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Immunosuppressants Flashcards

1
Q

What causes redness (rubor) in inflammation?

A

Increase in local blood flow cause by vasodilatation triggered by inflammatory mediators

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2
Q

What causes swelling (tumor) in inflammation?

A

Increase in vascular permeability causing proteins and fluid to leak from the vasculature

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3
Q

What is the triple response of Lewis?

A
  1. Flush
  2. Flare
  3. Wheal
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4
Q

What causes flush following a noxious stimulus?

A

Local release of vasodilator substances, such as histamine, from cells disturbed by the stimulus

Causes dilatation of capillaries

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5
Q

What causes flare following a noxious stimulus?

A

Neurogenic inflammation causes reddening to spread by axon reflex

AP sent antidromically along collateral branches causes release of vasodilatory substances, which cause vasodilatation of surrounding arterioles

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6
Q

What causes wheal following a noxious stimulus?

A

Histamine causes increased vascular permeability leading to localised swelling

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7
Q

Which receptors mediate the inflammatory effects of histamine?

A

H1 receptors

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8
Q

What is orthodromic propagation of an action potential?

A

From sensory nerve to spinal cord

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9
Q

What is antidromic propagation of an action potential?

A

Along collateral branches

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10
Q

Give two inflammatory substances that collateral nerve branches might secrete?

A
  1. Calcitonin gene-related peptide (CGRP)

2. Substance P

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11
Q

What are the actions of CGRP?

A

Directly causes vasodilatation

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12
Q

What are the actions of substance P?

A
  1. Directly causes vasodilatation

2. Potent activator of mast cell degranulation

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13
Q

What is the effect of mast cell degranulation?

A

Local production of histamine

Causes vasodilatation and increased vascular permeability

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14
Q

What is dermatographic urticaria?

A

Triple response is exaggerated

Largely idiopathic

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15
Q

How is dermatographic urticaria treated?

A
  1. H1-receptor antagonists

2. Omalizumab

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16
Q

What causes inflammation?

A
  1. Noxious stimuli
  2. Bacterial/viral/fungal infection
  3. Autoimmune reactions
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17
Q

How do pathogens cause inflammation?

A
  1. Release of toxins
  2. Lysis of host cells, liberating inflammatory factors
  3. Activation of innate and adaptive immune systems
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18
Q

Which inflammatory factors may be liberated by pathogen lysis of host cells?

A

ATP

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19
Q

Which pathogen secretes alpha-haemolysin?

A

Uropathogenic E. coli

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20
Q

What is the effect of alpha-haemolysin?

A

Induces calcium oscillations in cells

Causes synthesis of IL-6 and IL-8 (pro-inflammatory cytokines)

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21
Q

What kind of receptors are toll-like receptors (TLRs)?

A

Receptor tyrosine kinase

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22
Q

Where is TLR4 expressed?

A

Plasma membrane

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23
Q

What does TLR4 detect?

A

Lipopolysaccharide

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24
Q

What does TLR8 detect?

A

ssRNA

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25
Q

What is the effect of TLR activation?

A

Initiates production of pro-inflammatory mediators

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26
Q

What are some of the pro-inflammatory mediators produced following TLR activation?

A
  1. Prostaglandins
  2. Histamine
  3. TNFα
  4. IL-1
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27
Q

What is the role of TNFα and IL-1 in inflammation?

A
  1. Induce production of further cytokines
  2. Increase vascular permeability
  3. Cause expression of adhesion molecules on the endothelium of post-capillary venules
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28
Q

What is the function of cell adhesion molecules?

A

Leukocytes adhere to them, enabling them to migrate out of the vascular system and into tissues so that they may attack pathogens

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29
Q

What process guides leukocyte migration?

A
  1. Pathogen-generated chemotaxins

2. Host chemokines induced by pathogen

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30
Q

What does exudate contain?

A

Components of:

  1. Complement system
  2. Coagulation system
  3. Fibrinolytic system
  4. Kinin system
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31
Q

How is factor XII activated?

A

Upon contacting negatively-charged substances such as collagen

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32
Q

What is the role of factor XIIa?

A

Production of:

  1. Plasmin
  2. Thrombin
  3. Bradykinin
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33
Q

What are the roles of plasmin and thrombin in complement?

A

Hydrolyse C3 to C3a and C3b

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34
Q

What is the role of C3a?

A

Stimulates mast cells

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35
Q

What is the role of C3b?

A
  1. Attaches to pathogens aiding their destruction by white blood cells
  2. Cleaves C5 to C5a and C5b
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36
Q

What is the role of C5a?

