Week #8 Flashcards
(123 cards)
1
Q
List some ways in which Mast cells can be activated internal and external
A
External
- allergen (IgE)
- stings
- mechanical stimulation
- uv light/heat
- osmotic stimuli hypertonic saline
- vancomycin
Internal
- activated complement
- neuropeptides
2
Q
How does exercise induce a change in osmolarity and what is the effect on Mast cells?
A
- in exercise minute ventilation rises and this causes loss of fluid in the airway and then consequently the osmolarity of the airway fluid rises and that change triggers Mast cell degranulation
3
Q
Atopic individuals are those which?
A
Have produced allergen specific IgE that has now bind to Mast cells and has sensitised them
4
Q
What is the intracellular signalling that occurs upon cross linking of the FcεR1 receptors upon IgE binding to allergen
A
- Adjacent IgE molecules bind allergen (external)
- Adjacent ΙgΕ receptor FcεR1 (α, β & 2γ) cluster
- β & γ chains phosphorylated (internal)
- Recruitment and activation of cellular tyrosine kinase Syk
- Phospholipase C phosphorylation and activation and activation of the MAPK pathway
- Phospholipase C goes onto cause degranulation through protein kinase C activity and Ca2+ release as well as activations of arachadonic acid metabolites and cytokine gene transcription
- MAPK pathway also results in cytokine gene transcription and the activation of the arachadonic acid pathway
5
Q
In a Mast cell response what is released at each time point:
Immediate?
Rapid (10-30 minutes)?
Late?
A
Immediate
- release of preformed mediators, Histamine, Heparin, Tryptase, TNF-alpha
Rapid
- Arachodonic acid activation
- Cys-LTs
- PGD2
Slow
- IL-4
- IL-5
- GM-CSF
6
Q
Mast cells release IL-4, IL-5 and GM-CS, what is their role?
A
- IL-4 reinforces the Th2 phenotype and results in more IgE production
- IL-5 recruits eosinophils
- GM-CSF promotes the survival of eosinophils and activates macrophages
7
Q
What are some of the actions of histamine and where is it acting? i.e. H1 or H2
A
- Pain & itch (sensory nerve activation) (H1 receptors)
- Bronchospasm (H1 receptors)
- Mucus secretion (H1 receptors)
- Vasodilatation - hypotension (H1 receptors)
- Increased vascular “leak” - hypovolemia (H1 receptors)
- CNS - increased wakefullness (H1 receptors)
- Positive inotropic and chronotropic (H2 receptors expressed in heart)
- Gastric acid secretion (H2 receptors)
8
Q
Product of AA metabolism: Cyteinyl leukotrienes
How is LTC4 synthesised?
What is the action (local and systemic) of LTC4 and metabolites (LTD4 and LTE4)?
A
- Glutathione-S-transferase is responsible for the synthesis of LTC4 from LTA4
- LTC4 and metabolites (LTD4 and LTE4) act on CysLT1 receptor
- Thought to have a mainly pathophysiological role and so are a good drug target
- Local action can include airway smooth muscle contraction causing bronchoconstriction and can also cause increased mucous secretion and oedema
- Systemic action-together with histamine can cause massive vasodilatory response contributing to anaphylaxis
- also cause leak from vessels which together with histamine can cause hypovolemia
9
Q
The Arachodonic acid pathway is split into two parts, what are they?
A
The prostoglandin half and the leukotriene half
10
Q
What are some of the drug targets in the Arachodonic acid pathway
A
- Note that aspirin has no real effect in asthma indicating that PGD2 has a limited role to play even thoug it is a bronchoconstrictor
11
Q
Role of cytokine release by Mast cells upon activation in alergy.
What are the cytokines released and what is the role of each?
