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Infection and immunity > Malcom Watson Semester 1 > Flashcards

Malcom Watson Semester 1 Flashcards

1
Q

What is meant by infection?

A

The process of microbes colonising a host

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2
Q

What is immunity?

A

Protection from infection/disease byinitiation of repair mechanisms. (this includes autoimmunity)

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3
Q

What is the primary goal of inflammation?

A

The primary goal of the inflammatory process is to remove the cause of injury.

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4
Q

What are the FIVE cardinal signs of inflammation?

A
  1. Heat
  2. Redness
  3. Swelling
  4. Pain
  5. Loss of function
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5
Q

Discuss the two different ‘types’ of heat involved in inflammation

A
  1. Heat in an individual tissue(s) - this is caused predominantly by increased blood flow to the area
  2. systemic fever - the purpose of this it to help eliminate infectious agents
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6
Q

How does swelling occur during inflammation?

A

Changes in vascular permeability leads to leakage of plasma and therefore oedema.

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7
Q

What is the cause of redness during inflammation?

A

Increased blood flow to the site of infection

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8
Q

What are neuropeptides and where are they released from? Give examples.

A

Neuropeptides are bioactive molecules which mediate nociception and act on blood vessels and other receptors to cause vasodilation. They are released from sensory neurones into the periphery. CGRP and substance P are neuropeptides.

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9
Q

What occurs when CGRP acts/stimulates mast cells?

A

Release of histamine, PG and ATP

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10
Q

Outline the processes that follow injury to the skin.

A
  1. Skin injury leads to activation of mast cells
  2. Histamine activates sensory neurons via H1 receptors and leads to neuropeptide release: CGRP and substance P
  3. Plasma exudation occurs (due to CGRP and substance P, this leads to further stimulation of mast cells)
  4. Vasodilation occurs (due to CGRP and substance P)
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11
Q

What is the cause of a typical wheal and flare?

A 
Wheal = pale raised welt on the skin, caused by the release of serum from mast cells
Flare = caused by dilation of blood vessels in the surrounding area
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12
Q

What causes of loss of function in the inflammatory process?

A

Tissue destruction or alternatively from pain which therefore inhibits the mobility or from severe swelling that prevents movement in that area.

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13
Q

What percentage of the UK population is affected by RA?

A

1-2%

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14
Q

What ratio of male to females have RA?

A

3:1 female to male ratio

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15
Q

What is the average age of onset for RA?

A

variable onset around 30-50 years of age

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16
Q

Briefly outline the mechanisms that occur during RA

A

Loss of cartilage and bone erosion mediated by proteinases.
- mainly Matrix Metallo Proteinases (MMP) secreted by the tissue cells synovial fibroblasts and chondrocytes
Tissue cells are activated by infiltrating leukocytes
Fibrosis tissue formation (scarring) occurs and we get loss of mobility.
T and B lymphocytes help to maintain cytokine production

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17
Q

What type of proteinases are involved in destruction in RA? What cells are they released from?

A

Matrix metallo proteinases (MMP) released from synovial fibroblasts and chondrocytes

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18
Q

What is the main function of macrophages in immune defence?

A

Defence via phagocytosis and respiratory burst. Major source of cytokines

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19
Q

What is respiratory burst?

A

Rapid release of reactive oxygen species (ROS)

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20
Q

What surface antigen is expressed on T helper cells?

A

CD4+

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21
Q

What surface antigen is expressed on T cytotoxic cells?

A

CD8+

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22
Q

Outline the role of T cells

A

Adaptive immune system
T cell subsets secrete different cytokines.
Active B cells which produce antibodies

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23
Q

What inflammatory mediators are released from the cell membrane?

A

PGs/eicosanoids, leukotrienes and platelet activating factor (PAF). Are all lipid in nature.

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24
Q

What inflammatory mediators are released from plasma?

A

Bradykinin and complement (C3A, C5a)

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25
Q

What are inflammatory/chemical mediators?

A

Diverse molecules produced by the host in response to infection and immune reactions. They have low specificity and act to promote and affect inflammation.

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26
Q

What is inflammation beneficial?