A
  1. Activates mast cells
  2. Chemoattractive for white blood cells
  3. Activates white blood cells
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37
Q

How is the membrane attack complex formed?

A

One subunit each of C5b, C6, C7 and C8

12-1 subunits of C9

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38
Q

What is the role of the membrane attack complex?

A

Attaches to bacterial membranes and forms a pore

Induces lysis

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39
Q

Where do cells involved in inflammation leave the bloodstream?

A

Venules

not arterioles

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40
Q

Which white blood cells are the first to reach the site of injury?

A

Neutrophils

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41
Q

What are selectins?

A

Adhesion molecules

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42
Q

What causes neutrophils to be tethered to and captured by the endothelium?

A

Interaction between endothelium P-selectin and neutrophil-expressed ligands, such as P-selectin glycoprotein 1

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43
Q

What interactions does firm arrest and adhesion of neutrophils involve?

A

Between neutrophil expressed integrins such as lymphocyte-associated antigen 1 and intercellular adhesion molecule 1 expressed by the endothelium

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44
Q

How long does transmigration across endothelium and basement membrane take?

A

~15 minutes

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45
Q

What does transmigration of neutrophils require?

A
  1. Integrins

2. Adhesion molecules such as platelet/endothelial cell adhesion molecule 1

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46
Q

What are the two routes of neutrophil transmigration?

A
  1. Paracellularly

2. Transcellularly

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47
Q

What is fMLF?

A

Bacteria derived

Attracts neutrophils to bacterial invader

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48
Q

How do neutrophils eliminate pathogens?

A
  1. Phagocytosis
  2. Degranulation
  3. NETs
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49
Q

What molecules might a neutrophil secrete to kill pathogens?

A
  1. ROS

2. Antibacterial proteins

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50
Q

What antibacterial proteins might a neutrophil secrete to kill pathogens?

A
  1. Cathepsin
  2. Lysozyme
  3. Defensins
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51
Q

What is neutrophil degranulation?

A

Release of antibacterial proteins into extracellular fluid

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52
Q

What are NETs?

A

Neutrophil extracellular traps

Composed of core DNA element alongside enzymes that immobilise pathogens

Prevents spread and facilitates phagocytosis

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53
Q

What receptors do mast cells have?

A
  1. TLRs
  2. C3a
  3. C5a
  4. IgE
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54
Q

What does stimulation of mast cell receptors cause?

A

Release of:

  1. Histamines
  2. Heparin
  3. Leukotrienes
  4. NGF
  5. Preformed packets of cytokines
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55
Q

What is histamine formed from?

A

Histidine by histidine decarboxylase

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56
Q

Where is histamine found at the cellular level?

A
  1. Mast cells
  2. Basophils
  3. Enterchromaffin-like cells in gut
  4. Histaminergic neurons in brain
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57
Q

How is histamine packaged in mast cells and basophils?

A

In acidic granules with nigh molecular weight heparin called macroheparin

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58
Q

How is histamine released from mast cells?

A

Granules exocytosed following increased levels of intracellular calcium

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59
Q

How do C3a and C5a induce degranulation?

A

Gi-coupled receptors

βγ subunits activate PLCβ

Induces intracellular calcium release via IP3

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60
Q

How does substance P induce degranulation?

A

Via Mas-related gene X2 receptors

Gq coupled

PLCβ/IP3 mediated calcium release

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61
Q

How does IgE induce degranulation?

A

Allergen-induced cross-linking of IgE with its receptor FcεRI induces phosphorylation of adaptor protein linker for activation of T cells

Causes activation of PLCγ/IP3 mediated calcium release

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62
Q

What are the four histamine receptors?

A
  1. H1
  2. H2
  3. H3
  4. H4
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63
Q

How does the H1 receptor mediate its effects?

A

Gq/11-coupled

PLCβ

IP3 + DAG/PKC

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64
Q

What is H1 receptor important in?

A
  1. Inflammation
  2. Smooth muscle contraction in ileum, uterus and bronchioles
  3. Blood vessel dilatation
  4. Triple response
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65
Q

How does the H2 receptor mediate its effects?

A

Gs-coupled

Increased AC

Increased cAMP/PKA

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66
Q

What is the H2 receptor important in?

A
  1. Gastric acid secretion

2. Increased heart rate

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67
Q

How does the H3 receptor mediate its effects?

A

Gi-coupled

Decreased AC

Decreased cAMP/PKA

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68
Q

What is the H3 receptor important in?

A

Inhibitory autoreceptor in CNS

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69
Q

How does the H4 receptor mediate its effects?

A

Gi-coupled

Decreased AC

Decreased cAMP/PKA

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70
Q

What is the H4 receptor important in?

