Immunosuppressants Flashcards
(273 cards)
1
Q
What causes redness (rubor) in inflammation?
A
Increase in local blood flow cause by vasodilatation triggered by inflammatory mediators
2
Q
What causes swelling (tumor) in inflammation?
A
Increase in vascular permeability causing proteins and fluid to leak from the vasculature
3
Q
What is the triple response of Lewis?
A
- Flush
- Flare
- Wheal
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
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
6
Q
What causes wheal following a noxious stimulus?
A
Histamine causes increased vascular permeability leading to localised swelling
7
Q
Which receptors mediate the inflammatory effects of histamine?
A
H1 receptors
8
Q
What is orthodromic propagation of an action potential?
A
From sensory nerve to spinal cord
9
Q
What is antidromic propagation of an action potential?
A
Along collateral branches
10
Q
Give two inflammatory substances that collateral nerve branches might secrete?
A
- Calcitonin gene-related peptide (CGRP)
2. Substance P
11
Q
What are the actions of CGRP?
A
Directly causes vasodilatation
12
Q
What are the actions of substance P?
A
- Directly causes vasodilatation
2. Potent activator of mast cell degranulation
13
Q
What is the effect of mast cell degranulation?
A
Local production of histamine
Causes vasodilatation and increased vascular permeability
14
Q
What is dermatographic urticaria?
A
Triple response is exaggerated
Largely idiopathic
15
Q
How is dermatographic urticaria treated?
A
- H1-receptor antagonists
2. Omalizumab
16
Q
What causes inflammation?
A
- Noxious stimuli
- Bacterial/viral/fungal infection
- Autoimmune reactions
17
Q
How do pathogens cause inflammation?
A
- Release of toxins
- Lysis of host cells, liberating inflammatory factors
- Activation of innate and adaptive immune systems
18
Q
Which inflammatory factors may be liberated by pathogen lysis of host cells?
A
ATP
19
Q
Which pathogen secretes alpha-haemolysin?
A
Uropathogenic E. coli
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)
21
Q
What kind of receptors are toll-like receptors (TLRs)?
A
Receptor tyrosine kinase
22
Q
Where is TLR4 expressed?
A
Plasma membrane
23
Q
What does TLR4 detect?
A
Lipopolysaccharide
24
Q
What does TLR8 detect?
A
ssRNA
25
What is the effect of TLR activation?
Initiates production of pro-inflammatory mediators
26
What are some of the pro-inflammatory mediators produced following TLR activation?
1. Prostaglandins
2. Histamine
3. TNFα
4. IL-1
27
What is the role of TNFα and IL-1 in inflammation?
1. Induce production of further cytokines
2. Increase vascular permeability
3. Cause expression of adhesion molecules on the endothelium of post-capillary venules
28
What is the function of cell adhesion molecules?
Leukocytes adhere to them, enabling them to migrate out of the vascular system and into tissues so that they may attack pathogens
29
What process guides leukocyte migration?
1. Pathogen-generated chemotaxins
| 2. Host chemokines induced by pathogen
30
What does exudate contain?
Components of:
1. Complement system
2. Coagulation system
3. Fibrinolytic system
4. Kinin system
31
How is factor XII activated?
Upon contacting negatively-charged substances such as collagen
32
What is the role of factor XIIa?
Production of:
1. Plasmin
2. Thrombin
3. Bradykinin
33
What are the roles of plasmin and thrombin in complement?
Hydrolyse C3 to C3a and C3b
34
What is the role of C3a?
Stimulates mast cells
35
What is the role of C3b?
1. Attaches to pathogens aiding their destruction by white blood cells
2. Cleaves C5 to C5a and C5b
36
What is the role of C5a?
1. Activates mast cells
2. Chemoattractive for white blood cells
3. Activates white blood cells
37
How is the membrane attack complex formed?
One subunit each of C5b, C6, C7 and C8
| 12-1 subunits of C9
38
What is the role of the membrane attack complex?
Attaches to bacterial membranes and forms a pore
Induces lysis
39
Where do cells involved in inflammation leave the bloodstream?
Venules
| not arterioles
40
Which white blood cells are the first to reach the site of injury?
Neutrophils
41
What are selectins?
Adhesion molecules
42
What causes neutrophils to be tethered to and captured by the endothelium?