A
  1. Increased supply of cells and chemical mediators to the site of infection.
  2. Allows removal of damaged tissues and infectious agents
  3. Supply of new materials for repair
  4. Indicates body to rest (via pain and loss of function)
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27
Q

What affects does histamine have on blood vessels?

A

Vasodilation and increased vascular permeability?

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28
Q

What affects does the eicosanoids PGE2 and PGI2 have on blood vessels?

A

Vasodilation

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29
Q

What affects does the eicosanoids LTB4 and LTC4 have on blood vessels?

A

Increased vascular permeability

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30
Q

Bradykinin and complement C3a and C5a cause what?

A

Increased vascular permeability

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31
Q

What agents increase plasma leakage via a neutrophil dependent mechanism?

A

LTB4, fMLP, C5a, IL-8

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32
Q

What agents increase plasma leakage directly on the endothelium?

A

Histamine and bradykinin

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33
Q

Outline the synthesis of histamine

A

L-Histidine
Histidine decarboxylase
Histamine

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34
Q

What is tritoqualine?

A

Inhibitor of histidine decarboxylase

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35
Q

What does histaminase do?

A

Produces imidazol acetic (which is inactive)

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36
Q

Where is histamine stored?

A

Mainly in mast cells also found in circulating basophils

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37
Q

Where are mast cells mainly located?

A

Located in the skin, lungs, gut and nasal mucosa

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38
Q

Outline the main components of mast cells

A

Histamine is basic and the other main component is high MW heparin which is acidic.

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39
Q

By what process is histamine released from mast cells?

A

Exocytosis, triggered by a raise in calcium levels

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40
Q

Outline what happens in cutaneous response to histamine or an allergen ‘triple response’

A
  1. arterial vasodilation (local reddening)
  2. oedema formation (wheal)
  3. axon reflex (flare) - release of neuropeptides due to stimulation of sensory nerve fibres and antidromic impulse
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41
Q

H1 receptors is a GPCR, what is it coupled to? What happens when activated

A

Gq coupled
Leads to phospholipase C (PLC) activation which results in calcium levels elevation (leads to mast cell degranulation)
Smooth muscle contraction.

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42
Q

H2 receptor is a GPCR, what is it coupled to? What happens when activated

A

Gs coupled to adenylyl cyclase leading to cAMP elevation.
Vascular smooth muscle relaxation.
Vasodilator
Gastric acid secretion

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43
Q

Give an example of an h1 receptor antagonist?

A

Antihistamines - chlorphenamine, astemizole, loratidine

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44
Q

Why do newer antihistamines not cause drowsiness?

A

Newer drugs have decreased lipophilicty and cannot pass the BBB.

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45
Q

Give an example of a H2 receptor antagonist

A

Cimetidine, ranitidine

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46
Q

What are eicosanoids?

A

Refers to PGs and other related compounds. Oxidation products derived from a C20 unsaturated fatty acid, production is considerably increased during inflammation.

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47
Q

What are eicosanoids derived from?

A

C20 unsaturated acids - arachidonic acid (and dihomogammalinoleic acid, eicosapentanoic acid). All cells in the body contain arachidonic acid primarily as a component of the membrane phospholipids.

48
Q

What happens to arachidonic acid when tissues are exposed to pathological stimuli?

A

AA is produced from membrane phospholipids by the action of phospholipase A2 (PLA2) and is then converted into different eicosanoids.
Also can be produced from diacylglycerols

49
Q

What enzyme is responsible for the production of leukotrienes from arachidonate?

A

Lipoxygenases

50
Q

What enzyme is responsible for prostaglandin synthesis from arachidonate?

A

prostaglandin synthase

51
Q

Outline the four main physiological functions of prostaglandins (PGs)

A
  1. initiation of labour - PGF2alpha and PGE2
  2. inhibition of gastric acid secretion, increased gastric mucus production PGE2
  3. Vascular (PGI2) - inhibition of platelet aggregation, vasodilator
  4. Vascular - TXA2. Causes platelet aggregation/vasoconstrictor
52
Q

What are the classical eicosanoids?