A
  1. Chemotaxis

2. Cytokine release

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71
Q

Which two enzymes metabolise histamine?

A
  1. Histaminase

2. Histamine N-methyltransferase

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72
Q

How does histaminase metabolise histamine?

A

Oxidatively deaminates histamine

Produces imidazole acetaldehyde

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73
Q

How does histamine N-methyltransferase metabolise histamine?

A

Catalyses transfer of methyl group onto nitrogen of imidazole ring

Produces NT-methylhistamine

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74
Q

What are the pathophysiological roles of histamine?

A
  1. Allergy
  2. Anaphylaxis
  3. Driver of symptoms of mastocytosis
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75
Q

What is mastocytosis?

A

Too many mast cells present leading to an excessive allergic-type attack

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76
Q

What causes mastocytosis?

A

Gain of function mutation in receptor tyrosine kinase c-kit/CD117

Causes enhanced mast cell proliferation and survival

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77
Q

Which drugs may be used to treat pathology associated with histamine?

A
  1. Sodium cromoglycate
  2. Salbutamol
  3. Salmeterol
  4. Theophylline
  5. Omalizumab
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78
Q

What are anti-histamines?

A

H1-receptor antagonists

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79
Q

What is the main treatment of anaphylactic shock?

A

Adrenaline injection

Administered intramuscularly or intravenously

Counteracts systemic vasodilatation and reduced tissue perfusion

Relieves bronchospasm

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80
Q

When is imatinib efficacious in treating mastocytosis?

A

In patients without D816V c-Kit mutation

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81
Q

What are H2-receptor antagonists used for?

A

Reduce gastric acid secretion

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82
Q

What is the pH at the mucosal surface of the stomach?

A

pH 6-7

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83
Q

What is the effect of gastrin on histamine release?

A

It enhances it by acting on CCK2 receptors

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84
Q

What are the treatments for peptic ulcers?

A
  1. H2-receptor antagonists
  2. Proton pump inhibitors
  3. Antacids
  4. Cholinergic blockade and vagotomy
  5. Eradication of H. pylori infection
  6. Stopping NSAID use
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85
Q

How do NSAIDs contribute to gastric ulcers?

A

Inhibit prostaglandin synthesis

PGE2 acts on ECL cells to inhibit gastric acid secretion and increase mucin and bicarbonate secretion

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86
Q

How is bradykinin formed?

A

Action of kallikrein upon kininogens

Factor XIIa converts plasma pre-kallikrein to kallikrein

Kallikrein clips HMW-kininogen to bradykinin

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87
Q

What is another term for Factor XII?

A

Hageman factor

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88
Q

What does kallikrein cleave LMW-kininogen to?

A

Kallidin

In tissues

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89
Q

How is bradykinin inactivated?

A

Kininase I removes C terminal arginine to form des-Arg-bradykinin

Kininase II removes two C terminal amino acids

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90
Q

What is another term for kininase II?

A

Angiotensin-converting enzyme

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91
Q

What is des-Arg-bradykinin?

A

Product of bradykinin breakdown by kininase I

Agonist at bradykinin B1 receptors

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92
Q

What kind of receptors are the bradykinin receptors?

A

Gq-coupled GPCR

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93
Q

When are B1 receptors most active?

A

Upregulated during inflammation

By actions of IL-1 and inflammatory cytokines

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94
Q

When are B2 receptors most active?

A

Constitutively expressed

Potently activated by bradykinin and kallidin

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95
Q

What is the result of bradykinin receptor activation in the endothelium?

A

Increase in [Ca2+]

Activates cytosolic phospholipase A2

Increases PGI2 production and eNOS

Causes vasodilatation

Activates nociceptors and drives pain

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96
Q

How does bradykinin induce nociceptor activation?

A

Activation of Gq GPCRs

Activation of PKC

Phosphorylates numerous ion channels involved in pain

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97
Q

What is the role of C1-esterase inhibitor?

A

Inhibits kallikrein

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98
Q

What is hereditary angiooedema?

A

Mutation in gene encoding C1-esterase inhibitor

Excessive levels of bradykinin

Sufferers experience periods of severe and painful swelling

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99
Q

What are the four main groups of cytokines?

A
  1. Interleukins
  2. Cytokines
  3. Colony-stimulating factors
  4. Interferons
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100
Q

What are the key pro-inflammatory interleukins?

A
  1. Il-1

2. TNFα

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101
Q

What are the pro-inflammatory interleukins released by?

A

Macrophages

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102
Q

What is the role of the pro-inflammatory interleukins?

