what material?

A

antigenic material

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223
Q

What does antigenic material stimulate in human beings?

A

an immune response that develops the adaptive immune system (adaptive immunity to a pathhogen)

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224
Q

What is vaccination?

A

administration of antigenic material to stimulate an immune response that develops the adaptive immune system and immunological memory

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225
Q

What aspect of the immune system is exploited by vaccines?

A

immunological memory

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226
Q

What is meant by a ‘naive immune cell’?

A

an immune cell that has matured but not yet been exposed to antigen

227
Q

Which naïve immune cells can go on to develop immunological memory?

A
  • CD4 T cells (CTL)
  • CD8 T cells (Th)
  • B cells
228
Q

What process occurs in order for a naive immune cell to develop immunological memory?

A

clonal expansion + contraction

229
Q

What is meant by clonal expansion + contraction?

A

T and B cells are stimulated to proliferate, some die off, and some survive and go on to develop immunological memory

230
Q

How do the affinities between IgG and IgM antibodies compare?

A
  • IgG is high affinity

- IgM is low affinity

231
Q

Sketch a graph showing the response from IgM antibody and IgG antibody comparatively. Label the axes, the point of primary inoculum and the re-exposure to the inoculum.

A

…

232
Q

Memory responses from the immune system are said to be…

A

qualitatively and quantitatively superior

233
Q

Name the 4 different types of vaccine.

A
  • live attenuated
  • killed/inactivated
  • toxoid
  • subunit
234
Q

What is meant by an attenuated pathogen?

A

one that is still able to replicate but not cause full blown disease in individual

235
Q

What are examples of live attenuated vaccines?

A
  • intranasal immune virus
  • BCG
  • MMR
  • VZG
  • Zostervax
236
Q

How has the intranasal flu vaccine been engineered?

A

the virus can only replicate at 34 degrees which is the temperature inside the nose

237
Q

Why are live attenuated vaccines useful?

A

they produce strong immune responses

238
Q

What patient group are live attenuated vaccines contraindicated in?

A

immunocompromised !!

239
Q

Patients on what class of medications cannot have live attenuated vaccines?

A

immunosuppressants

240
Q

State some examples of immunosuppressant medications.

A
  • azathioprine
  • ciclosporin
  • chloroquine
  • hydroxychloroquine
  • prednisolone
  • methotrexate
241
Q

What type of vaccine is: rotavirus, Zostervax, VZV, BCG, MMR?

A

live attenuated

242
Q

Name some examples of killed/inactivated vaccines.

A
  • hepatitis A
  • SALK polio
  • hep B
  • rabies
243
Q

Why are killed/inactivated vaccines useful?

A

they produce a potent immune response

244
Q

What patient group are killed/inactivated vaccines safe in?

A

immunocompromised

245
Q

What is the state of pathogen in killed/inactivated vaccines? How is this achieved?

A
  • unable to replicated

- inactivated via heat, radiation or chemicals

246
Q

What type of vaccines are hepatitis A, SALK polio, and rabies vaccines?

A

inactivated/killed

247
Q

What is found within a toxoid vaccine?

A

toxins produced by pathogens

248
Q

What are examples of toxoid vaccine?

A
  • diphtheria
  • tetanus
  • DTP (has other components too)
249
Q

How does a toxoid vaccine stimulate an immune response?

A

the immune response needs to produce antibodies to neutralise the toxin
this is the vaccine target

250
Q

What is DTP?

A

a vaccine combined with heat killed pertussis, diphtheria toxin and tetanus toxin

251
Q

What types of vaccine are tetanus, diphtheria and DTP?

A

toxoid vaccines

252
Q

What is the target of the immune response within a subunit vaccine?

A

the subunit of a virus e.g. a surface protein, polysaccharide or polysaccharide conjugate which can be made by recombinant protein tech

253
Q

What are examples of subunit vaccines?

A
  • hepatitis B
  • pneumococcal
  • meningococcal C
  • HiB
  • HPV
254
Q

What type of vaccines are hepatitis B, pneumococcal, meningococcal C, HiB, and HPV?

A

subunit vaccines

255
Q

What are the brand names of the meningococcal vaccine?

A
  • Prevenar

- Pneumovax II

256
Q

What aspect of immunity do vaccines attempt to replicate?

A

the correlates of natural immunity to pathogens e.g. encapsulated bacteria such as S. pneumoniae

257
Q

What protection does S. pneumoniae have against the immune system?

A

polysaccharide cell wall

  • stops complement binding and neutrophil killing
258
Q

How do we know that the natural correlates of bacteria are antibodies?

A

those with antibody deficiencies are unable to mount a sufficient immune response to encapsulated bacterial infections

259
Q

What do the antibodies bound to S. pneumonia do? What are vaccines designed to facilitate?

A
  • enhance neutrophil killing by opsonisation

- designed to facilitate the production of anti-polysaccharide antibodies

260
Q

What are the two types of B cell responses?

A
  • T-cell dependent

- T-cell independent

261
Q

antibodies target polysacc capsule and do whta?

A

bind and help activate complement cascase and facilitate neutrophil killing via opsonisation

262
Q

What type of B cell response recognises conformational protein epitopes (e.g. shapes)?

A

T-cell dependent

need T cell help to fully activate

263
Q

What type of B cell response recognises repetitive pattern of sugars (can cross link the B receptors)?

A

T-cell independent

can do so without and produce antibody

264
Q

What is an example of a macromolecule from a pathogen that has lots of repetitive patterns?

A

polysaccharide

265
Q

How is the repetitive pattern of polysaccharide recognised by B cell receptors?

A

the repetitive pattern is able to crosslink multiple B cell receptors

266
Q

What are examples of encapsulated bacterial infections?

A
  • pneumonia
  • meningitis
  • conjunctivitis
  • sinusitis
  • otitis
267
Q

How does age compare between the two types of B cell response?

A

T-cell dependent: any age

T-cell independent: only efficient after 2 years of age !!

268
Q

How does antibody quality compare between the two types of B cell response?

A

T-cell dependent: high affinity antibody

T-cell independent: low affinity antibody

269
Q

How does class-switching compare between the two types of B cell response?

A

T-cell dependent: yes

T-cell independent: limited

270
Q

How does immunological memory compare between the two types of B cell response?

A

T-cell dependent: yes

T-cell independent: limited

271
Q

How does antigen-type recognised compare between the two types of B cell response?

A

T-cell dependent: protein

T-cell independent: carbohydrate, lipid, nucleic acid

272
Q

What age groups do encapsulated bacterial infections affect? Why?

A
  • the very young and very old
  • in the very young, the T-cell independent response is not very efficient yet
  • this response is used to recognise polysaccharide in encapsulated bacteria and produce antibodies`
273
Q

What does Pneumovax II (PPV23) contain?

A

capsular polysaccharide derived from 23 serotypes of diff pneumococcal bacteria

274
Q

What does Prevenar (PCV13) contain?

A

capsular polysaccharide derived from 13 diff serotypes of pneumococcal bacteria CONJUGATED TO carrier protein + adjuvant

275
Q

What age group is Pneumovax II (PPV23) used in? Why?