A

Prostaglandins, prostacylcins, thromboxanes, leukotrienes

53
Q

What are non-classical eicosanoids?

A

Lipoxins, resolvins, ispoprostanes, endocannbinoids

54
Q

What is the difference between classical and non-classical eicosanoids?

A

Non-classical eicosanoids are very difficult to detect in the body as have a short half life. They have different biological activities to classical eicosanoids

55
Q

True/False : Eiscosanoids are preformed in cells.

A

False. Unlike histamine, eicosanoids are NOT preformed in cells, they are generated from phospholipid precursors on demand. Phospholipase A2 is a calcium dependent enzyme that breaks down phospholipid bilayer to arachidonic acid.

56
Q

Outline the metabolism of arachidonic acid to produce eicosanoids.

A

Unlike histamine, eicosanoids are NOT preformed in cells, they are generated from phospholipid precursors on demand. Phospholipase A2 is a calcium dependent enzyme that breaks down phospholipid bilayer to arachidonic acid.

Free arachidonic acid is then metabolism by either COX enzymes to produce prostaglandins OR lipoxygenases to produce Leukotrienes.

57
Q

Outline the role/functions of EP2 and IP receptors on vascular smooth muscle

A

EP2 and IP are vasodilator ‘pro-inflammatory receptors’.
Found on vascular smooth muscle - cause vasodilation (Gs coupled, adenylycyclase and cAMP levels increase)
Also enhances plasma extravasation.

58
Q

Outline the function of EP2 receptors on leukocytes.

A

ANTI-INFLAMMATORY.
Still Gs coupled, the increased cAMP levels ‘switch off’ the leukocyte and therefore will decrease any inflammatory responses mediated by the leukocytes.

59
Q

What receptor does thromboxane act upon? What happens when it binds?

A

TP.

Gq coupled to PLC, leads to raised Ca2+ and smooth muscle CONSTRICTION.

60
Q

What receptor does PGF2 act on? What happens when it binds?

A

FP.

Gq coupled to PLC, leads to raised Ca2+ and smooth muscle CONSTRICTION.

61
Q

What receptors does PGE2 target?

A

Four PGE2 receptors: EP1 to EP4

62
Q

What is the role of PGE2 in pain?

A

PGE2 increases responses to pain by potentiating histamine and bradykinin which leads to increased nerve activity.

63
Q

What is the role of PGE2 in fever?

A

Fever results from elevation of the thermoregulatory set point. Regulated by the production and action of PGE2 in the anterior hypothalamus. PGE2 acts through the EP3 receptor.

64
Q

Discuss the two isoforms of cycoxoygenase

A

Cyclo-oxygenase exists in two isoforms. They have 60% homology.
The critical amno acid residue in position 523 is isoleucine in COX-1 and valine in COX-2.
Removal of this 523 residue leads to loss of catalytic activity.

COX-1:
- consistutive ‘house-keeping’ enzyme, widely expressed

COX-2: induced in inflammatory cells when exposed to inflammatory stimuli. Induced by cytokines IL-1, TNF, groeth factors.

65
Q

COX-2 is induced by what?

A

Cytokines, IL-1, TNF, growth factors

66
Q

COX-2 is inhibited by what?

A

Glucocorticoids, and cytokine IL-4.

67
Q

What is meant by receptor specificity?

A

Whereby only the intended target is affected cross the therapeutic dose range.

68
Q

What is the common mechanism of NSAIDS?

A

Inhibition of COX-1 and 2. Different selectivity depending which NSAID.

69
Q

How do we study the potency ratio of an NSAID for COX-1 OR 2?

A

IC50 value
COX-1 inhibition is measured as platlet thromboxane production
COX-2 is measured as monocyte PGE2

70
Q

What is the IC50 ratio of aspirin?

A

0.3

71
Q

What is the IC50 ratio for naproxen?

A

1.1.

72
Q

What is the IC50 ratio for diclofenac?

A

20

73
Q

What are the side effects of NSAIDs?

A

gastric irritation, bleeding, renal toxicity.

74
Q

What causes the side effect of bleeding with NSAIDs?

A

Bleeding tendency is due to the blocking of COX-1. COX-1 has a role in homeostatic platlet production.