A
  1. Induce expression of further cytokines
  2. Promote proliferation and maturation of other immune cells
  3. Cause fever (IL-1 only)
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103
Q

What are the key anti-inflammatory interleukins?

A
  1. IL-10

2. IL-1ra

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104
Q

What is the role of anti-inflammatory interleukins?

A
  1. Inhibit expression of cytokines

2. Inhibit some T cell responses

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105
Q

Give three examples of chemokines

A
  1. CCL3
  2. CXC
  3. CX3C
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106
Q

What is the role of CCL3?

A

Induces mast cell degranulation

Acts at CCR1 receptors

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107
Q

What kind of receptors are chemokine receptors?

A

GPCR

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108
Q

What is the role of IFNα and IFNβ?

A

Anti-viral activity

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109
Q

What is the role of IFNγ?

A

Induces TH1 responses

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110
Q

What is the role of colony-stimulating factors?

A

Stimulate formation of maturing colonies of leukocytes

Used to overcome deficits in a person’s white blood cell count

111
Q

What is nerve growth factor released from?

A
  1. Macrophages

2. Mast cells

112
Q

What is nerve growth factor?

A

Potent sensitising agent

Causes allodynia

113
Q

How does nerve growth factor cause allodynia?

A

High affinity NGF receptor tropomyosin-related kinase A

114
Q

What are lipid mediators?

A
  1. Leukotrienes
  2. Platelet-activating factor
  3. Prostanoids
115
Q

How are lipid mediators produced?

A

On demand from membrane phospholipids by phospholipases

116
Q

What is the main precursor for lipid mediators?

A

Arachidonic acid

117
Q

What is the rate-limiting step for eicosanoid synthesis?

A

Liberation of arachidonic acid from membrane phospholipids

Involves PLA2

118
Q

How is cytosolic PLA2 activated?

A

By combination of phosphorylation and calcium

Stimulated by:

  1. Bradykinin at B2 receptors to raise calcium
  2. TNFα at TNFR1 to promote MAPK phosphorylation
  3. TNFα at TNFR2 to raise calcium
119
Q

What is the precursor of platelet-activating factor?

A

Lysoglyceryl-phosphorylcholine (lysoPAF)

120
Q

How are leukotrienes synthesised?

A

By lipoxygenase enzymes from arachidonic acid

121
Q

What are lipoxygenase enzymes?

A

Cytosolic enzymes

Expressed primarily in lungs and leukocytes

122
Q

What is 12-HETE?

A

Chemotaxin

Produced from arachidonic acid by 12-lipoxygenase

123
Q

What is leukotriene A4?

A

Produced from arachidonic acid by 5-lipoxygenase

124
Q

What is LTA4 converted to?

A
  1. LTB4 in cells expressing LTA4 hydrolase

2. LTC4 in cells expressing LTC4 synthase

125
Q

What is LTC4 converted to?

A

LTD4 and LTE4

126
Q

What are cysteinyl leukotrienes (cysLT)?

127
Q

What kind of receptors are leukotriene receptors?

128
Q

What kind of receptors are BLT receptors?

A

Gq or Gi-coupled GPCR

129
Q

What kind of receptors are cysLT receptors?

A

Gq coupled GPCR

130
Q

What is the role of LTB4?

A
  1. Potent chemoattractant
  2. Activator of neutrophils and macrophages
  3. Upregulates neutrophil adhesion molecule expression
  4. Promotes macrophage cytokine release
131
Q

What is the role of cysLTs?

A
  1. Cause bronchoconstriction
  2. Increase vascular permeability
  3. Increase mucous secretion
132
Q

Which cells release cysLTs?

A
  1. Mast cells

2. Eosinophils

133
Q

How are lipoxins synthesised?

A
  1. 12-lipoxygenase conversion of LTA4 to LXA4

2. 15-lipoxygenase conversion of arachidonic acid to 15-HETE, which is converted by 5-lipoxygenase to LXA4

134
Q

What receptor does LXA4 bind to?

A

Formylpeptide receptor 2

Gi-coupled

135
Q

What is the effect of LXA4?

A
  1. Reduce neutrophil chemotaxis
  2. Reduce degranulation
  3. Antagonist of cysLT1 receptors
136
Q

What is the effect of platelet-activating factor?

A
  1. Increases thromboxane production in platelets
  2. Spasmogenic
  3. Chemotactic for neutrophils
  4. Activates PLA2
137
Q

How are prostaglandins synthesised?

A

Metabolism of arachidonic acid by cyclo-oxygenase enzymes

138
Q

Where is COX-1 expressed?

A

Constitutively in most tissues

139
Q

Where is COX-2 expressed?