A
- IL-4 (Th2 IgE), IL-5(eosinophil recruitment), TNF and GM-CSF(eosinophil survival and macrophage activation)
- produced in response to activation of transcription factors-so it is a slow onset
12
Q
What are some inhibitors of mast cell activation
endogenous and exogenous
A
- endogenous=PGE2, adrenaline and cortisol
- Exogenous (pharmacological)
- Disodium cromoglycate/Nedocromil sodium
- Omalizumab
13
Q
Omalizumab
A
- A humanised murine monoclonal antibody
- Administered subcutaneously
- Omalizumab directed against the alpha subunit binding region of the IgE
- The IgE can no longer bind the high affinity receptor on the Mast cell
- Must be administerred sub-cutaneously and is very expensive
14
Q
Disodium cromoglycate/Nedocromil sodium
A
- very well tolerated
- modest anti-inflammatory action only
- not effective in all patients
- reduction in Mast cell activation but mechanims not entirely clear
- cause annexin-1 release which can resolve inflammation as it
- annexin-1 is one of the medaitors of the glucocorticoid ant-inflammatory activity
*
- annexin-1 is one of the medaitors of the glucocorticoid ant-inflammatory activity
- cause annexin-1 release which can resolve inflammation as it
15
Q
H1 receptor antagonists
A
- urticaria
- atopic dermatitis (adjunct to steroids)
- hayfever (allergic rhinitis)
- anaphylaxis & angioedema (adjunct to adrenaline)
- bites & stings
- motion sickness (muscarinic antagonist activity)
Note that H1 receptor antagonists are not useful in colds or asthma
16
Q
Are H1 receptor antagonists good for treating colds and asthma?
A
nope
17
Q
What are the three generations of antihistamines (i.e. H1 receptor antagonists)
A
- Sedative- chlorpheniramine, promethazine
- Sedation may be neutral/beneficial in treatment of allergic condition, but sufficient to interfere with lifestyle.
- Non-sedative (poor entry into CNS)-terfenadine, astemizole
- Lack anti-muscarinic activity and GIT effects but can cause rare, sudden ventricular arrhythmia (withdrawn)
- Newer non-sedative agents-cetirizine, loratidine
- Reduced risk of unwanted cardiac effects
18
Q
What are the two phases of Type I Hypersensitivity?
A
- Sensitization
- Response (effector phase)
- local or systemic (rare)
- Local=rhinitis, bronchoconstriction, conjunctivitis
- Systemic=anaphylaxis
- Responses have an immediate and a delayed phase
- local or systemic (rare)
19
Q
DC cannot actually make IL-4, so how are Th2 cells induced?
A
- DC make IL-33 instead which then acts on nearby basophils which then make IL-4 which then acts on the T cells to induce the Th2 phenotype and they go on to make more IL-4 themselves
- New Nature paper says now that perhaps basophils express MHC-II and can stimulate CD4 T cells directly
20
Q
Wheal and Flare (type I hypersensitivity)
A
- immediate (minutes)
- due to preformed mediators from mast cells
- redness-vasodilation
- soft swelling-leakage of plasma from venules
- dependent on IgE
21
Q
Late response (hypersensitivity type I)
A
- Late (hours-days)
- due to induced mediators from mast cells (leukotrienes, cytokines etc)
- hard swelling-accumulation of leukocytes
- neutrophils, Th2 cells and eosinophils
22
Q
Allergic reaction can occur in the skin, GI tract or airways or blood vessels
what occurs in each?
A
23
Q
Eosinophils involved in late phase response (cellular response)
how do they cause damage?
how are they activated and recruited?
and what happens to them when they are activated?
A
- produce toxic granule-derived basic proteins and free radicals
- responsible for tissue damage/remodeling
- produce chemical mediators
- Epithelial cell activation, inflammatory cell recruitment and activation
Special Chemokine produced by epithelial cells is called eotaxins and is responsible for eosinophil recruitment
Decreased threshold of activation and degranulation
(increased senstivity)
- after activation get ↑ number of FcERI on surface and IgE binding
- decrease the threshold for activation
24
Q
How do corticosteroids work against allergies?
A
- inhibit the transcription of many pro-inflammatory genes (cytokines etc) and cause broad immunosupression
- so can be harmful in that we get a non-sepcific dampening of the immune response which could lead to susceptibility to infection
- another side effect is bone deminerilization
- because of both of these reasons prolonged use is not recommended
25
Immunotherapies/Desensitization
* Attempt to induce tolerance
* T cell tolerance
* may induce anergy
* switch the Th response-perhaps to Th1
* induce apoptosis
* or perhaps throught the induction of a Treg response
26
Type IV hypersensitivity
* A Th1 response but can involve CD8 T cells in some cases
* Can be elicited by
* microbial infection
* intradermal injection of protein antigens
* contact with chemicals etc absorbed through skin
* There is a sensitization phase where Th1 cells are induced and travel back to site of exposure
* But there is no immediate response (no wheal and flare)
* that is becasue the response is all cellular
27
What is the mechanism of conntact hypersensitivity?