A
  • > 65 and >2 years if at clinical risk
  • able to mount a T-cell independent response to the polysaccharides within the vaccine that normally make up the bacteria’s cell wall (subunit)
276
Q

How does Prevenar work? (hint: what type of B cell response?)

A
  • generates T cell dependent response
  • APC presentation to T cell, leading to B cell activation
...
joined to carrier protein, picked up
B cell activation + antigen presentation to cognate T cell
< - ->
APC with antigen presentation to T cell
277
Q

What age group is Prevenar (PCV23) used in? Why?

A
  • routine immunisation at 2, 4 and 12 months of age
  • able to mount sufficient T-cell dependent B cell response

ligating B cell

278
Q

Adjuvants help the local release of what?

A

chemokines and cytokines

to augment immune response to protein target

279
Q

What do adjuvants facilitate?

A

the activation of recruitment of APCs

280
Q

What do adjuvants depot?

A

antigen

281
Q

What do adjuvants do? (3)

A
  • help local release of cytokine and chemokine
  • facilitate recruitment of APCs
  • antigen depot
282
Q

What are the two types of adjuvants?

A
  • live attenuated

- artificial

283
Q

Why are live attenuated adjuvants naturally immunogenic?

A

they contain PAMPs

284
Q

What are 2 examples of artificial adjuvants?

A
  • alum

- emulsified squalene

285
Q

What is alum? artificial adjuvant

A

hydrated double sulphate salt of aluminium

286
Q

What is emulsified squalene? artificial adjuvant

A

naturally occurring compound found in shark liver oil, olives, vegetable oils, rice bran

287
Q

why artifical adjuvants better?

A

= more potent immune repsosne

= long lasting immunity ☺

288
Q

What is herd immunity?

A

when enough of the population is vaccinated against a pathogen

289
Q

What factors affect herd immunity?

A
  • susceptibility of hosts
  • nasopharyngeal carriage
  • vaccine effectiveness
  • coverage rates
  • force of transmission
  • crowding
290
Q

If 1 person with measles spent time with 100 unvaccinated people, how many would: a) get infected b) get infected w complications and c) be unaffected

A
  • 90 would get infected
  • 7 would get infected w complications
  • 10 people would be unaffected
291
Q

How many people will a single person with measles infect on average in a susceptible population?

A

12

292
Q

How does effectiveness compare between vaccines? Give an example.

A
  • some vaccines can be more effective than others

- tetanus>pneumococcal

293
Q

Apart from efficacy, what else can vary between vaccines when considering vaccine effectiveness? Give an example.

A
  • the length of effectiveness

- e.g. pertussis needs a catch-up vaccine

294
Q

At what percentage coverage are vaccination programmes most effective? Why?

A
  • > 90%

- the pathogen prevalence is significantly reduced

295
Q

A percentage vaccine coverage lower than what is ineffective? Why? Give two examples.

A
  • <90%
  • the pathogen is still present and can be transmitted
  • Nigeria polio virus, MMR uptake in UK
296
Q

What are the major proteins found in influenza A?

A
  • haemagglutinin (H)

- neuraminidase (N)

297
Q

What combination of influenza A protein was responsible for the swine and Spanish flu?

A

H1N1

298
Q

What combination of influenza A protein was responsible for the bird flu?

A

H5N1

299
Q

What is the evasive mechanism that means we need a flu vaccine every year?

A

antigenic drift

300
Q

What evasive mechanism can cause a pandemic by entering an animal host? Use the example of influenza A.

A
  • antigenic shift
  • if two strains (one human, one animal) infect an animal, that could generate a new strain
  • nobody will have immunity to this new strain
301
Q

What patient groups receive the annual flu vaccine?

A
  • healthcare workers
  • > 65 years old
  • > 2 years old
  • pregnant
  • at risk groups (asthmatics, COPD, DM, etc.)
302
Q

Flu vaccines have a protein found in a substance people have an allergy to. What is this protein, and can vaccines be safely administered to patients with this allergy? Why or why not?

A
  • ovalbumin
  • yes, if no history of severe anaphylaxis due to the low ovalbumin content
  • if history of anaphylaxis, must be done in hospital setting
303
Q

annual flu vaccine- caution with what patients?

A

egg allergic patients

- most can be vaxxed safely in general practive woth low ovalbumin content vaccs unless prev anaphylaxis to egg

304
Q

What is the key component of SARS-CoV-2 that mediates its infection? How does it do this?

A
  • spike protein

- permits entry into respiratory epithelium by binding to ACE2

305
Q

What do COVID-19 vaccines target?

A

the spike protein on SARS-CoV-2

306
Q

What do the Pfizer and Moderna vaccine contain?

A

mRNA for the spike protein

307
Q

How do the Pfizer and Moderna vaccines work?

A
  • the mRNA for the spike protein from the vaccine is translated by ribosomes in the deltoid muscle
  • macrophages then pick up the spike protein and present it to the adaptive immune system
308
Q

What does the Astrazeneca virus contain?

A

DNA coding spike in modified chimpanzee adenovirus

309
Q

How does the AstraZeneca virus work?

A

the DNA is transcribed and translated into spike protein

310
Q

What patient vaccine history should be considered before giving vaccines?

A
  • any previous vaccination
  • any previous reaction to vaccine (rare)
  • any allergy
  • any immunosuppression or whether they’re immunocompromised
  • any close contact to an immunocompromised as live vaccines can shed
311
Q

Why is vaccine history important to consider for the pneumococcal vaccines?

A

PPV23 cannot be given within 5 years as it can reduce the response

312
Q

What is the main information source to consult for vaccines?

A

the green book

313
Q

Part 4: Autoimmunity

Basis of immune tolerance
Immunopathogenesis of autoimmune disease
Basis of treatment of autoimmune disease
Drugs predisposing to autoimmunity

A
314
Q

Where do T cells come from?

A

derived from the bone marrow

315
Q

What is the precursor of a T cell?

A

a myeloid cell

316
Q

What stem cells are harvested for bone marrow transplants (BMT)?

A

CD34 haemopoetic stem cells

317
Q
  1. After differentiating in the bone marrow, where do T cell precursors go?
A

to the thymus to mature

318
Q
  1. After maturing in thymus, where do T cells go?
A

to the lymph node

the naive CD4 and CD8 T lymphocytes

319
Q

T cells only recognise antigen when presented…

A

in the context of MHC

i.e. antigen presenting cell with MHC and antigen attached
connect to
T cell receptor on T cell

320
Q

how do stem cells become matute cells i.e. steps they change to

A

stem cells -> multipotent progenitor cells -> comitted precursor cells -> mature cells

321
Q

How do TCR of CD4 cells recognise peptide?

A

recognise peptide presented by _professional APC (B cells, DC, macrophages) _ in the context of MHC II

322
Q

How do TCR of CD8 cells recognise peptide?

A

recognise peptide presented by nucleated cells in the context of MHC I

323
Q

What class of MHC is presented on all nucleated cells? What T cell recognises peptide bound to it?