A

Induced in inflammation

Some constitutive expression

140
Q

What are the sources of prostanoids in inflammation?

A
  1. PGE2 and PGI2 produced locally by tissues
  2. PGD2 released by mast cells
  3. PGE2 and TXA2 released by macrophages in chronic inflammation
141
Q

What receptors to prostanoids act at?

142
Q

What are DP1, EP2, EP4 and IP receptors?

A

Prostanoid receptors

Gs-coupled

Increase cAMP production

143
Q

What are EP1, FP and TP receptors?

A

Prostanoid receptors

Gq-coupled

Increase [Ca2+]

144
Q

What are DP2 and EP3 receptors?

A

Prostanoid receptors

Gi-coupled

Decrease cAMP production

145
Q

What is the role of PGD2?

A
  1. Vasodilatation
  2. Inhibition of platelet aggregation
  3. Relaxation of GI/uterine smooth muscle via DP1 receptors
  4. Bronchoconstriction via TP receptors
146
Q

What is the role of PGE2?

A
  1. Bronchial/GI smooth muscle contraction via EP1
  2. Bronchodilatation
  3. Vasodilatation
  4. Relaxation of GI smooth muscle via EP2
  5. Fever via EP3
  6. Sensitisation of nociceptors via EP4
147
Q

What is the role of PGI2?

A
  1. Vasodilatation

2. Inhibition of platelet aggregation

148
Q

What is the role of TXA2?

A
  1. Vasoconstriction
  2. Bronchoconstriction
  3. Platelet aggregation
149
Q

What is the role of PGF2α?

A
  1. Uterine contraction in humans

2. Bronchoconstriction in cats/dogs

150
Q

How does platelet aggregation balance shift following damage to endothelium?

A

Shifts towards TXA2

151
Q

What is fish oil high in?

A

Eicosapentanoic acids

152
Q

What do eicosapentanoic acids produce?

A

PGI3 and TXA3

Protection against heart attacks

153
Q

How do NSAIDs act?

A

COX inhibitors

Most act by entering hydrophobic channel on enzyme and forming hydrogen bonds with arginine 120

Prevents entrance of fatty acids into catalytic domain

Therefore inhibit production of prostaglandins

154
Q

How do the hydrophobic channels of COX enzymes differ

A

COX-1 = narrow

COX-2 = wider

155
Q

What is the main feature of COX-2 selective NSAIDs?

A

Bulky sulphur-containing side group that doesn’t fit in COX-1

156
Q

What is the most common side effect of NSAIDs?

A

GI bleeding

157
Q

What is the risk associated with COX-2 inhibitors?

A

Increased myocardial risk

Due to decreased PGI2 production leading to less vasodilatation and more platelet aggregation

158
Q

How does aspirin act?

A

Acetylates serine 530

Irreversibly inactivates COX

159
Q

What are the effects of aspirin at low doses?

A

Inhibits platelet aggregation

160
Q

What is the result of aspirin acetylating COX-2?

A

Produces 15R-HETE instead of usual intermediates

Converted to aspirin-triggered lipoxin by 5-lipoxygenase

161
Q

What are the effects of aspirin-triggered lipoxin?

A

Similar to LXA4

Explains anti-inflammatory effects of aspirin

162
Q

What are the side effects of NSAIDs?

A
  1. GI bleeding
  2. Renal insufficiency
  3. Nephropathy
  4. Stroke/MI
  5. Bronchospasm
163
Q

What is Reye’s Syndrome?

A

Occurs almost exclusively in children

Hepatic encephalopathy

Occurs when aspirin taken for treating viral symptoms

164
Q

What is salicylism?

A

Result of aspirin overdose

Result of Krebs cycle inhibition and uncoupling of oxidative phosphorylation

Increased O2 consumption so increased CO2 production

Stimulates chemoreceptors, increasing ventilation, leading to alkalosis

Compensated by increased renal bicarbonate excretion

Causes fever, vomiting, coma and death

165
Q

How is salicylism treated?

A

Fluids

Bicarbonate

Activated charcoal adsorbs aspirin in GI tract

Haemodialysis in severe cases

166
Q

What are the effects of paracetamol?

A
  1. Analgesic

2. Antipyretic

167
Q

How does paracetamol act?

A

COX inhibitor

Some COX-2 selectivity

Reduces site responsible for production of PGH2 and PGG2

168
Q

How is paracetamol eliminated?

A
  1. Conjugation via hepatic conjugation enzymes

2. Metabolised to NAPQI by oxidases

169
Q

How is NAPQI metabolised normally?

A

Conjugated to glutathione

170
Q

What does NAPQI do in cases of paracetamol overdose?