(Delayed Hypersensitivity type IV)
pentadecacatechol as example
* thought that because pentadecacatechol is so small it must haptenise by binding to some other intracellular protein and then that is expressed on MHC-II molecules
* licensing of DC occurs and activation of Th1 cells
* this is sensitization
* and then on secondary exposure we get a response that is seen as the delayed type hypersensitivity IV
* Th1 and IFNy production
28
Mycobacterium Tuberculosis is a Type IV hypersensitivity?
* yes
* infects the macrophages
* M.tuberculosis multiply in macrophage and then CD4 T cells and CD8 T cells will arrive to try to clear infection and then basically it just goes in circles
* so the immune system just walls the infeciton off and these are called granulomas
* The good news is that the DTH response restricts the growth of the microbe, so that 90% of those infected are not infectious and never know they are infected
* The bad news is that in a small number of individuals, the DTH response interrupts respiratory function
29
Celiac Disease
Role of DQ2, tTg2 and gliadins
* type IV but need repeated exposure (so kind of like contact hypersensitivity as opposed to the TB hypersensitivity)
* DTH response that targets components of gliadin protein and then this leads to damage of the small intestine-hyperplasia of villin etc results in low metabolism in the gut
* 90% of patients are HLA DQ2 positive
* also the presence of autoantibodies to gliadins and Tissue transglutaminase are an indicator
**Role of DQ2, tTg2 and gliadins**
* HLA-DQ2 prefers amino acid side chains with negative charges
* because the pocket is positively charged
* gliadins-rich in glutamine=positive charge
* but then tTg2 changes then glutamine to glutamate so that it can can bind DQ2 very easily (deamidation)
30
Diagram of Celiac disease pathophysioogy
31
Post puberty are men or women more likely to get asthma?
Women
32
Asthma inflammation
Diagram of cells and mediators
33
What are the classes of drugs used to treat airway obstruction? Provide an example of each
* Relievers-relieve ASM shortening,
* controllers-control ASM shortening,
* Preventors-prevent ASM shortening, prevent bronchiol wall oedema and prevent mucus hypersecretion
34
What happens if you get a person to do shallow breathing for an hour? i.e. what happens to their airways?
what happens in expiration
* The ASM will actually be more likely to contract due to less filling of the alveoli with air and thus less resistanc to ASM contraction
* can convert someone to an asthmatic airway phenotype
* In **expiration** load decreases and there will be an increase in airway resistance and an increased liklihood of airway collapse
35
What is the airway smooth muscle contractile mechanism in response to calcium?
* Increase in intracellular calcium
* Acivation of calmodulin and this activates myosin light chain kinase
* Myosin light chain is phosphorylated and then causes the actomyosin filament to acquire ATPase activity
* The ATPase activity allows for energy for the cross bridges to cycle
* cross bridges between actin and myosin break and reform sliding past each other resulting in overall cell shortening
36
The contractile mechanism
How does the intracellular Ca2+ levels rise?
How does the intracellular Ca2+ levels fall?
**Increase**
* Phospholipase C acivation which leads to inositol trisphosphate activation which causes Ca2+ release from intracellular stores
**Decrease**
* plasma Ca2+ ATPase - extrusion across plasma membrane sarcoplasmic reticulum Ca2+ATPase (SERCA)
* increase uptake of calcium into internal SR stores
37
Cysteil Leukotrienes are \_\_?\_\_ times as potent as histmaine in terms of bronchoconstriction?
300
and provide a much more protracted response-i.e. effect remain for longe
38
Endogenous mediators that relax airways and endogenous mediators that contract airways?
39
What is the role rho kinase and protein kinase C?
What is the role of protein kinase A?
* inhibits myosin light chain phosphatase
* activate myosin light chain phosphatase
40
What is a definition of airway hyperesponsiveness?
* Airways respond to early and by too much to histmaine leukotrienes etc
41
Short acting Beta-2 Adrenoceptor agonists?
Adverse effects?
* Short-acting - salbutamol, terbutaline (SABA)
* mainstay of acute bronchodilator therapy
* Key features- short acting agents: rapid (2 - 5 min) onset β2 selective (very important)
**Adverse effects**
* tachycardia, tremor, hypokalemia
* Other features- variable degrees of efficacy
* Tolerance (measurable - may be important)
* increasing evidence showing that suggests increased use may cause increased morbidity in certain individulas
*
2
42
How does the Beta-2 Adrenoceptor relax airway smooth muscle?
and what is the action of protein kinase A (3 main actions)
* Receptor has Gs protein coupling which activates adenylate cyclase which generates cAMP
* cAMP activates protein kinase A
* protein kinase A indirectyl increases activity of SERCA **and** inhibit the IP3R calcium receptor
* Protein Kinase A also acts to phosphorylate the myosin light chain kinase to deactivatge it and can also phosphrylate and activate the myosin light chain phosphatase
43
Long acting Beta Agaonists (LABA)
Why is it administerred concomitantly with an inhaled GCS
* Salmeterol - slow onset, 12 hrs duration (twice daily)
* Formoterol - rapid onset, 12 hrs duration (twice daily)
* Indacaterol - rapid onset, 24 hrs duration (once-daily)
reduce number of exacerbations - anti-inflammatory?