A
  • MHC I

- CD8

324
Q

What class of MHC is presented on professional APCs? What T cell recognises peptide bound to it?

A
  • MHC II

- CD4

325
Q

What are examples of professional APCs?

A
  • dendritic cells
  • B cells
  • macrophages
326
Q

MHC is said to be highly…

A

polymorphic

327
Q

What does HLA stand for?

A

human leukocyte antigen

328
Q

What 3 proteins make up MHC I?

A

HLA-A, HLA-B, HLA-C

329
Q

What 3 proteins make up MHC II?

A
  • HLA-DP
  • HLA-DQ
  • HLA-DR
330
Q

How many alleles are there for the proteins that make up MHC (both classes)? Why?

A
  • 6
  • 1 allele from mother, 1 from father
  • 3 diff HLAs for each MHC class
331
Q

With tissue typing, what must be ensured regarding the donor and the recipient?

A

the haplotype matches between the two

332
Q

What geographical correlation is found for a specific MHC II allele? State the allele, and the correlation.

A
  • HLA-DR4

correlation between autoreactivity for this allele and autoimmune conditions:
type 1 diabetes,
rheumatoid arthritis
multiple sclerosis

333
Q

The cost of diversity is…

A

autoreactivity

334
Q

What is the estimated recognition capacity of 1 TCR?

A

can recognise >1 000 000 peptides

335
Q

_ + _ = autoimmune disease.

A

autoreactivty
+
environmental/genetic/epigenetic factors
= autoimmune disease

336
Q

_ alone is not enough for autoimmune disease.

A

Autoreactivity alone is not enough for autoimmune disease

337
Q

How do we know that autoreactivity is not enough for autoimmune disease?

A

20% of health individuals in a study had titre positive for ANA yet don’t have autoimmune disease

338
Q

What has to happen before we get an autoimmune disease?

A
  • autoreactivity

- other checks need to break

339
Q

ANA link with age?

A

prevalence increases with age

340
Q

What is central tolerance and where does it occur?

A
  • the thymus

- thymic epithelial cells delete autoreactive T cells

341
Q

What special cells help in positive thymic selection?

A

thymic cortical epithelial cells

342
Q

What do thymic cortical epithelial cells have on their surface?

A

MHC II

343
Q

What are the 2 stages of thymic central tolerance?

A
  • positive selection

- negative selection

344
Q

positive thymic selection: what is being checked for between MHC II and TCR?

A

is there enough contact between them to allow binding?

if so: T cell gets survival signal and can progress ☺

345
Q

What is necessary for positive thymic selection?

A

the progenitor T cell must be able to bind to the MHC II of the thymic cortical epithelial cell with its TCR

346
Q

What is the result of positive thymic selection?

A

survival signals are sent from the thymic cortical epithelial cell to the progenitor T cell

347
Q

Following positive thymic selection, where do progenitor T cells go?

A

to the thymus medulla

348
Q

Where does negative thymic selection occur?

A

thymic medulla

349
Q

What special cells help in negative thymic selection?

A

thymic medullary epithelial cells

350
Q

What do these special cells (-ve selection) have on their surface?

A

MHC II + self-antigen/peptide

351
Q

When is a T cell killed (and potentially autoreactive cell is purged) during negative thymic selection?

A

if it binds too tightly to the MHC II (with TCR) + self-antigen/peptide on the surface of the thymic medullary epithelial cell

352
Q

When is a T cell considered safe in negative thymic selection? What happens to it?

A
  • when it binds loosely to MHC II + self-peptide presented on the thymic medullary epithelial cell
  • it can leave the thymus and enter the circulation
353
Q

When does a T cell have the potential to produce a regulatory T cell?

A

when it binds neither tightly nor loosely to MHC II + self-antigen/peptide presented by thymic medullary epithelial cells

354
Q

Summarise the possible outcomes of negative selection.

A

The progenitor T cell could:

  • bind too tightly to thymic MHC II + self-peptide = killed/deletion
  • bind loosely to MHC II + self-peptide, = leaves thymus, released to periphery (circul)
  • bind neither too loosely or too tightly = potentially becomes a regulatory T cell
355
Q

What steps occur before positive selection (in cortex)?

autoimmunity

A
  • T cell progenitor/precursor enters thymus

- TCR arranged B chain first = rearranged B chain (VDJ)

356
Q

Where in the thymus does positive selection occur?

A

the thymus cortex

357
Q

What occurs in positive selection?

autoimm

A
  • the rearranged beta chain is bound to a generic alpha chain + tested to see whether it can bind to MHC II on the thymic cortical epithelial cell
358
Q

What happens involving the TCR if a T cell successfully passes positive selection?

A

alpha chain is also rearranged to produce a complete TCR

359
Q

What happens in negative selection in medulla?

autoimm

A

progenitor T cell’s receptor is tested to see how tightly it binds to MHC II + self-peptide

360
Q

Where does a T cell go once it passes negative selection?

A

enters the circulation

361
Q

Summarise what central tolerance in the thymus.

autoimm

A
  • progenitor T cell enters thymus cortex
  • beta-chain’s VDJs are rearranged and paired to generic alpha chain
  • TCR tested to see if it can bind to MHC II on thymic cortical epithelial cell
  • if it can, alpha chain VDJ genes rearranged to produce complete TCR
  • T cell then enters medulla
  • TCR tested to see if it binds too tightly to MHC II + self-peptide
  • if binds tightly, naïve T cell released into circulation
362
Q

When a CD4 T cell arrives at the lymph node, what can it do?

A

differentiate into different Th cells:

Th1/2/7

363
Q

What does a CD4 cell that differentiates to a Th1 cell release? What immune cell does this activate and what does it do?

A
  • releases IFN-gamma

- activates macrophage against intracellular bacteria

364
Q

What does a CD4 cell that differentiates to a Th2 cell release? What immune cell does this activate and what does it do?

A
  • IL-4/5

- activates eosinophils against worms and parasites

365
Q

What does a CD4 cell that differentiates to a Th17 cell release? What immune cell does this activate and what does it do?

A
  • IL-17

- activates neutrophils against extracellular bacteria

366
Q

What happens when a CD8 T cell enters the lymph node?

A

recognises MHC I on virally-infected cells and kills them

367
Q

CD8 killing virally infected cells is an…

A

MHC-I dependent process

368
Q

What do natural killer cells do?

A

kill virally infected and tumour cells

that have lost expression of MHCI ‘missing self’

369
Q

How do virally infected and tumour cells hide from CD8?

A

downregulate MHC-I on their surface

370
Q

What class of cytokines (and what of them specifically) help upregulate MHC I on cell surfaces?

A
  • interferons

- IFN-alpha and IFN-beta

371
Q

What T cells regulate peripheral tolerance?

A

regulatory T cells

372
Q

What do regulatory T cells have on their surface?

A
  • potentially autoreactive TCR
  • FOXP3+
  • CD25
373
Q

What do regulatory T cells upregulate when their receptor is engaged?