A

Oxidises thiol groups of cellular proteins

Major hepatic and renal toxicity

171
Q

What are the symptoms of paracetamol overdose?

A

24-48 hours post-ingestion

Begin with nausea and vomiting

Liver failure-induced death

172
Q

Which drugs may be administered to prevent liver toxicity following paracetamol overdose?

A

Substances that increase hepatic glutathione production

  1. Acetylcysteine
  2. Methionine
173
Q

What is the toxic dose of paracetamol?

A

150mg/kg body weight

174
Q

How does alcohol increase risk of paracetamol toxicity?

A

Upregulates Cyp2E1

Converts paracetamol to NAPQI

175
Q

Why is paracetamol not suitable for cats?

A

They lack ability to conjugate salicylate with glycine

176
Q

Why are high 5HT levels observed in the serum after coagulation?

A

Platelets contain 5HT and release it during activation and aggregation

177
Q

What is the effect of 5HT in the blood?

A
  1. Induces further platelet aggregation

2. Causes vasoconstriction

178
Q

Which cells express 5HT?

A
  1. Platelets
  2. Intestinal enterochromaffin cells
  3. Serotonergic neurons of enteric and central nervous systems
179
Q

How is 5HT synthesised?

A

From tryptophan by:

  1. Tryptophan hydroxylase (Tph)
  2. L-aromatic acid decarboxylase
180
Q

What is the rate-limiting step in 5HT synthesis?

A

Tryptophan hydroxylase step

181
Q

Where is SERT expressed?

A

Serotonin transporter

Platelets

182
Q

What is the role of SERT?

A

Enables platelets to become loaded with 5HT

183
Q

How is 5HT degraded?

A
  1. Oxidative deamination by monoamine oxidase

2. Oxidation

184
Q

What is the degradation product of 5HT?

A

5-hydroxyindoleacetic acid (5-HIAA)

185
Q

How is 5-HIAA excreted?

A

In the urine

186
Q

What kind of receptor is 5-HT1A – F?

A

Gi-coupled

187
Q

What kind of receptor is 5-HT2A – C?

A

Gq-coupled

188
Q

What kind of receptor is 5-HT3?

A

Ionotropic receptor/ligand gated ion channel

189
Q

What kind of receptor is 5-HT4?

A

Gs-coupled

190
Q

What kind of receptor is 5-HT5A?

A

Gi-coupled

191
Q

What kind of receptor is 5-HT6?

A

Gs-coupled

192
Q

What kind of receptor is 5-HT7?

A

Gs-coupled

193
Q

What is emesis?

194
Q

What are the two key components governing emesis?

A
  1. Vomiting centre
  2. Chemoreceptor trigger zone (CTZ)

Located in medulla

195
Q

How is the CTZ activated?

A
  1. Circulating chemicals
  2. Visceral afferents
  3. Input from vestibular nuclei
196
Q

What receptors are found in the CTZ that mediate emesis?

A

5-HT3 receptors

197
Q

Which animals cannot vomit?

A
  1. Rodents

2. Horses

198
Q

What is migraine?

A

Severe headache

Unilateral

Throbbing

Accompanied by nausea and vomiting, photophobia and prostration

199
Q

What is aura?

A

Progressive visual disturbance associated with onset of migraine

200
Q

What are the three main hypotheses for migraine attacks?

A
  1. Vascular hypothesis
  2. Brain hypothesis
  3. Inflammation hypothesis
201
Q

What is the vascular hypothesis for migraine attacks?

A

Intracerebral vasoconstriction causes aura

Extracerebral vasodilatation causes headache

202
Q

What is the brain hypothesis for migraine attacks?

A

Wave of cortical spreading depression across brain strongly associated with aura

Slowly propagating wave of near complete depolarisation

Silences neuronal electrical activity

203
Q

What is the inflammation hypothesis for migraine attacks?

A

Activation of trigeminal nociceptors that innervate meninges and extracranial blood vessels

Causes pain and neurogenic inflammation

204
Q

What occurs to 5-HT during migraine?

A

Blood 5-HT levels drop

Urine 5-HIAA levels rise

205
Q

What are the two phases of the adaptive response?

A
  1. Inductive phase

2. Effector phase

206
Q

Which receptors do activated CD4+ cells express?

A

IL-2 receptors

207
Q

Which cytokines do activated CD4+ cells express?

A

IL-2

Autocrine

208
Q

What is the effect of IL-2 on CD4+ cells?

A

Generation and proliferation of TH0 cells

209
Q

What is the effect of autocrine action of IL-4?

A

Production of TH2 cells

210
Q

What is the effect of TH2 cells?