* benefit of chronic bronchodilatation
**Side effects**
* tolerance develops to bronchoprotective effects
* same with the SABAs in that with extensive usage may result in increased asthma morbidity
* indicated for prophylaxis only
* monotherapy associated with increased morbidity/mortality
Because the rationale is that asthma is bad enough to justify a LABA it should also be combined with inhaled GCS in single actuator
44
Muscurinic receptor antagonists
How do they stop ASM contraction
and name two examples and there time of action
* parasympathetic cholinergic nerves into the airway that terminate adjacent to smooth muscle
* upon irritation of the airways etc the nerves are activated and acetylcholine released from the nerves act on M3 receptors on the smooth muscle and cause contraction
* Ipratropium bromide-short acting
* Tiotropium bromide-long acting (LAMA)
45
The lung works to maintain a:
PaO2=?
PaCo2=?
pH=?
PaO2 refers to partial O2 pressure in the arteries
100mmHg
40mmHg
7.4
46
Capital A=
lowercase a=
I=
V=
Alveolus
artery
reffering to inspired air
veins
47
Image of pulmonary diffusion across the alveolar capillary membrane
What are someof the properties of the membrane
The membrane is epithelium of the alveolus and a monolayer of endothelium of the blood vessel and is designed for diffusion due to:
1. Thin = 0.5 micron
2. Large surface area = 50 - 100 m
3. Alveolar volume = 3 - 6 L
4. Capillary volume = 80 ml
(greater if ↑ cardiac output)
48
The two kinds of work associated with inspiration are?
* Insipration is an active process as the friction must be overcome-**resistive work of breathing**
* and work of overcoming the elasticity of the lungs is the **elastic work of the lungs**
49
3 main functions of the Respiratory system are?
1. Oxygenate pulmonary arterial blood
2. Remove carbon dioxide from blood
3. Maintain acid-base balance
(because CO2 is an acid)
50
What are the muscles involved in inspiration and what is their innervation
At rest what is the WOB of these muscles?
* The diaphragm is the main muscle and it is innervated by the phrenic nerve
* The external ICM which are innervated by the intercostal nerves
* 3% of total oxygen usage
51
If there is an obstruction of airflow the resistive work of breathing will be much higher and expiration will also become active
What are some consequences of this obstruction?
* Recruitment of accessory muscles (scalene and sternomastoid muscles)
* Increased oxygen consumption by respiratory muscles
* Risk of respiratory muscle fatigue, if the airway obstruction is severe
* respiratory muscle fatigue can lead to ventilatory failure which is said to occur when PaCO2 is greater than 50mmHg
52
What are the pressure changes during expiration and inspiration that occur in the alveolar space and the pleural cavity?
53
Normal FEV1/FVC is?
and what happens to the FEV1 and FVC during obstructive pulmonary disease?
* Normally is around 80% in young healthy individual
* should always be above 70% even in the more elderly
* In OPD the FEV1/FVC can be very low=39%
54
Normal flow loops and abnormal flow loops due to Obstruction
* flow loops are flow vs volume graphs
* usually triangular in expiration and rounded in inspiration
* If obstructed the expiration may be flattened
55
In general the breathing pattern of someone with airflow obstruction will be?
* deep, slow breaths
56
Gas Trapping?
* In some cases of severe airflow obstruction affecting the lower airways, air can be trapped beyond obstructed airways
* ie it can be inspired but not exhaled.
* This causes high TLC, RV and RV/TLC
(measured by body plethysmography, not by spirometry)
57
What arre the effects of airway obstruction?
i.e. physiological effects
1. Increased sensation of breathing
2. Increased respiratory muscle effort
3. Active exhalation
4. Prolonged inspiration and expiration
5. Altered pattern of breathing
6. Reduced maximum ventilation
7. (Gas trapping in some cases)
58
Ventialtion perfusion ration (V/Q)
What is normal?
what is abnormal and what is the consequence of a low V/Q?