Interaction between endothelium P-selectin and neutrophil-expressed ligands, such as P-selectin glycoprotein 1
43
What interactions does firm arrest and adhesion of neutrophils involve?
Between neutrophil expressed integrins such as lymphocyte-associated antigen 1 and intercellular adhesion molecule 1 expressed by the endothelium
44
How long does transmigration across endothelium and basement membrane take?
~15 minutes
45
What does transmigration of neutrophils require?
1. Integrins
| 2. Adhesion molecules such as platelet/endothelial cell adhesion molecule 1
46
What are the two routes of neutrophil transmigration?
1. Paracellularly
| 2. Transcellularly
47
What is fMLF?
Bacteria derived
Attracts neutrophils to bacterial invader
48
How do neutrophils eliminate pathogens?
1. Phagocytosis
2. Degranulation
3. NETs
49
What molecules might a neutrophil secrete to kill pathogens?
1. ROS
| 2. Antibacterial proteins
50
What antibacterial proteins might a neutrophil secrete to kill pathogens?
1. Cathepsin
2. Lysozyme
3. Defensins
51
What is neutrophil degranulation?
Release of antibacterial proteins into extracellular fluid
52
What are NETs?
Neutrophil extracellular traps
Composed of core DNA element alongside enzymes that immobilise pathogens
Prevents spread and facilitates phagocytosis
53
What receptors do mast cells have?
1. TLRs
2. C3a
3. C5a
4. IgE
54
What does stimulation of mast cell receptors cause?
Release of:
1. Histamines
2. Heparin
3. Leukotrienes
4. NGF
5. Preformed packets of cytokines
55
What is histamine formed from?
Histidine by histidine decarboxylase
56
Where is histamine found at the cellular level?
1. Mast cells
2. Basophils
3. Enterchromaffin-like cells in gut
4. Histaminergic neurons in brain
57
How is histamine packaged in mast cells and basophils?
In acidic granules with nigh molecular weight heparin called macroheparin
58
How is histamine released from mast cells?
Granules exocytosed following increased levels of intracellular calcium
59
How do C3a and C5a induce degranulation?
Gi-coupled receptors
βγ subunits activate PLCβ
Induces intracellular calcium release via IP3
60
How does substance P induce degranulation?
Via Mas-related gene X2 receptors
Gq coupled
PLCβ/IP3 mediated calcium release
61
How does IgE induce degranulation?
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
62
What are the four histamine receptors?
1. H1
2. H2
3. H3
4. H4
63
How does the H1 receptor mediate its effects?
Gq/11-coupled
PLCβ
IP3 + DAG/PKC
64
What is H1 receptor important in?
1. Inflammation
2. Smooth muscle contraction in ileum, uterus and bronchioles
3. Blood vessel dilatation
4. Triple response
65
How does the H2 receptor mediate its effects?
Gs-coupled
Increased AC
Increased cAMP/PKA
66
What is the H2 receptor important in?
1. Gastric acid secretion
| 2. Increased heart rate
67
How does the H3 receptor mediate its effects?
Gi-coupled
Decreased AC
Decreased cAMP/PKA
68
What is the H3 receptor important in?
Inhibitory autoreceptor in CNS
69
How does the H4 receptor mediate its effects?
Gi-coupled
Decreased AC
Decreased cAMP/PKA
70
What is the H4 receptor important in?
1. Chemotaxis
| 2. Cytokine release
71
Which two enzymes metabolise histamine?
1. Histaminase
| 2. Histamine N-methyltransferase
72
How does histaminase metabolise histamine?
Oxidatively deaminates histamine
Produces imidazole acetaldehyde
73
How does histamine N-methyltransferase metabolise histamine?
Catalyses transfer of methyl group onto nitrogen of imidazole ring
Produces NT-methylhistamine
74
What are the pathophysiological roles of histamine?
1. Allergy
2. Anaphylaxis
3. Driver of symptoms of mastocytosis
75
What is mastocytosis?
Too many mast cells present leading to an excessive allergic-type attack
76
What causes mastocytosis?
Gain of function mutation in receptor tyrosine kinase c-kit/CD117
Causes enhanced mast cell proliferation and survival
77
Which drugs may be used to treat pathology associated with histamine?