A

immunosuppressive molecules

374
Q

What is an example of an immunosuppressive molecule and what does it do?

A
  • CTLA-4

- strips APCs of CD80 and CD86 (costimulatory factors) reducing their ability to activate T cells

375
Q

What are CD80 and CD86?

A

costimulatory factors

376
Q

What do regulatory T cells directly do and how?

A
  • directly kill other immune cells

- Granzyme/perforin dependent process

377
Q

What do T regulatory cells produce?

give 2 examples

A

immunosuppressive cytokines

  • TGF-beta
  • IL-10
378
Q

What is CTLA-4?

A

an immunosuppressive molecule that suppresses APCs ability to activate T cells

379
Q

What does IL-2 do?

A

necessary for expansion of T cells

380
Q

What are IL-10 and TGF-beta?

A

immunosuppressive cytokines

381
Q

Summarise the actions of centrally generated T regulatory cells

A
  • release immunosuppressive molecules (CLTA-4) which act on APCs
  • release immunosuppressive cytokines (IL-10, TGF-beta)
  • directly kill other immune cells (Granzyme/perforin-dependent process)
  • upregulate CD25 to deprive T cells of IL-2, necessary for expansion
382
Q

Normally, an APC will recognise and present pathogen peptide. What happens that can trigger the peripheral generation of a T regulatory cell?

A

an APC accidentally expressing a self-antigen and presenting that in the context of pMHC

383
Q

What happens when an APC accidentally presents self-antigen (without DAMPs and PAMPs)?

A

if a naive CD4 T cell recognises it, it can be induced to become a peripherally generated regulatory T cell

(sim job to thymic T cells)

384
Q

What are two ways to describe the way T regulatory cells are generated?

A
  • thymic generated (bind not too tightly or not too loosely to self-antigen on MHC II)
  • peripherally generated (by accidental presentation of self-antigen by APC in context of pMHC)
385
Q

Autoimmune disease is _, self-directed _ caused by autoreactive _ and _ _ responses, ultimately arising from a _ of _ _ to self _.

A

autoimmune disease is inappropriate, self-directed inflammation caused by autoreactive B and T cell responses, ultimately arising from a failure of immune tolerance to self-antigens.

386
Q

What are Witebsky’s postulates?

A

a set of criteria to define autoimmune conditions

387
Q

Witebsky’s postulates require direct evidence of what?

A

autoantibody or autoreactive T cells that can transfer disease (e.g. transplacentally)

388
Q

Give an example of direct evidence provided for Witebsky’s postulates.

A

A pregnant mother with Grave’s disease can pass on her autoantibodies to her baby which will have the disease for the half-life of the autoantibodies

389
Q

Witebsky’s postulates require indirect evidence following what?

A

reproduction of disease in an animal model

390
Q

Witebsky’s postulates require clinical clues from…

A

disease presentation, genetics (e.g. strong MHC association) and response to immunosuppressive treatment

391
Q

What is required within Witebsky’s postulates?

A
  • clinical evidence of autoreactive T cells or autoantibodies that can transfer disease (e.g. transplacentally)
  • indirect evidence following reproduction in an animal model
  • clinical clues from disease presentation, genetics (e.g. strong MHC association), and response to immunosuppressive treatment
392
Q

Why are clinical clues from the response to immunosuppressive treatment criteria included in Witebsky’s postulates?

A

all autoimmune diseases should respond to immunosuppressive treatment

393
Q

Autoimmune disease is caused when what goes wrong?

A

central and peripheral tolerance

5-7% adults affected
2/3rds women

394
Q

What are the 3 categories of things that can break tolerance?

A
  • genes
  • environment
  • immune regulation
395
Q

Give examples of gene-related factors that can break tolerance.

A
  • MHC II (alleles)
  • twin studies
  • signalling genes
396
Q

Give examples of environment-related factors that can break tolerance.

A
  • smoking (risk factor for rheumatoid arthritis)
  • microbiome (antibiotics, IBS)
  • vitamin D
397
Q

Give examples of immune regulation-related factors that can break tolerance.

A
  • hormonal effects
  • C. jejuni - GBS
  • Coxsackie virus - T1DM

?? unsure still

398
Q

mechanism 1 of autoimmunity:

How does the beta cell mass progressively change in type I diabetes? Why does this occur?

A
  • decreases

- CD8 T cells kill pancreatic beta cells

399
Q

When do type I diabetics become symptomatic? What are they said to totally be at that point?

A
  • when 30% of the beta cell mass remains

- insulin dependent

400
Q

What autoantibodies cause myasthenia gravis?

A
  • IgG1

- IgG3

401
Q

How do autoantibodies cause myasthenia gravis? (2 effects)

A

after binding to the ACh receptor on the posynaptic membrane on the neuromuscular junction, they can:
(endocytosis+ degradation)

  • cause complement cascade activation-> MAC formed by ac5-c9, allows free ion movement + messes up electrical polarity of memb
  • if divalent, crosslink receptors causing internalisation of receptor and delaying synaptic transmission
402
Q

What are the clinical consequences of myasthenia gravis?

A
  • when patient is asked to look up for a long period of time, ptosis occurs where eyelids will progressively droop
  • when patient asked to close eyes for a maximum of 10 seconds, muscle fatigue will be noticed in the eyelids when opening
403
Q

What is a pannus?

A

an extra growth on a joint in rheumatoid arthritis

404
Q

Which immune cells drive rheumatoid arthritis?

A

CD4 T cells

405
Q

What does the pannus produce in rheumatoid arthritis? (3)

A
  • antigen
  • proinflammatory cytokines
  • growth factors
406
Q

What enzymes are involved in the autoimmunity mechanism of rheumatoid arthritis?

A

matrix metalloproteases (MMPs) –> tissue destruction

407
Q

What can occur specifically in antibody positive rheumatoid arthritis?

A

immune complexes can deposit in inflammation site and perpetuate inflammation

408
Q
  1. Describe the autoimmune mechanism behind rheumatoid arthritis.
A
  • CD4 T cells release inflammatory cytokines IL-17 and IFN-gamma
  • pannus on joint produces antigen, proinflammatory cytokines and growth factors
  • MMPs lead to joint tissue destruction
  • immune complexes perpetuate inflammation
409
Q

What are the 2 strategies for treating autoimmune diseases of the endocrine system?

A
  • replace hormone

- block hormone

410
Q

Give 2 examples of replacing the hormone as a strategy for treating endocrine autoimmune disease.

A
  • thyroxine in autoimmune hypothyroidism

- insulin in type 1 diabetes

411
Q

Give an example of blocking the hormone as a strategy for treating endocrine autoimmune disease.

A

(if too much hormone)…

carbimazole in Grave’s disease (anti-TSH-R autoantibodies)

412
Q

What are the 4 immune suppression strategies?

A
  • generic
  • cell-specific
  • pathway-specific
  • molecule-specific
413
Q

Give an example of a generic immune suppression strategy.

A

steroids

414
Q

Give an example of a cell-specific immune suppression strategy.