What is the bodies response to low V/Q?
* Gas exchange efficiency depends on equal perfusion and ventilation of a single alveolar-capillary unit so we want equal numbers of O2 moleucles arriving with heamoglobin numbers
* consequence of uneven ventilation means that in some A/C units there will be less ventilation and therefore blood will not be fully oxygenated as it leaves a low V/Q unit
* Shunt is an extreme form of low V/Q where V/Q=0
* compensatory mechanism where lung redirects blood flow from airways not being well ventilated is achieved through arterioles constriction
* However this compensation is not fully complete and this can have downstream effects such as raising pulmonary artery pressures
*
59
High V/Q?
* High V/Q units result in wasted ventilation because there is more ventilation of units than is required to oxygenate any blood passing through these units
* → ↑ physiological dead-space (with little effect on PaO2)
60
The A-a gradient for oxygen
* We can measure the PaO2 but we must estimate the PAO2
* Use the ideal gas equation
* PAO2 = PiO2 – PaCO2 / RQ
* use 0.8 for RQ and 150mmHg for PiO2 as sea level
* A (A-a) gradient equals the PAO2-PaO2
* normal is \<15 to 30
* if higher than 30 than there is a gas exhange abnormality
* i.e. overall gas exchange is lower than would be expected with that level of O2 in the alveoli
61
Eclipse phase of viral replication is?
* eclipse period-all the virus components are being made and then they are assembled within the cells and then they are released.
* For every single cell that has been infected by one virus we have 10^8 viral particles coming out
62
Viral replication cycle diagram
63
What are the receptors for HIV virus on host cells?
and what is the ligand that HIV virus uses?
and what is thr process of binding?
* CD4 is one of the receptors
* CCR5 is the the co-receptor
* sometimes the virus can change to CXCR4 and swap the mode of infection into cells.
* glycoprotein 41 and glycoprotein 120
1. Binding of gp120 to CD4 triggers conformational change of the glycoprotein
2. this conformation change allows for the hydrophobic gp41 to move outsdide of the gp120 and then this allows for binding to the CCR5
64
What are the two methods of viral penetration into the host cell?
And what does HIV do?
* Fuse with membranes if they have envelopes
* either virus type (enveloped or not enveloped) can also enter through endocytosis which invoves invaginations of the cell membrane to form vesicles in the cell cytoplasm
* uncoating then occurs
* HIV binds to the cytoplasm and releases contents
65
In general where do DNA viruses replicate?
In general where do RNA viruses replicate?
What are some exceptoions to this rule?
* Nucelus
* Cytoplasm
* HIV is a RNA virus but must replicate in the Nucleus as it has to integrate into the host genome.
* Poxvirus is a DNA virus but is so big it doesnt have to fuse with host genome and just uses all its own DNA
66
Polio virus is a ssRNA +ve sense virus. What does this mean?
How does polio virus obtain its "special" polymerase?
* means that the RNA is the same as the mRNA
* so protein components can be synthesised
* But need a RNA dependent RNA polymerase to replicate more genome-no such polymerase exists in our cells
* Polio virus can undergo translation of the +ve sense RNA which will then fold in certain way such that active sites are constructed
* then the proteins are autocleaved into the various compenents and one of the compenents is a RNA dependent RNA polymerase
*
67
Most DNA viruses _____ carry their own polymerase.
\_\_\_\_\_ is an exception
* do not
* poxvirus
* carries entire genome and replicates in cytoplasm
*
68
* -ve strand viruses \_\_\_\_carry an RNA polymerase
* but most +ve viruses \_\_\_\_\_
* an exception is the ______ that need an RNA dependent DNA polymerase
* do
* don't
* retroviruses
69
Helical structure viruses all have \_\_\_\_\_\_
Icosahedral viruses can be either _____ or \_\_\_\_\_
* envelopes
* non enveloped or enveloped
70
How do enveloped viruses budd to exit the host cell.
Give two examples
* Patches of viral envelope glycoproteins accumulate in the host cell plasma membrane.
* Capsid proteins and nucleic acid condense directly adjacent to the cell membrane.
* The membrane surrounding the nucleocapsid then bulges out and becomes "nipped off" to form the new enveloped virion.
71
What in another method enveloped viruses can use to obtain their envelope?
* Some enveloped viruses utilize the cellular secretory
pathway to exit the cell. Virus particles enclosed within Golgi derived vesicles are released to the outside of the cell when the transport vesicle fuses with the cell membrane.