1. Sodium cromoglycate
2. Salbutamol
3. Salmeterol
4. Theophylline
5. Omalizumab
78
What are anti-histamines?
H1-receptor antagonists
79
What is the main treatment of anaphylactic shock?
Adrenaline injection
Administered intramuscularly or intravenously
Counteracts systemic vasodilatation and reduced tissue perfusion
Relieves bronchospasm
80
When is imatinib efficacious in treating mastocytosis?
In patients without D816V c-Kit mutation
81
What are H2-receptor antagonists used for?
Reduce gastric acid secretion
82
What is the pH at the mucosal surface of the stomach?
pH 6-7
83
What is the effect of gastrin on histamine release?
It enhances it by acting on CCK2 receptors
84
What are the treatments for peptic ulcers?
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
85
How do NSAIDs contribute to gastric ulcers?
Inhibit prostaglandin synthesis
PGE2 acts on ECL cells to inhibit gastric acid secretion and increase mucin and bicarbonate secretion
86
How is bradykinin formed?
Action of kallikrein upon kininogens
Factor XIIa converts plasma pre-kallikrein to kallikrein
Kallikrein clips HMW-kininogen to bradykinin
87
What is another term for Factor XII?
Hageman factor
88
What does kallikrein cleave LMW-kininogen to?
Kallidin
In tissues
89
How is bradykinin inactivated?
Kininase I removes C terminal arginine to form des-Arg-bradykinin
Kininase II removes two C terminal amino acids
90
What is another term for kininase II?
Angiotensin-converting enzyme
91
What is des-Arg-bradykinin?
Product of bradykinin breakdown by kininase I
Agonist at bradykinin B1 receptors
92
What kind of receptors are the bradykinin receptors?
Gq-coupled GPCR
93
When are B1 receptors most active?
Upregulated during inflammation
By actions of IL-1 and inflammatory cytokines
94
When are B2 receptors most active?
Constitutively expressed
Potently activated by bradykinin and kallidin
95
What is the result of bradykinin receptor activation in the endothelium?
Increase in [Ca2+]
Activates cytosolic phospholipase A2
Increases PGI2 production and eNOS
Causes vasodilatation
Activates nociceptors and drives pain
96
How does bradykinin induce nociceptor activation?
Activation of Gq GPCRs
Activation of PKC
Phosphorylates numerous ion channels involved in pain
97
What is the role of C1-esterase inhibitor?
Inhibits kallikrein
98
What is hereditary angiooedema?
Mutation in gene encoding C1-esterase inhibitor
Excessive levels of bradykinin
Sufferers experience periods of severe and painful swelling
99
What are the four main groups of cytokines?
1. Interleukins
2. Cytokines
3. Colony-stimulating factors
4. Interferons
100
What are the key pro-inflammatory interleukins?
1. Il-1
| 2. TNFα
101
What are the pro-inflammatory interleukins released by?
Macrophages
102
What is the role of the pro-inflammatory interleukins?
1. Induce expression of further cytokines
2. Promote proliferation and maturation of other immune cells
3. Cause fever (IL-1 only)
103
What are the key anti-inflammatory interleukins?
1. IL-10
| 2. IL-1ra
104
What is the role of anti-inflammatory interleukins?
1. Inhibit expression of cytokines
| 2. Inhibit some T cell responses
105
Give three examples of chemokines
1. CCL3
2. CXC
3. CX3C
106
What is the role of CCL3?
Induces mast cell degranulation
Acts at CCR1 receptors
107
What kind of receptors are chemokine receptors?
GPCR
108
What is the role of IFNα and IFNβ?
Anti-viral activity
109
What is the role of IFNγ?
Induces TH1 responses
110
What is the role of colony-stimulating factors?
Stimulate formation of maturing colonies of leukocytes
Used to overcome deficits in a person's white blood cell count
111
What is nerve growth factor released from?
1. Macrophages
| 2. Mast cells
112
What is nerve growth factor?
Potent sensitising agent
Causes allodynia
113
How does nerve growth factor cause allodynia?
High affinity NGF receptor tropomyosin-related kinase A
114
What are lipid mediators?
1. Leukotrienes
2. Platelet-activating factor
3. Prostanoids
115
How are lipid mediators produced?
On demand from membrane phospholipids by phospholipases
116
What is the main precursor for lipid mediators?