A

Activate B cells to proliferate and give rise to plasma cells and memory B cells

211
Q

Which cytokines cause the differentiation of TH0 cells into TH1, TH17 and iTreg cells?

A
  1. IL-2
  2. IL-6
  3. IL-10
212
Q

What are Tregs responsible for?

A

Restrain immune response

Prevent excessive immune response

213
Q

What is the effect of TH1 and TH17 cells?

A

Secrete cytokines that activate macrophages

214
Q

What is the autocrine effect of IL-2 on CD8+ cells?

A

Generate cytotoxic T cells

215
Q

What is the role of cytotoxic T cells?

A

Kill virally infected cells

216
Q

In which conditions does TH1 response predominate?

A
  1. IDDM
  2. MS
  3. Rheumatoid arthritis
  4. Graft rejection
217
Q

In which conditions does TH2 response predominate?

218
Q

What are corticosteroids?

A

Mimic action of endogenous glucocorticoids

Suppress immune response

219
Q

Where are glucocorticoids synthesised?

A

Adrenal cortex

220
Q

What causes glucocorticoid synthesis?

A

Circulating ACTH released from pituitary gland

221
Q

What controls ACTH synthesis?

A

Corticotrophin-releasing factor

Released from hypothalamus

222
Q

What are some of the metabolic actions of corticosteroids?

A
  1. Decreased uptake of glucose by muscle/fat
  2. Increased gluconeogenesis
  3. Increased protein catabolism
  4. Decreased protein anabolism
  5. Redistribution of fat
223
Q

What are the inflammatory actions of corticosteroids?

A
  1. Decreased activity of monocytes
  2. Decreased clonal expansion of T and B cells
  3. Decreased activity of leukocytes
  4. Decreased proinflammatory cytokine production
  5. Decreased eicosanoid production
  6. Increased release of anti-inflammatory factors
  7. Switch from TH1 to TH2 response
224
Q

What are the main anti-inflammatory cytokines?

A
  1. IL-10
  2. IL-1ra
  3. Lipocortin 1
  4. Secretory leukocyte inhibitory protein
  5. IKB
225
Q

Which receptor do corticosteroids bind to?

A

Glucocorticoid receptor (GRα)

226
Q

What kind of receptor is the glucocorticoid receptor?

A

Nuclear receptor

Present as homomer in cytoplasm

Bound to heat shock protein 90

227
Q

What is the effect of corticosteroids binding to their receptor?

A

Forms homodimers

Transactivate or transrepress range of genes

228
Q

How can ligand-bound GRα regulate gene expression?

A
  1. Binds to positive glucocorticoid response element
  2. Binds to negative glucocorticoid response element
  3. Binds to Fos/Jun AP-1 regulatory site
  4. Prevents binding of P65 and P50 to NFKB site
229
Q

What are the side effects of corticosteroid treatment?

A
  1. Opportunistic infection
  2. Impaired wound healing
  3. Oral thrush
  4. Osteoporosis
  5. Hyperglycaemia
  6. Muscle wasting
230
Q

What is Cushing’s syndrome?

A

Due to excess cortisol

Also caused by ACTH-secreting tumour (pituitary adenoma causes Cushing’s disease)

231
Q

What are the symptoms of Cushing’s syndrome?

A
  1. Pot-bellied appearance
  2. Hair loss
  3. Polydipsia
  4. Polyuria
232
Q

What is the length of action of hydrocortisone?

233
Q

What is the length of action of dexamethasone?

A

> 48 hours

234
Q

What is Addison’s disease?

A

Adrenal glands fail to produce sufficient steroid hormones

235
Q

What can corticosteroids be used to treat?

A
  1. Addison’s disease
  2. Asthma
  3. Inflammatory skin conditions
  4. Rheumatoid arthritis
  5. Prevent graft rejection
  6. Reduce cerebral oedema
236
Q

What is asthma?

A

Intermittent attacks of wheezing and shortness of breath

  1. Inflammation of airways
  2. Bronchial hyperactivity
  3. Reversible bronchoconstriction
237
Q

How does an immune response arise in allergic asthma?

A
  1. Dendritic cell in airway submucosa takes up allergen
  2. Presents allergen to CD4+ T cell
  3. Development of TH0 cell
  4. Gives rise to TH2 lymphocytes
238
Q

What do TH2 lymphocytes do in asthma?

A
  1. Release IL-5
  2. Release IL-4
  3. Release IL-13
239
Q

What is the role of IL-5 in asthma?

A

Eosinophil priming

240
Q

What is the role of IL-4 and IL-13 in asthma?