A

calcineurin inhibitors (CNIs)

415
Q

Give an example of a pathway-specific immune suppression strategy.

A

Janus kinase inhibitors (JAKi)

416
Q

Give an example of a molecule-specific immune suppression strategy.

A

anti-cytokine monoclonals

417
Q

What are the advantages of the generic immune suppression strategy?

A
  • older so side effects well established

- cheaper

418
Q

What strategy of immune suppression do glucocorticoids fall under?

A

generic - steroids

419
Q

How do glucocorticoids work?

A

bind to glucocorticoid receptor in cytoplasm then trafficked to nucleus, where it modulates gene expression

420
Q

Why is steroid use limited?

A

it causes broad toxicity

421
Q

What portion of autoimmune/inflammatory conditions are responsive to steroids?

A

the vast majority

422
Q

What do steroid-sparing agents do?

A

reduce the need for steroids

423
Q

Give examples of the toxicities produced by steroid use.

A
  • steroid-induced diabetes mellitus
  • hypertension (mineralocorticoid)
  • dyslipidaemia
  • weight gain
424
Q

What drug is first used to suppress cancer?

A

methotrexate

425
Q

How do antimetabolites work?

A

block the pathway of nucleotide synthesis

426
Q

What is the theory concerning lymphocytes in autoimmune disease that explains why antimetabolites work?

A

lymphocyte turnover predicted to be significantly higher in autoimmune conditions
so by depriving cells of metabolites needed for DNA synthesis they will enter cell arrest/ death

427
Q

What class of drugs is methotrexate?

A

antimetabolites

428
Q

How does methotrexate work?

A

inhibits difolate reductase (necessary for thymidine synthesis)

429
Q

What class of drugs is azathioprine?

A

antimetabolite

430
Q

How does azathioprine work?

A

converted to 6-MP (inhibits purine synthesis)

431
Q

What class of drugs is MMF?

A

antimetabolite

432
Q

How does MMF work?

A

inhibits inosine 5-monophosphate dehydrogenase, necessary in de novo purine synthesis

433
Q

What is MMF selective for? Why?

A

lymphocytes, as these depend on the de novo purine synthesis pathway as opposed to the salvage pathway

434
Q

Give 2 examples of calcineurin inhibitors.

A

tacrolimus, ciclosporine

435
Q

Explain the pathway involving calcineurin.

A
  • complex TCR signalling cascade involves PLC, calcineurin and NFAT (trans factor)
  • NFAT is translocated to nucleus leading to increased expression of IL-2 receptor, necessary for T cell proliferation
436
Q

What is a key side effect of calcineurin inhibitors?

A

chronic renal toxicity

437
Q

What is the target of anti-TNF-alpha?

A

TNF-alpha

438
Q

What conditions can anti-TNF alpha be used to treat?

A

rheumatoid arthritis, ankylosing spondylitis, IBD, psoriasis, psoriatic arthritis

439
Q

What does anti-TNF alpha increase the risk of?

A

reactivated TB

440
Q

What is the target of tocilizumab?

A

IL-6 receptor

441
Q

What conditions is tocilizumab used to treat?

A

rheumatoid arthritis, JIA, cytokine release syndrome

442
Q

What infection does tocilizumab increase the risk of?

A

straphylococcal skin infection, infections w/o fever or CRP

443
Q

What does rituximab target?

A

CD20 (B cells)

444
Q

What conditions is rituximab used to treat?

A

rheumatoid arthritis, lymphomas/leukaemias, various autoantibody mediated conditions

445
Q

What infection does rituximab increase the risk of?

A

hypogamma, PML

446
Q

What does eculizumab target?

A

C5

447
Q

What is eculizumab used to treat?

A

atypical HUS, PNH

448
Q

What infection does eculizumab increase the risk of and why? (think about its target)

A

meningococcal, as it targets C5 which is responsible for complement-mediated lysis against meningitis

449
Q

What are 3 examples of JAK inhibitors?

A
  • baricitnib
  • tofacitinib
  • ruxolitinib

target downstream signaling kinases

450
Q

What state can cancer induce in the body?

A

immunosuppression

451
Q

How do tumour/cancer cells induce immunosuppression?

A
  • release CTLA-4 which can bind to CD4 T cells
  • release PD-1 ligand which can bind to CD8 T cells switching them off
  • encourage regulatory T cells to suppress natural immune responses
452
Q

What drugs interrupt the way cancer dodges the immune system?

A

immune checkpoint inhibitors

453
Q

What is ipilumumab?

A

an anti CTLA-4 Ig1

454
Q

What immune cells does ipilumumab deplete, and what immune cells does it kill?

A
  • depletes T regulatory cells that express CTLA-4 via ADCC

- kills immune cells expressing protective CTLA-4

455
Q

immune related adverse effetcs: effect of blocked CTLA-4?

A

enhances anti tumour activity

456
Q

What condition can people treated with ipilumumab develop? Why?

A
  • pan hypothyroidism

- immune cells in the pituitary stalk express protective CTLA-4 which is blocked by ipilumumab

457
Q

What are CD8 cells also known as?

A

CTLs = cytotoxic T lymphocytes

458
Q

What are pembrolizumab and nivolimuab?

A

anti-PD-1 drugs

459
Q

How do pembrolizumab and nivolimuab work?

A

block intra-tumour PD-1 ligand which normally switches off CD8 cells

460
Q

What is the autoreactive consequence of pembrolizumab and nivolimuab?

A

break is removed from potentially autoreactive T cells

461
Q

Summary of all the immune-related adverse events when people treated with immune checkpoint inhibitors?

A 
thyroiditis, hyperthy/hypothy
rash, vitiligo
anaemia, thrombocytopenia
myocarditis
vasculitis
colitis
...
462
Q

What is lupus?

A

butterfly rash

463
Q

Give examples of drugs that can induce lupus.

A

antiarrhythmics:

  • promacainamide
  • quinidine

antihypertensive
- hydralazine

464
Q

What is meant by slow acetylators?

A

i.e. metabolism slower

465
Q

How is drug-induced lupus caused?

A
  • occurs in slow acetylators
  • drug reacts with reactive oxygen species (ROS)
  • leads to product binding to nuclear protein
  • produces neoantigen, which is not recognised by immune system
  • leads to rash (lupus- ANA+ histone+ DNA-)
466
Q

How is drug-induced lupus cured?

A

withdrawal of drug

467
Q

Part 5: allergic disease + immunotherapy

immunopathogens of allergic disease
drugs to trwat
allergen immunotherapy
allergy mimics

A
468
Q

establishing immunological tolerance: 2 types?

A

thymus

periphery

469
Q

mucosal surfaces help establish what?

A

tolerance to antigen

470
Q

How do mucosal surfaces help establish tolerace to antigens?

A 
mucus blocks contact
epithelium and tight junctions
intraepithelial lymphocytes
sentry cells (DC/ILC)
lymphatic system
MALT (mucosal associte lymhoidal tissues) - generates IgA preventing allergen uptake
471
Q

3 types of unwanted allergen that mucosal surfaces help establish tolerance to?