Arachidonic acid
117
What is the rate-limiting step for eicosanoid synthesis?
Liberation of arachidonic acid from membrane phospholipids
Involves PLA2
118
How is cytosolic PLA2 activated?
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
What is the precursor of platelet-activating factor?
Lysoglyceryl-phosphorylcholine (lysoPAF)
120
How are leukotrienes synthesised?
By lipoxygenase enzymes from arachidonic acid
121
What are lipoxygenase enzymes?
Cytosolic enzymes
Expressed primarily in lungs and leukocytes
122
What is 12-HETE?
Chemotaxin
Produced from arachidonic acid by 12-lipoxygenase
123
What is leukotriene A4?
Produced from arachidonic acid by 5-lipoxygenase
124
What is LTA4 converted to?
1. LTB4 in cells expressing LTA4 hydrolase
| 2. LTC4 in cells expressing LTC4 synthase
125
What is LTC4 converted to?
LTD4 and LTE4
126
What are cysteinyl leukotrienes (cysLT)?
LTC4-E4
127
What kind of receptors are leukotriene receptors?
GPCR
128
What kind of receptors are BLT receptors?
Gq or Gi-coupled GPCR
129
What kind of receptors are cysLT receptors?
Gq coupled GPCR
130
What is the role of LTB4?
1. Potent chemoattractant
2. Activator of neutrophils and macrophages
3. Upregulates neutrophil adhesion molecule expression
4. Promotes macrophage cytokine release
131
What is the role of cysLTs?
1. Cause bronchoconstriction
2. Increase vascular permeability
3. Increase mucous secretion
132
Which cells release cysLTs?
1. Mast cells
| 2. Eosinophils
133
How are lipoxins synthesised?
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
What receptor does LXA4 bind to?
Formylpeptide receptor 2
Gi-coupled
135
What is the effect of LXA4?
1. Reduce neutrophil chemotaxis
2. Reduce degranulation
3. Antagonist of cysLT1 receptors
136
What is the effect of platelet-activating factor?
1. Increases thromboxane production in platelets
2. Spasmogenic
3. Chemotactic for neutrophils
4. Activates PLA2
137
How are prostaglandins synthesised?
Metabolism of arachidonic acid by cyclo-oxygenase enzymes
138
Where is COX-1 expressed?
Constitutively in most tissues
139
Where is COX-2 expressed?
Induced in inflammation
Some constitutive expression
140
What are the sources of prostanoids in inflammation?
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
What receptors to prostanoids act at?
GPCRs
142
What are DP1, EP2, EP4 and IP receptors?
Prostanoid receptors
Gs-coupled
Increase cAMP production
143
What are EP1, FP and TP receptors?
Prostanoid receptors
Gq-coupled
Increase [Ca2+]
144
What are DP2 and EP3 receptors?
Prostanoid receptors
Gi-coupled
Decrease cAMP production
145
What is the role of PGD2?
1. Vasodilatation
2. Inhibition of platelet aggregation
3. Relaxation of GI/uterine smooth muscle via DP1 receptors
4. Bronchoconstriction via TP receptors
146
What is the role of PGE2?
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
What is the role of PGI2?
1. Vasodilatation
| 2. Inhibition of platelet aggregation
148
What is the role of TXA2?
1. Vasoconstriction
2. Bronchoconstriction
3. Platelet aggregation
149
What is the role of PGF2α?
1. Uterine contraction in humans
| 2. Bronchoconstriction in cats/dogs
150
How does platelet aggregation balance shift following damage to endothelium?
Shifts towards TXA2
151
What is fish oil high in?
Eicosapentanoic acids
152
What do eicosapentanoic acids produce?
PGI3 and TXA3
Protection against heart attacks
153
How do NSAIDs act?
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
How do the hydrophobic channels of COX enzymes differ
COX-1 = narrow
COX-2 = wider
155
What is the main feature of COX-2 selective NSAIDs?
Bulky sulphur-containing side group that doesn't fit in COX-1
156
What is the most common side effect of NSAIDs?
GI bleeding
157
What is the risk associated with COX-2 inhibitors?
Increased myocardial risk
Due to decreased PGI2 production leading to less vasodilatation and more platelet aggregation
158
How does aspirin act?