75
Q

Why was refecoxib withdrawn from market?

A

Due to its incidence of thromoembolic events due to suppresion of COX-2 but no effect on COX-1 (COX-2 selective NSAID) these leads to an imbance of TXA2 production.

76
Q

Outline the anti-thrombotic actions of aspirin.

A

Aspirin irreversibly acetylates platlet cyclo-oxygenase, thus platlet TXA2 production ceases. PGI2 is still released, acts on IP receptor = vasodilator. Therefore useful in acute MI, coronary artery bypass etc.

77
Q

what is the main enzyme responsible for leukotriene synthesis?

A

5-lipooxygenase

78
Q

What are the actions of LTC4 and LTD4?

A

1.Bronchoconstriction
also increases the effects of other constrictor agents.

2.Oedema. stimulates increased vascular permeability (neutrophil independent)

79
Q

What is the MOA of montelukast?

A

Leukotriene antagonist.

80
Q

What are the actions of LTB4?

A

Increased vascular permeability - neutrophil dependent.

AND potent chemotactic agent (activation of leukocytes)

81
Q

Zileuton inhibits what enzyme?

A

5-lipooxygenase

82
Q

How do glucocorticoids inhibit the production of eicosanoids?

A

Inhibits PLA2 transcription and induce synthesis of endogenous PLA2 inhibitor ‘lipocortin’

83
Q

What are the 4 steps of leukocyte migration?

A
  1. Circulation
  2. Tethering/rolling
  3. Firm adhesion
  4. Trans migration
84
Q

What mediates tethering and rolling of leukocytes?

A

Mediated by selectins and addressins

85
Q

What are selectins?

A

Lectin like adhesion molecules. Bind to CHO structures (weakly).

86
Q

What type of selectin do leukocytes express?

A

L selectin. Constitutively expressed on leukocytes, activation of leukocyte leads to transient increase in avidity

87
Q

What type of selectin(s) do endothelium cells express?

A

P (platlet) selectin Stored in granules, rapidly (minutes) translocated to the cell surface upon activation e.g. by thrombin or histamine

E-selectin. Endothelial expression is induced by cytokines (IL-1 and TNF) or by LPS. Expression requires de novo protein synthesis (from AA), therefore slow (approx. 2-6 hours)

88
Q

What is leukocyte adhesion deficiency-II (LAD II)?

A

Defective frucose metabolism, therefore leukocytes do not express selectin ligands. Get a decreased ‘rolling’ response on E or P selectins. Patients have severely impaired neutrophil accumulation in skin inflammation (

89
Q

Rolling of leukocytes along the endothelial cell surface activates what?

A

Integrins. Leads to firm adhesion via these integrins.

90
Q

What are integrins?

A

Integrins are heterodimeric proteins expressed on leukocytes and most other cells. Leukocyte integrins have a common B2 chain, but three forms of the alpha chain (l, m and X). So three possible heterodimers.

91
Q

Outline the regulation of leukocyte adhesion.

A

Basal expression of integrins. Leukocyte activation inductions a confirmational change (increased affinity) and the clustering of integrins (increased avidity) and can then bind to ICAM on endothelium.

92
Q

Intercellular adhesion molecule (ICAM) - 2 is expressed where?

A

Receptor basally expressed on the endothelium that binds with integrin on leukocytes.

93
Q

What is leukocyte adhesion deficiency? (LAD-1)

A

Different from LAD-II.

Patients suffer from recurrent bacterial infections w/o pus. Leukocytes do not adhere as deficient in B2 integrin.

94
Q

VLA-4 integrin is expressed on eosinophils, monocytes and T cells. What does it bind to?

A

Binds vascular cell adhesion molecule (VCAM). VCAM-1 is induced by cytokines and mediates the adhesion of eosinophils and monocytes to vascular endothelium.

95
Q

What is Natalizumab (Tysabri) and what is it used for?

A

Anti VLA-4 mAB. Used for relapsing multiple sclerosis (MS).

96
Q

How do leukocytes transmigrate from the blood to the site of infection?