A

commensals
aeroallergens
food

472
Q

what do DC cells do (establishing tolerance to antigen)

A

DC on the surface

high dose antigen at mucosal surface -> anergy/deletion

or

chronic low dose stimulation of immune system at mucos surface -> Treg (IL-10, TGF-beta)

473
Q

what do B cells do (establishing tolerance to antigen)

A

Dimeric IgA prevents allergen uptake (B cells)

474
Q

spectrum: What are the different types of allergy? and how are they each mediated?

A

type 1 hypersensitivity - IgE mediated

type 4 hpersensitivity - T cell mediated

non IgE mediated diseases

others + adverse reactions

475
Q

examples of each types of allergy on spectrum?

A

type 1 hypersensitivity - IgE mediated - anaphylaxis, true food allergy, hayfever, venom allergy

type 4 hpersensitivity - T cell mediated - contact dermatitis

non IgE mediated diseases - food induced enterocolitis, eosinophilic, oesphagitis

others - SJS-TEN spectrum, NSAID hypersensitivity, urticarias

476
Q

Describe type 1 hypersensitivity.

A 
B cell producing antigen specific IgE after T cell hep and Th2 cytokines (L-4)
(class switches to produce antigen specific IgE)

IgE receptors on mast cells containing histamine

antigen binds to high affinity IgE receptors = mast cell degranulation = histamine released within minutes as mediators already preformed
innate IS

477
Q

Describe type 1 hypersensitivity.

A 
B cell producing antigen specific IgE after T cell hep and Th2 cytokines (L-4)
(class switches to produce antigen specific IgE)

IgE receptors on mast cells containing histamine

antigen binds to high affinity IgE receptors cross linked = mast cell degranulation = histamine (tryptase lipid mediators cysLT, PGD2_ released into circ within minutes as mediators already preformed
innate IS

478
Q

how is type 1 hypersensitivity assessed? (2)

A

sudden rise in histamine -> immediate symptoms

most type 1 hypers. recs happen wothin mins of allergen exposure

can measure histamine(in mins) ot mast cell tryptase: inc over 24 hrs, highest at approx 2-3 hrs - NICE)

479
Q

What does histamine cause? (5)

A

vasodilatation
(endothelium releases NO - hypotension)
(fluid leak - angiodema)

sneezing (via neurostimulatory effects)

regulates sleep/wake (antihistamines cause drowiness)

mucus secretion 
(direct effect on glandular tissues = hypersecretion)

expulsion of digested food from GI tract - plugs up lungs in asthmatic, casing nasty mucus plugging up = hypoxia

480
Q

What drugs are used to manage type 1 hypersensitivity?

A

antigen = densensitisation

anti IgE =blocks

mast cell stabilisier = stops granulation eg steroids/ sodium chromoglycate

HISTAMINE RECEPTORS: antihistamines

physiolgical instabilitiy = fixes effects of histamine eg adrenaline

481
Q

example anti-IgE drug used to treat type 1 hypersensitivity

A

Omalizumab

482
Q

How can you test for type 1 hypersensitivity? in lab

A

measure allergen specific IgE

measure mast cell tryptase and histamine- less reliable

483
Q

Why do we need IgE mediated immunity?

A

neutrophil cant engulf some infection eg parasitic worm infection - IgE bind to antigens, bind to eosonophils causing degranulation

484
Q

(hygiene hypothesis)

Why is there hypothetically an increase in allergic disease?

A

reduced early pathogen exposure which woud lead to increased default Th2 differntiation

485
Q

basis of anti parasite immunity?

A

too big for phagocytes
igE attaches to helminth
eosinophils bind to IgE -> degranulated
Helminth killed w toxic granules and O2- and N radicals
IL-14 inc goblet cell mucus prodn to expel parasite

486
Q

What factors make someone less like to get allergy?

A

pets
live in countryside
youngest child

487
Q

Why does eczema cause failure of tolerance?

A

barrier dysfuction + S. aureus colonisation more likely

cutaneous exposure to innocuous antiges through broken sskin rather than the normal mucosal routes
leads to a failure to establish norml tolerance
failure of tolerance = allergy
in through skin

488
Q

What factors cause allergic disease?

A 
- environment
early life exposure to antigens
infections (RSV)
hygiene
antibiotics
maternal smoking
diet
air polluiton
chlorine
genetics
  • genes
    polymorphisms (IL4 receptor or FceR0

filaggrin (barrier)

…but probab a combination

489
Q

What type of allergy is allergic rhinitis and what are the types?

A

seasonal - pollen: tree/grass/weed

perennial rhinitis - house dust mites, pets, molds (all year)

type 1

490
Q

What are the steps of treatment for allergic rhinitis?

A
  1. PRN non sedating AH, allergen avoidance (close windows, dont dry laundry outside when mowing lawn) 1M before season
  2. regular OR non-sedating AH - during problem season
  3. add topical intranasal steroid eg fluticasone
  4. increase non sedating AH to BD, try dymista/ montelukast if asthmatic
  5. antigen desensitisation
491
Q

topical treatments dont work for allergic rhinitis when?

A

if mucus already present

  1. start treatment early (1m before season)
  2. saline nasal washes
492
Q

How do you use nasal spray?

A 
shake well with cap on for 10 seconds
hold upright and spray away from you
gently blow your nose
shake an take cap off
tilt head forwards a little bit
point nozzle slightly outwards
block other nostril with finger
spray and breathe in gently
take nozzle out and breathe out via mouth
repeat in other nostril
wipe nozzle and replace cap
493
Q

Why may there be treatment faiure with allergic rhinitis?

A

right diagnosis?
unilateral symptoms - pain, discharge, crusting = refer ENT
non-allergic rhinitis? exercise, food, cold

treated too late?
try nasal washes
start treatment 1M before allergen season

compliance
inhaler technique
dymista tastes disgusting - try Avamys (but no local AH)

try immunotherapy?

494
Q

role of allergist:

What are the different types of type 1 hypersensitivity? 3

A

true food allergy - sensitised to highly stable storage proteins within nut - high risk of anaphylaxis

oral allergy syndrome - primary sensitisation to aeroallergen (pollen). cross reactivity with ubiquitious and unstable plant proteins = oral tingling and itchines only

LTP allergy = sensitised to lipid transfer proteins- cross reactiviy w other LTP in plant based products (eg apple) moderate risk of systemic reaction

495
Q

What is childhood-onset asthma?

A

T2 type asthma

  • allergic asthma - anti IgE treatment -exercise induced
  • late onset eosinophilic asthma - aspirin exacerbated respiratory disease
496
Q

What is adult-onset asthma?

A

NON T2 type asthma

  • obesity associated asthma
  • smooth muscle mediates paucigranulocytic asthma
  • smoking related neutrophilic asthma
497
Q

whens desensitisation therapy recommended as tretament?.

A

when standard optimal therpay failed

498
Q

desensitisation therapy not suitable for ?