Acetylates serine 530
Irreversibly inactivates COX
159
What are the effects of aspirin at low doses?
Inhibits platelet aggregation
160
What is the result of aspirin acetylating COX-2?
Produces 15R-HETE instead of usual intermediates
Converted to aspirin-triggered lipoxin by 5-lipoxygenase
161
What are the effects of aspirin-triggered lipoxin?
Similar to LXA4
Explains anti-inflammatory effects of aspirin
162
What are the side effects of NSAIDs?
1. GI bleeding
2. Renal insufficiency
3. Nephropathy
4. Stroke/MI
5. Bronchospasm
163
What is Reye's Syndrome?
Occurs almost exclusively in children
Hepatic encephalopathy
Occurs when aspirin taken for treating viral symptoms
164
What is salicylism?
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
How is salicylism treated?
Fluids
Bicarbonate
Activated charcoal adsorbs aspirin in GI tract
Haemodialysis in severe cases
166
What are the effects of paracetamol?
1. Analgesic
| 2. Antipyretic
167
How does paracetamol act?
COX inhibitor
Some COX-2 selectivity
Reduces site responsible for production of PGH2 and PGG2
168
How is paracetamol eliminated?
1. Conjugation via hepatic conjugation enzymes
| 2. Metabolised to NAPQI by oxidases
169
How is NAPQI metabolised normally?
Conjugated to glutathione
170
What does NAPQI do in cases of paracetamol overdose?
Oxidises thiol groups of cellular proteins
Major hepatic and renal toxicity
171
What are the symptoms of paracetamol overdose?
24-48 hours post-ingestion
Begin with nausea and vomiting
Liver failure-induced death
172
Which drugs may be administered to prevent liver toxicity following paracetamol overdose?
Substances that increase hepatic glutathione production
1. Acetylcysteine
2. Methionine
173
What is the toxic dose of paracetamol?
150mg/kg body weight
174
How does alcohol increase risk of paracetamol toxicity?
Upregulates Cyp2E1
Converts paracetamol to NAPQI
175
Why is paracetamol not suitable for cats?
They lack ability to conjugate salicylate with glycine
176
Why are high 5HT levels observed in the serum after coagulation?
Platelets contain 5HT and release it during activation and aggregation
177
What is the effect of 5HT in the blood?
1. Induces further platelet aggregation
| 2. Causes vasoconstriction
178
Which cells express 5HT?
1. Platelets
2. Intestinal enterochromaffin cells
3. Serotonergic neurons of enteric and central nervous systems
179
How is 5HT synthesised?
From tryptophan by:
1. Tryptophan hydroxylase (Tph)
2. L-aromatic acid decarboxylase
180
What is the rate-limiting step in 5HT synthesis?
Tryptophan hydroxylase step
181
Where is SERT expressed?
Serotonin transporter
Platelets
182
What is the role of SERT?
Enables platelets to become loaded with 5HT
183
How is 5HT degraded?
1. Oxidative deamination by monoamine oxidase
| 2. Oxidation
184
What is the degradation product of 5HT?
5-hydroxyindoleacetic acid (5-HIAA)
185
How is 5-HIAA excreted?
In the urine
186
What kind of receptor is 5-HT1A – F?
Gi-coupled
187
What kind of receptor is 5-HT2A – C?
Gq-coupled
188
What kind of receptor is 5-HT3?
Ionotropic receptor/ligand gated ion channel
189
What kind of receptor is 5-HT4?
Gs-coupled
190
What kind of receptor is 5-HT5A?
Gi-coupled
191
What kind of receptor is 5-HT6?
Gs-coupled
192
What kind of receptor is 5-HT7?
Gs-coupled
193
What is emesis?
Vomiting
194
What are the two key components governing emesis?
1. Vomiting centre
2. Chemoreceptor trigger zone (CTZ)
Located in medulla
195
How is the CTZ activated?
1. Circulating chemicals
2. Visceral afferents
3. Input from vestibular nuclei
196
What receptors are found in the CTZ that mediate emesis?
5-HT3 receptors
197
Which animals cannot vomit?
1. Rodents
| 2. Horses
198
What is migraine?
Severe headache
Unilateral
Throbbing
Accompanied by nausea and vomiting, photophobia and prostration
199
What is aura?