A

Involves CAMS (cell adhesion molecules) and chemoattractants. Chemotaxins attract and activate leukocyte movement.

97
Q

what are chemokines?

A

SELECTIVE chemotaxins. Large family of proteins produced in response to iL-2, TNF and bacteria.

98
Q

What are CXC chemokines?

A

Neutrophil attractants.

99
Q

Give an example of a plasma product that is a chemotaxin

A

C3a, C5a

100
Q

Give an example of a bactieral product that is a chemotaxin

A

fMLP

101
Q

Cells move at different rates in response to infection. Put the following in order:

Monocytes
Neutrophils
Lymphotcytes

A

Neutrophils - always first at site of infection
Monocytes
Lymptocytes

Therefore neutrophils = acute inflammation
Mono and lympho = chronic inflammation.

102
Q

What is diapedesis?

A

The passage of blood cells through the intact walls of the capillaries, typically in inflammation.

103
Q

what is cartilage? what is it function(s)?

A

Connective tissue made of cells and extracellular matrix.. Cells in the matrix are involved in renewal and repair. Cartilage provides smooth robust surface over the bone. Protects the bone from mechanical wear.
Joint cartilage comprises mainly of:
- fibrosis protein ‘collagen’
- proteoglycan

104
Q

What produces cartilage?

A

Chondrocytes

105
Q

What is proteoglycan?

A

Chondroitin sulphate (polysaccharide) linked to aggrecan (protein). As it is highly sulphated, it is charged and binds to water.

106
Q

What are synovial fibroblasts?

A

Forms a capsule around the join, generally a very thin membrane (only a few cells thick). Secretes: lipid mediators, cytokines, enzymes and matrix materials.

107
Q

Outline tissue damage in RA.

A

Bone and cartilage loss
Proteoglycans lost rapidly in RA –> shock absorption impaired, loss of joint function and pain
Proteoglycans have an open porous structure - highly accessible and thus sensitive to break down by several proteinases.
Collagen loss is slower, but completely irreversible.

108
Q

What inhibits MPPs in the body?

A

Inhibited by endogenous Tissue Inhibitors of Metallo Proteinases TIMPS.

109
Q

How are MMPs activated?

A
  1. the TIMP pro-peptide attached to the catalytic site via cysteine maintains the MMP in its inactive state
  2. the interaction between the cysteine and the active zinc ion is disrupted e.g. by proteolytic removal of the pro-peptide or by the action oragnomeraurials and chaotropic agents on the thiol of the cysteine residue.
  3. the active site becomes accessible and MMP is activated.

THE PRO-PEPTIDE DOMAIN IS NOT NEEDED FOR MMP TO ACQUIRE ACTIVITY -> ONLY THE DISRUPTION BETWEEN THE ZINC AND THE CYSTEINE THIOL INTERACTION IS ABSOLUTELY REQUIRED.

110
Q

How does marimastat inhibit MMP?

A

Targets zinc in the target site (hydroxamate series of inhibitors). Mimics the MMP substrate ‘collagen’

111
Q

What is the problem with hydroxamate MMP inhibitors?

A

Lack of specificity - acts on most metalloenzymes (that have a zinc binding site)
This can lead to many ADR inc. musculoskeletal syndrome

112
Q

how can we increase the specificity of MMP inhibitors?

A

Utilise the complementary amino acid sequence of collagen for MMP as well as targeting zinc

113
Q

How are serine and cysteine proteinases inhibited in the body?

A

Endogenous inhibitors by SERPINs

114
Q

what is the role of ROS in RA?

A

synovial tissue in RA undergoes cycles of hypoxia and reperfusion causing oxidative stress.
Generation of superoxide (O2-), h2o2 and NO mediate important cell functions and promote the formation of hydroxyl radical (OH-) and peroxcyntriate (ONOO-)
Leads to tissue injury and modulation of cell function.

115
Q

What are the effects of RONs?

A

DNA damage
activation fo inflammatory gene transcription e.g. NFKB
Amino acid modifications, which may cause immunogenicity or inactivation of serpins
Matrix modifications
cell apoptosis and necrosis

Infection and immunity (13 decks)

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