72
What are some of the outcomes viral infections can have on a cell
73
What are two kinds of cytopathic effects that can be seen with light microsceop that indicate viral infected cells
74
What are some of the ways Viruses can gain genetic diversity that cna lead to viral evolutution
* Genetic mutation, especially is RNA viruses with low fidelity polymerases
* Recombination
* swapping parts of the viral genome due homologous recombination-so can only be achieved between related viruses
* Reassortment
* when two different viruses infect the same host and if the viruses have segmented genomes then there can be swapping of sections of genes.
75
Acyclovir
What is it's mechanism of action and why does it not kill our cells?
* used to treat herpesvirus infections
* when DNA is being synthesised new bases are incorparated into the growing chain as nucleoside trisphophate
* **Acyclovir** is a gaunosine analogue
* but it is not cyclic so does not have the 3' OH group require for continuation of the chain
* But it does that the 4' OH group to allow incorparation of the acyclovir into the DNA chain
* **Acyclovir** does not kill or cells becasue we do not have the enzyme required to add the first phsophate group onto the molecule so it cannot be incorparated into our DNA as it is not tri-phosphorylated
* Herpesviridae has **Herpesviridae thymidine kinase** enzyme that is able to add this first phosphate group
*
76
What are some of the barriers in the respiratory tract that help to prevent infection with viruses?
* Mucus which traps any viral particels
* cilia which can beat up th mucus and can then be coughed up
* alveoli macrophages
* temperature gradient
* i.e. lowe temperature in the upper airways
* IgA in the respiratory tract
77
Where does rhinovirus like to infect and what does it cause?
* rhinovirus infects the upper respiratory tract but remain localised to the upper airways as it grows better in the cooler airways of the throat and nose
78
What are the most likely viral causes of the following Local Respiratory tract infection?
* URTI
* Pharyngitis
* Influenza like illness
* Croup (trachea and larynx)
* Bronchiolitis
* Pneumonia
* rhinovirus, coronavirus, adenovirus
* adenovirus
* influenza virus, RSV
* parainfluenza
* RSV, parainfluenza 3
* RSV, parainfluenza 3, influenza virus, adenovirus
79
Respiratory tract infections: Systemic
Provide an example and explain its pathogenesis
* Measles
* Virus starts replicating in the URT, and then drains to lymph node and infects macrophages, lymphocytes and dendritic cells.
* Then the measles virus goes all around the body and infects all areas.
* It can also return to epithelial cells in lung and mouth.
* The infection is highly contagious and can result in transient immunosupression due to the infection of the immune cells
80
Barries to viral infection in the alimentary tract
* sequestration in intestinal contents (constant movement of contents and allows contact with specific receptors)
* mucus
* stomach acidity
* intestinal alkalinity
* proteolytic enzymes secreted by the pancreas
* lipolytic activity of bile
* IgA
* scavenging macrophages
81
Viruses that infect the intentinal tract are normally resistant to bile and acid secretions and so these viruses are normally?
* non enveloped
82
What are M cells, and how do viruses use them to their advantage?
* M cells ingest and deliver antigens to underlying lymphoid tissue by transcytosis
* Some enteric viruses use this pathway to gain entry to deeper tissues, others infect and destroy M cells
83
What site does roatvirus infect and what symptoms does it cause and what enables it to survive in these conditions?
and what does the viral protein NSP4 do?
* Rotavirus is spread via feacal oral route and must be very hardy to survive passage through the gut and in the environment
* has a triple caspid
* core capsid, inner capsid and outer capsid
* infects and destroys intestinal epithelial cells and M cells and causes diarrhea
* through the decreased absorption of the enterocytes
* NSP4 protein secreted by the virus also increases the fluid secretion of the remaining intestinal cells, which intensifies the diarrhea
84
Enterovirus infections
Where do they infect?
and what can they cause?
* Part of the Picornavirus family
* Virus enters via aerosol or ingestion and then replicates in the oropharynx and then can get into blood-vireamia
* will also repilcate in respiratory tact and whilst in the intentine will be shed in feaces
* vireamia can result in different systemic infections
* menigitis-many enterovirus infections
* CNS infection (polio)
* Skin-Group A Coxsackie virus-oral ulcers and hand foot and mouth disease
* Muscle-Group B Coxsackie virus-myocarditis
85
The pathway from the epithelium to the skin is through the \_\_\_\_
* lymph node
86
A Vireamia can have virus in the _____ or \_\_\_\_\_
* the plasma
* or cell associated
87
What does primary and secondary viraemia refer to?