Progressive visual disturbance associated with onset of migraine
200
What are the three main hypotheses for migraine attacks?
1. Vascular hypothesis
2. Brain hypothesis
3. Inflammation hypothesis
201
What is the vascular hypothesis for migraine attacks?
Intracerebral vasoconstriction causes aura
Extracerebral vasodilatation causes headache
202
What is the brain hypothesis for migraine attacks?
Wave of cortical spreading depression across brain strongly associated with aura
Slowly propagating wave of near complete depolarisation
Silences neuronal electrical activity
203
What is the inflammation hypothesis for migraine attacks?
Activation of trigeminal nociceptors that innervate meninges and extracranial blood vessels
Causes pain and neurogenic inflammation
204
What occurs to 5-HT during migraine?
Blood 5-HT levels drop
Urine 5-HIAA levels rise
205
What are the two phases of the adaptive response?
1. Inductive phase
| 2. Effector phase
206
Which receptors do activated CD4+ cells express?
IL-2 receptors
207
Which cytokines do activated CD4+ cells express?
IL-2
Autocrine
208
What is the effect of IL-2 on CD4+ cells?
Generation and proliferation of TH0 cells
209
What is the effect of autocrine action of IL-4?
Production of TH2 cells
210
What is the effect of TH2 cells?
Activate B cells to proliferate and give rise to plasma cells and memory B cells
211
Which cytokines cause the differentiation of TH0 cells into TH1, TH17 and iTreg cells?
1. IL-2
2. IL-6
3. IL-10
212
What are Tregs responsible for?
Restrain immune response
Prevent excessive immune response
213
What is the effect of TH1 and TH17 cells?
Secrete cytokines that activate macrophages
214
What is the autocrine effect of IL-2 on CD8+ cells?
Generate cytotoxic T cells
215
What is the role of cytotoxic T cells?
Kill virally infected cells
216
In which conditions does TH1 response predominate?
1. IDDM
2. MS
3. Rheumatoid arthritis
4. Graft rejection
217
In which conditions does TH2 response predominate?
Asthma
218
What are corticosteroids?
Mimic action of endogenous glucocorticoids
Suppress immune response
219
Where are glucocorticoids synthesised?
Adrenal cortex
220
What causes glucocorticoid synthesis?
Circulating ACTH released from pituitary gland
221
What controls ACTH synthesis?
Corticotrophin-releasing factor
Released from hypothalamus
222
What are some of the metabolic actions of corticosteroids?
1. Decreased uptake of glucose by muscle/fat
2. Increased gluconeogenesis
3. Increased protein catabolism
4. Decreased protein anabolism
5. Redistribution of fat
223
What are the inflammatory actions of corticosteroids?
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
What are the main anti-inflammatory cytokines?
1. IL-10
2. IL-1ra
3. Lipocortin 1
4. Secretory leukocyte inhibitory protein
5. IKB
225
Which receptor do corticosteroids bind to?
Glucocorticoid receptor (GRα)
226
What kind of receptor is the glucocorticoid receptor?
Nuclear receptor
Present as homomer in cytoplasm
Bound to heat shock protein 90
227
What is the effect of corticosteroids binding to their receptor?
Forms homodimers
Transactivate or transrepress range of genes
228
How can ligand-bound GRα regulate gene expression?
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
What are the side effects of corticosteroid treatment?
1. Opportunistic infection
2. Impaired wound healing
3. Oral thrush
4. Osteoporosis
5. Hyperglycaemia
6. Muscle wasting
230
What is Cushing's syndrome?
Due to excess cortisol
Also caused by ACTH-secreting tumour (pituitary adenoma causes Cushing's disease)
231
What are the symptoms of Cushing's syndrome?
1. Pot-bellied appearance
2. Hair loss
3. Polydipsia
4. Polyuria
232
What is the length of action of hydrocortisone?
233
What is the length of action of dexamethasone?
>48 hours
234
What is Addison's disease?
Adrenal glands fail to produce sufficient steroid hormones
235
What can corticosteroids be used to treat?
1. Addison's disease
2. Asthma
3. Inflammatory skin conditions
4. Rheumatoid arthritis
5. Prevent graft rejection
6. Reduce cerebral oedema
236
What is asthma?