A
  1. Switch B cells into producing IgE

2. Induce IgE receptor expression in mast cells and eosinophils

241
Q

What is the effect of allergen-induced FcεRI cross-linking in asthma?

A
  1. Mast cell degranulation
  2. Release of histamine
  3. Release of CysLTs

Causes powerful bronchoconstriction and increase in vascular permeability

242
Q

What factors do mast cells release in an acute asthma attack?

A
  1. IL-4
  2. IL-5
  3. IL-13
  4. TNFα
  5. Chemotaxins that recruit macrophages and eosinophils
243
Q

What occurs in the delayed phase of an asthma attack?

A
  1. Eosinophils recruited to mucosal surface
  2. Release CysLTs and granule proteins
  3. Damage to epithelium resulting in airway hypersensitivity
244
Q

Which granule proteins are released in the delayed phase of an asthma attack?

A
  1. Eosinophil cationic protein

2. Eosinophil major basic protein

245
Q

What is the effect of epithelial cell loss in the airway?

A

Nociceptive C-fbires more accessible to irritant stimuli, leading to hypersensitivity

246
Q

What are the two types of treatment for asthma?

A
  1. Bronchodilators

2. Anti-inflammatories

247
Q

When are bronchodilators used?

A

Acute attacks

248
Q

When are anti-inflammatories used?

A

Prophylactically

To limit inflammatory components of acute and late phase of response

249
Q

Where do β2-adrenoreceptor agonists act?

A

Gs-coupled β2-adrenoreceptors in bronchial smooth muscle induce relaxation and bronchodilation

In mast cells, inhibits degranulation

250
Q

What are the side effects of β2-adrenoreceptor agonists?

A
  1. Tremor

2. Tachycardia

251
Q

Which drugs are used to treat COPD?

A

Long-acting β2-adrenoreceptor agonists, especially ultra-long-acting

252
Q

What is Grave’s disease?

A

Hyperthyroidism

Auto-antibodies to thyrotropin receptor causing increased thyroxine release

253
Q

What is Hashimoto’s disease?

A

Hypothyroidism

Autoantibodies against proteins involved in thyroxine synthesis

254
Q

What is myasthenia gravis?

A

Autoantibodies against nicotinic ACh receptor preventing effects of acetylcholine

255
Q

What is type 1 diabetes mellitus?

A

Antibodies against islet cells and insulin

256
Q

What is multiple sclerosis?

A

Immune attack against oligodendrocytes that form myelin sheaths

257
Q

What is primary biliary cirrhosis?

A

Immune attack against bile ducts of liver

258
Q

What is rheumatoid arthritis?

A

Immune attack on synovium surrounding joints

259
Q

What is responsible for the joint damage in rheumatoid arthritis?

A
  1. Activated TH1 cells
  2. Macrophages stimulated to release IL-1 and TNFα
  3. Causes release of metalloproteases from osteoclasts and fibroblasts
  4. Causes cartilage and bone destruction
  5. Exacerbated by infiltrating inflammatory cells
260
Q

What are the inflammatory cells involved in rheumatoid arthritis?

A

Neutrophils release proteases and ROS

261
Q

What is pannus formation?

A

Hyperplasia of synovium in rheumatoid arthritis

Fibroblast-like synoviocytes proliferate and invade the joint and release pro-inflammatory cytokines and proteases

262
Q

What are DMARDs?

A

Disease-modifying antirheumatic drugs

Reduce disease progression

Eg. methotrexate

263
Q

What are myeloma cells?

A

HPRT -ve

Immortalised tumour cells used for mAb production

264
Q

What are the two key domains of the antibody?

A
  1. Fc region

2. Fab region

265
Q

What does the Fc region do?

A

Reacts with cell surface Fc receptors expressed on neutrophils, macrophages and natural killer cells

266
Q

What does the Fab region do?

A

Fragment antigen binding

Contains variable and hypervariable regions that bind to antigen epitopes

267
Q

What is -ximab?

A

Chimeric mAb

268
Q

What is -axomab?

A

Rat/mouse hybrid

269
Q

What is -zumab?

270
Q

What is -umab?

271
Q

What are bi-specific antibodies?

A

Stitching together two halves of different antibodies

One binds target cell and one binds cytotoxic cell

Used in cancer

272
Q

What is the effect of afucosylation of antibodies?

A

Higher affinity for FcγRIII on NK cells

Overcome competition with serum IgG

273
Q

How can mAbs be modified to make them more potent?

A
  1. Bi-specific antibodies
  2. Afucosylation
  3. Conjugation with toxins
  4. Improved pharmacokinetics of Fc region

MODA Questions (7 decks)

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