* So infection may begin in peripheral epithelial tissue and then migrate to blood through lymph node-**primary viraemia**
* the virus may then migrate to liver or spleen where it will replicate up to large numbers and then migrate back into the blood-**secondary viraemia**
88
Viruses that can infect the foetus
* must be able to cross the placenta
* Can cause death and abortion by cytocidal viruses (eg.smallpox)
* Can cause developmental abnormalities by non-cytocidal viruses (eg. rubella, CMV)
89
Congenital rubella syndrome
* death and abortion by cytocidal viruses (eg. smallpox)
* developmental abnormalities by non-cytocidal
viruses (eg. rubella, CMV)
* babies often have mental defficiencies and heart defects etc
90
Tropisms of:
Rhinovirus
Rotavirus
Measles
Influenza virus
* URT with the cooler temperatures
* In the intestinal tract
* in lymphoid cells
* In large airways
* need tryptase clara enzyme sectreted by the cells
91
Immunopathology due to viral infections
How can antibody responses result in pathology?
How can CD4 T cells repsonse can result in pathology?
How can CD8 T cells repsonse can result in pathology?
* Antibody
* antibody-dependent enhancement of infection by FcR-mediated uptake of virus-Ab complexes into cells eg. Dengue hemorrhagic fever/shock syndrome
* antigen-antibody complexes deposited in the
kidney can cause glomerulonephritis and in the blood vessel, vasculitis eg. Hep B in chronic carriers
* CD4 T cells
* responsible for some viral rashes eg. measles
* induce cytokines that recruit eosinophils responsible for bronchiolitis in infants with respiratory syncytial virus (RSV) infection
* CD8 T cells
* contributes to liver damage in Hep B virus infection
* lysis of hepatocytes, recruitment of monocytes
and neutrophils
* yellow skin and eyes are a sign of liver damage
* old RBCs are destroyed by
macrophages in spleen
* heme from the hemoglobin is
converted to bilirubin (yellow)
92
Examples of viruses causing immunosupression?
* eg. HIV: replicates in CD4 T cells and kills
them and in monocytes and inhibits their
function
* eg. measles: temporary immunosuppression from nonproductive replication in T cells and macrophages; suppression of proliferation of non-infected T cells by infected DC displaying measles surface glycoproteins; suppression of IL-12 production
* leads to susceptibility to secondary
infections
93
Examples of viruses causing autoimmunity?
* molecular mimicry: Guillain-Barre syndrome which is a result of influenza proteins mimicing myelin-can result in demyelination of nerves
* Polyclonal B cell activation: by EBV
94
What is antigenic drift?
* Change in the antigenic structure of the virus
* Due to selection of variant viruses with amino acid substitutions in the viral glycoproteins that allow the virus to escape neutralization by pre-existing
antibody.
* Variant viruses arise spontaneously through errors in RNA replication giving rise to point mutations in the genes.
* In influenza, antigenic drift occurs on a **population scale** with different mutations accumulating as the virus moves from person to person. In HIV infection a diversity of strains may develop within a **single patient**
95
Viral inhibition of T cell priming by DC?
96
What methods can viruses use to evade the CD8 CTL response?
* **antigenic variation** will lead to the CTL not recognising the virally infected cell
* HIV nef induces **endocytosis of the Class I MHC**
* HSV protein binds to the cytosolic sode of TAP transporter and **prevents peptide translocation to ER**
* CMV can do the same but on the luminal side
* adenovirus binds to MHC peptide complex in ER and anchors it there so it **cannot get to the surface**
* EBV in latently infected B cells **inhibits the proteasom****e**
* HIV, RSV, and adenovirus can **shut down class I gene expression**
97
Individuals without NK cells are very susceptible to ______ infections
* Herpesviridae
*
98
How does CMV virus escape both CTL and NK immune responses?
* Human CMV encodes an MHC Class I-like molecule that is expressed on surface of infected cell and delivers a negative signal to NK cell but cannot itself
present peptides to CD8 T cells
99
Intepherons?
* Antiviral activity of interferons is mediated by the induction of particular cellular proteins or pathways in the IFN-treated cell
100
Interferon induction of PKR
* PKR phosphorylates itself in the presence of dsRNA
and then PKR phosphorylates eIF2alpha and that results in decreased translation of protein which inhibits viral replication
101
How do viruses avoid PKR activation?