Intermittent attacks of wheezing and shortness of breath
1. Inflammation of airways
2. Bronchial hyperactivity
3. Reversible bronchoconstriction
237
How does an immune response arise in allergic asthma?
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
What do TH2 lymphocytes do in asthma?
1. Release IL-5
2. Release IL-4
3. Release IL-13
239
What is the role of IL-5 in asthma?
Eosinophil priming
240
What is the role of IL-4 and IL-13 in asthma?
1. Switch B cells into producing IgE
| 2. Induce IgE receptor expression in mast cells and eosinophils
241
What is the effect of allergen-induced FcεRI cross-linking in asthma?
1. Mast cell degranulation
2. Release of histamine
3. Release of CysLTs
Causes powerful bronchoconstriction and increase in vascular permeability
242
What factors do mast cells release in an acute asthma attack?
1. IL-4
2. IL-5
3. IL-13
4. TNFα
5. Chemotaxins that recruit macrophages and eosinophils
243
What occurs in the delayed phase of an asthma attack?
1. Eosinophils recruited to mucosal surface
2. Release CysLTs and granule proteins
3. Damage to epithelium resulting in airway hypersensitivity
244
Which granule proteins are released in the delayed phase of an asthma attack?
1. Eosinophil cationic protein
| 2. Eosinophil major basic protein
245
What is the effect of epithelial cell loss in the airway?
Nociceptive C-fbires more accessible to irritant stimuli, leading to hypersensitivity
246
What are the two types of treatment for asthma?
1. Bronchodilators
| 2. Anti-inflammatories
247
When are bronchodilators used?
Acute attacks
248
When are anti-inflammatories used?
Prophylactically
To limit inflammatory components of acute and late phase of response
249
Where do β2-adrenoreceptor agonists act?
Gs-coupled β2-adrenoreceptors in bronchial smooth muscle induce relaxation and bronchodilation
In mast cells, inhibits degranulation
250
What are the side effects of β2-adrenoreceptor agonists?
1. Tremor
| 2. Tachycardia
251
Which drugs are used to treat COPD?
Long-acting β2-adrenoreceptor agonists, especially ultra-long-acting
252
What is Grave's disease?
Hyperthyroidism
Auto-antibodies to thyrotropin receptor causing increased thyroxine release
253
What is Hashimoto's disease?
Hypothyroidism
Autoantibodies against proteins involved in thyroxine synthesis
254
What is myasthenia gravis?
Autoantibodies against nicotinic ACh receptor preventing effects of acetylcholine
255
What is type 1 diabetes mellitus?
Antibodies against islet cells and insulin
256
What is multiple sclerosis?
Immune attack against oligodendrocytes that form myelin sheaths
257
What is primary biliary cirrhosis?
Immune attack against bile ducts of liver
258
What is rheumatoid arthritis?
Immune attack on synovium surrounding joints
259
What is responsible for the joint damage in rheumatoid arthritis?
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
What are the inflammatory cells involved in rheumatoid arthritis?
Neutrophils release proteases and ROS
261
What is pannus formation?
Hyperplasia of synovium in rheumatoid arthritis
Fibroblast-like synoviocytes proliferate and invade the joint and release pro-inflammatory cytokines and proteases
262
What are DMARDs?
Disease-modifying antirheumatic drugs
Reduce disease progression
Eg. methotrexate
263
What are myeloma cells?
HPRT -ve
Immortalised tumour cells used for mAb production
264
What are the two key domains of the antibody?
1. Fc region
| 2. Fab region
265
What does the Fc region do?
Reacts with cell surface Fc receptors expressed on neutrophils, macrophages and natural killer cells
266
What does the Fab region do?
Fragment antigen binding
Contains variable and hypervariable regions that bind to antigen epitopes
267
What is -ximab?
Chimeric mAb
268
What is -axomab?
Rat/mouse hybrid
269
What is -zumab?
Humanised
270
What is -umab?
Human
271
What are bi-specific antibodies?
Stitching together two halves of different antibodies
One binds target cell and one binds cytotoxic cell
Used in cancer
272
What is the effect of afucosylation of antibodies?
Higher affinity for FcγRIII on NK cells
Overcome competition with serum IgG
273
How can mAbs be modified to make them more potent?
1. Bi-specific antibodies
2. Afucosylation
3. Conjugation with toxins
4. Improved pharmacokinetics of Fc region