A

patients w poorly controlled asthma/ CVD - small risk of systemic reaction with SC IT

499
Q

types of desensitisation therapy.

A

SC vs sub lingual

depends on area.
cost and resources - NHS and allergy unmet need

500
Q

desensitisation timeline + symtpoms?

A

antigen dosing…. induction 12 weeks
maintenance 3-5 years..

symptoms reduce over time

501
Q

What are the 3 mechanisms of antigen desensitisation?

A
  1. minute doses of antigen -> mast cell undergoes piecemeal degranulation -> allergen specific IgE replaced by other IgE increaising activation threshold
  2. antigen, DC - bocks Th2 -> reduced IL4
    and induces Treg-> inc IL-10
    (expansn of allergen specific Tregs and redn in Th2)
  3. B cell
    reduced IgE
    inc IgG4
    block uptake of antigen
502
Q

what immunotherapy is available?

A

SC

  • common for venom (bee/wasp)
  • v effective
  • small risk of systemic reac and death
  • pollinex (grasS) licensed but most other allergens not
  • very labour intensive

sublingual

  • equally efficacious
  • cheaper, 1st dose in hospital, then daily sublingual tablet at home
  • granax licensed in uk for allergic rhinitis
503
Q

what is primary prevention of allergy?

A

children 4m-11m of age w severe eczema, egg allergy / both

gievn 6g peanut a week until reach 5 y/o

504
Q

what is type IV hypersensitivity?

A

contact dermititis

mediated by T cells -> inflamma nd oedema in skin
symptoms happen 24-72hrs after exposure to caustaive agent

different to

  • type 1 (IgE mediated)
  • irritant response
  • eczema

e..g localised form jewellery

505
Q

What is patch testing?

A

done by dermatologists

5d test w variable sensitivity + specificity

506
Q

What is acute/chronic urticaria?

must be distinguished from what?

A

looks like hives
often triggered by infections (common in), stress

must be distinguished from allergy

507
Q

how does acute/chornic urticaria occur?

A

into basophil:

  • BAC INFECTIONS
  • VIRAL INFECTIONS
  • allergens
  • neuroendocrine axis
  • autoantibodies (IgE/IgG)
  • cytokines (IL-4)

->
basophil produces/releases:
- platelet activating factor (PAF)
- IL-4, GM-CSF

  • histamine
  • pre-formed lipid mediators (PGD2, LTC4)
  • chrondriotin sulphate, elastases
508
Q

Part 6: drug allergy + anaphylaxis

A
509
Q

What are consequences of penicillin allergy? (5)

A
  • significant restriction in available antibiotics (when resistance is increasing) and inc use of fluoroquinolones, clindamycin, vancomycin
  • potential harm from other drugs
  • longer inpatients stays
  • higher incidence of antibiotic resistant infections
  • higher associated health care costs
510
Q

How can you improve communication to patients by

A

improve accuracy of drug allergy documentation + of referrals to allergy service

511
Q

How do you confirm a penicillin allergy? (4)

A
  1. retake history, timing of drugs, symptoms and other concurrent medical issues
    symptoms on day doesnt equal anaphylaxis
    type 1 symptoms are immediate and reproducible
  2. SPT/ID testing
    put small amount on skin and compare to a + control (pure histamine) and - control (saline)
  3. specific IgE (sIgE)
    looking for the antibody against the drug
  4. drug challenge
    look at risks vs benefits, monitor symptoms for an hour after administering
512
Q

what is the role of the pharmacist in allergy?

A

understand the difference between side effects and allergies

513
Q

What are normal side effects of penicillins?

A

nausea
diarrhoea
transaminitis
candida

514
Q

What are the use and normal side effects of macrolides?

A

promotes gastric motility

abdominal pain
nausea
diarrhoea

515
Q

What are normal side effects of opiates?

A

urticarial rash
itch
sedation
hallucinations

516
Q

What type of reaction is NSAID hypersensitivity?

A

non IgE mediated reactions

not a true allergy (just side effect of drug)

517
Q

What is the pharmacology of NSAIDs?

A

block COX-1 enzymes which inhibits the production of PG (widespread homeostatic funcs) from arachidonic acid = antiinflammatory effects

arachidonic acid builds up and 5-LO produces LTC4 and LTD4

effects = angiodema, urticaria, bronchoconstriction (normal hypersensitivity)

518
Q

What are alternatives to NSAIDs? 2

A

analgesic - paracetamol

COX–2 inhibitors

519
Q

What is red man syndrome?

A

vancomycin hypersensitivity

dependent on infusion rate (slow <10mg/min and add AH) want not given too quick

can happen on first dose

direct mast cell degranulation (not IgE mediated, vancomycin binds to mast cell)

520
Q

What is red man syndrome by vancomycin made worse by?

A

opiates - more mast cell degranulation

521
Q

What is rituximab, the side effect of first dose rituximab and how can you reduce it?

A

monoclonal antibody from mice targetting B cells so it binds to CD20

inflammation in human body; fever, chills, rigors, angiodema

give first dose with hydrocortisone and piriton to reduce inflammation

522
Q

rituximab MoA (for CD20 and B cell lymphoma)?

A

Nk cells -> ADCC to B cells, classical complement cascade

???

523
Q

What is Steven Johnson syndrome?

A 
severe cutaneous adverse rxn
idiosyncratic (hard to predict)
in early SJS: target lesions
if not stopped: mucosal desqumification
progresses to toxic epidermal necrolysis
early skin blistering
late widespread epidermal necrolysis
524
Q

What is SJS/TEN caused by and symptoms?

A

drug related: malaise, fever, feeling like skin on fire w/out obvious signs initialls

antibiotics (penicillins, sulfa containing drugs)
aromatic anticonvulsants (lamotrigiine, phenytoin, carbamazepine)
antiretrovirals (nevirapine)
allopurinol
NSAIDs

type 4 hypersen rxns

525
Q

What is SJS/TEN associaated with?

A

MHC-1 genetic linkages; implicates CD8+ T cells in pathogenesis

526
Q

What do you do if SJS is suspected?

A

stop the drug !!!

transfer to ITU or burns unit to look after lesions

527
Q

What is anaphylaxis?

A

acute, severe, life-threatening allergic reaction in a pre-sensitised individual, leading to a systemic response caused by the release of immune and inflammatory mediators from basophils and mast cells involving at least two organ systems (such as angiodema [around airway], vomiting [GI tract])

528
Q

What is the ABCDE management of anaphylaxis?

A

Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach

stop obvious triggers - remove drug etc.

529
Q

bee sting may potentially lead to what reactions?

A
  • airway compromise
  • wheeze, breathing difficulties
  • rapid CV collapse

urticaria, angioedema

530
Q

distributive shock (2 effects of histamine)?

A

hypotension
- histamine increases NO
tunica media relaxation

vascular leak (oedema and erythema)
- hist alters capillary permeability (tight junctions)
531
Q

4 effects of histamine?

A

distributive shock
1. hypotension
- hist increases NO
tunica media relaxation

  1. vascular leak (oedema + erythema)
    hist alters cpaillary permeability (tight juncs)

…

  1. bronchoconsticiton/ spasm (wheeze)
    - direct + indirect effects on bronchial smooth muscle
  2. mucus secretn (diarrhoea in GI tract)
    - direct effect on goblet cells of resp mucosa
532
Q

causes of anaphylaxis?

A

food
tatrogenic (dk but cause but inc w age)
insect sting

533
Q

7 cofactors for anaphylaxis?

A 
drugs: NSAIDs, ACEi- inc bradychinin, opiates- mast cells affected
exercise
EtOH
infections
hormones
route of delivery
antigen dose
534
Q

Why does injection of drugs hve the shortest time to arrest?

A

goes right into circulation as opposed to food/stings/oral drugs

535
Q

most important risl factors for cardiac arrest and death form perioperative anaphylaxis?

A

older patients
obese

asthma in young

536
Q

differential diagnosis of anaphylaxis?

A 
syncope/faint
anxiety induced hyperventilation
hypotension due to MI, blood loss, sepsis
scombroid poisoning
mastocytosis
carcinoid syndrome
vocal cord dysfunc
chronic urticaria + angioedema
C1-esteras inhib deficiency
exercise induced
direct mast cell activators- opioids
537
Q

4 AIRWAY danger signs?of anaphylaxis

A

persistent cough
vocal change (hoarse)
difficulty swallowing
swollen tongue

538
Q

4 BREATHING danger signs?of anaphylaxis

A

wheezy
noisy breathing
stridor
high RR

539
Q

4 CIRCULATION danger signs?of anaphylaxis

A

loss of consciousness
pre-syncope
confusion
impending doom

540
Q

What should you do if you have an anaphylactic reaction in terms of position?

A

lie flat w legs slight up

elevate feet- fluid

541
Q

What do you give to someone having an anaphylactic reaction?

A

oxygen
nebulised salbutamol
IV fluids
IM Ad (o.5mg 1:1000IM) repeat at 5 mins if needed

542
Q

How does adrenaline act?

A

↑ peripheral vasoconstriction
↑ peripheral vascular resistance
↑ BP + coronary artery perfusion

↓ vascular permeab + angioedema
-> bronchodilatation
↓ inflamm mediator release

stabilising physiologyu deranged by action of histamine

543
Q

3 types of IM Ad and when given?

A

Epipen
Emerade
Jext

give if any danger sign present- delay if risk factor for death

544
Q

What other drugs can you give for a anaphylxis rxn?

A

adjunct therapies:

  • antihistamines
  • steroids (200mg hydrocortisone)

cetirizine (non-sedating) - helpful if not given early

sedating AH not recommended e.g. piriton

545
Q

timeline of symtpoms for anaphylaxos (Ad)

A

after antigen exposure:
initial symptoms = mast cell degranulation
1-8 hrs…
second phase symptoms = de novo mediator sythesis

546
Q

when to admit patients after anaph and what to check?

A

admit patient for monitoring (12 hrs) check tryptase (0,2,24 hrs)

547
Q

What is included in the follow up for anapnhylaxis?

A

do they need Ad autoinjector to take home?
whats the risk of future allergen exposure?
refer to appropriate local allergy clinic

548
Q

How do you use an adrenaline autoinjector?

A

4 steps…

549
Q

How many allelles does MHC II have and what do they do?

A

HLA-DP
HLA-DQ
HLA-DR
one from father, one from mother

each bind to a different peptide

550
Q

why is Type 1 hypersensitivity symptoms reproducible?

A

as the Ig antibodies dont go away

551
Q

what is the difference between side effects and allergies?

A

with allergies your immune system dictates the response to the allergy but does not for side effects

552
Q

how do NSAIDs stop arachidonic acid from accessing catalytic site?

A

the NSAID will block both Cox1 and Cox2 inhibitors by binding at an arginine molecule halfway up the channel inhibiting the access of arachidonic acid and so inhibiting synthesis of prostaglandins PGI2 and PGE2, thromboxanes TGA2

553
Q

what symptoms will occur with patients with urticaria and angioedema?

A

urticaria: airway compromise
angioedema: rapid CV collapse

554
Q

how does histamine cause hypotension?

A

histamine increases NO release and so the BP will decrease

this causes organs to not be able to perfuse properly

555
Q

how does histamine cause vascular leak (oedema)?

A

histamine will alter the permeability of tight junctions and so these will open and fluid leaks out and eventually causes angioedema

556
Q

how does histamine cause bronchoconstriction/spasm?

A

it has direct and indirect effects on bronchial smooth muscle
- opens up the blood vessels and constricts airways and causes wheeziness

557
Q

how does histamine cause mucus secretion?

A

histamine has a direct effect on goblet cells of respiratory mucosa
- histamine can cause mucus plugging in the lungs and there is difficulty recruiting alveoli to ventilator capacity so adult cant breathe properly

558
Q

what can mucus plugging cause?

A

can cause patient to become rapidly hypoxic

559
Q

what is the purpose of the drug adrenaline?

A
  • increases peripheral vasoconstriction
  • increases peripheral vascular resistance
  • increases BP and coronary artery perfusion
  • decreases vascular permeability and angioedema
  • maintains bronchodilation
  • decreases inflammatory mediator release
560
Q

how often should you administer an adrenaline after first dose? how should it be administered

A

5 mins after first dose if needed

and should be given IM

561
Q

Inflammation key points.

think of it like a network of cells

A
  • all immune cells secrete cytokines of various sorts
  • chemokines= mols generally responsible for chemoattraction of other immune cells. cytokines generally direct cellular func rather than migration; they are not interchangeable but there is overlap.
  • most complement proteins are made by the liver (C3, C4). C1q which initiates the classical cascade is produced by myeloid lineage cells.
562
Q

describe consumption of complement?

A

means it is being used up - whole C3 and C4 is being turned into cleavage products as part of the activation of the complement cascade; clinically you can measure C3 and C4 - as it gets used up, levels in the blood go down in certain diseases. Low C3 is a marker of alternative cascade activation, low C4 is a good marker of classical cascade activation

563
Q

does both positive & negative selection occurs before forming the naive CD4/CD8 T Cells.
Or is it the naive T cells that undergo positive/negative selection?

A

thymocytes enter the thymus and undergo positive and then negative selection within the thymic cortex and medulla respectively. The final goal of this process is to produce a naive T cells.

564
Q

difference between monoclonal and polyclonal immunoglobulins

providence of polyclonal immunoglobulin

there are two broad therapeutic uses for polyclonal immunoglobulin - immunomodulation and immunoglobulin replacement and appreciate there is a strict governance process over the use of Ig in the NHS

broad array of monoclonal antibodies used for different therapeutic purposes; some target cells (e.g. CD20 - B cells), some target cytokines (e.g. anti-TNF), some target complement (e.g. eculiziumab). You will find more details about certain monoclonals in the lectures to illustrate how they cause a secondary immunodeficiency - you will be expected to understand that there are potential immunological toxicities of administered these medicines.

A

Health.1 (12 decks)

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