* PKR needs long stretches of dsRNA to wrap around and become activated
1. EBV and adenoviruse make many small stretches of RNA-not long enough for PKR binding
2. Vaccinia and reovirus encodes molecules that bind the dsRNA instead and prevents PKR activation
3. Vaccinia uses a viral encoded homologue of eIF2alpha which competes for PKR which inhibits phosphorylation of eIF2alpha
102
Genetic factors influencing susceptibility to viral infection
* Inherited defects eg. absence of Ig class
* Polymorphisms in genes controlling immune responses eg. MHC genes
* interferon-inducible genes (MxA and MxB)
* proteins that interfere with the influenZa life-cycle
* receptor genes eg. CCR5
* In HIV infections a delta 32 mutation in CCR5 can prevent HIV infections
103
Non genetic factors influencing susceptibility to viral infection
* age - newborns and the aged are more susceptible to severe disease (immature and waning immune response) but young suffer less from immunopathology
* malnutrition - decreases resistance
* hormones, pregnancy - males and pregnant
women more susceptible
* dual infections - may result in more severe
disease
* confusing Th1 and Th2 responses
104
What are the conducting and respiratory parts of the respiratory system?
Conducting part
* nasopharynx, trachea, bronchi, bronchioles. Carry and condition air
Respiratory parts
* only the alveoli
105
What is the function of the folowing structures found in the nasopharynx?
Sinuses
Olfactory epithelium
Turbinates
* for phonation and conditioning of air
* for smell
* turbinates warm the air and and moistens the air, failure to do so would result in dehydration
106
Anatomy of the URT
107
What is the function of the Larynx and the Epiglottis?
* epiglottis and larynx divert food and drink from airways
* larynx (uppermost part of trachea) is organ of phonation (sound production)
* Air forced over vocal cords leads to vibrations
108
Anatomy of the larynx
109
What is the respiratory epithelium? and where is it?
* line nasopharynx and airways but these are the conductiong vessels-counterintuitive-not areas of respiration
* pseudostratified columnar epithelium with cilia (30%)
* lots of goblet cells and deep glands (30%)
* sensory cells to initiate coughing to expel irritants (3%)
* Basal (stem) cells (30%) in base of epithelium renew the epithelium
* Serous cells (3%)
110
What is the role of ciliated cells?
* Mucus layer, (with trapped particles) swept upwards by cilia to epiglottis
* Ends up in the stomach for sterilisation
* Smoking destroys cilia, so cough must shift mucus
upwards from the lungs
111
What is the trachea comprised of and where is it?
* Beneath the larynx is the trachea
* Comprised of a stiff wall of hyaline cartilage that is C shaped with trachealis muscle on the back
* smooth muscle is also there which can contract when we try to cough something up
112
What are the three layers in the trachea and what are they comprised of?
* mucosa, submucosa and adventitia
* Mucosa is comprised of the respiratory epithelium sitting on a lamina propria
* Submucosa is comprised mainly of connective tissue with large mucus glands which produce the mucus of the respiratory tract
* Adventitia contains cartilage and outer layer
of connective tissue
113
What is the structure of the bronchus?
* Initially like trachea, but thinner walls
* Cartilage ring becomes **cartilage plates** in intrapulmonary bronchi
* Smooth muscle at the boundary between the lamina propria and submucosa
* Glands still present
* Lymphoid nodules present
114
What is the structure of the bronchioles?
* Bronchioles have no cartilage but there is still a respiratory epithelium with smooth muscle
* Bronchioles steadily loose goblet cells and ciliated cells and we get more clara cells as the vessels keep branching-but still conduction vessels
* goblet cells dissapear then ciliated cells-important that as this is the way that the cilia can sweep up all the mucous dripping down
115
What are Clara cells?
* Clara cell-columnar/cuboidal with short microvilli (projections that cannot move)
* produce surfactant to destroy surface tension because the airways are moist-soap or detergent allows us to keep airways open
* Clara cells may neutralise toxins and become more common with more branching of conducting pathways
116
What is the structure of terminal bronchioles?
* Last part of the conducting system still have SM-single layer or two layers
* no goblet cells
* still cuboidal epithelium with some cilia but mainly clara cells with microvilli
* Give rise to respiratory bronchioles
117
Whart are Respiratory bronchioles comprised of?
* First respiratory structures, alveoli, appear intermittently
* Alveoli are thin walled pouches
* The epithelium of the respiratory bronchiole is cuboidal to squamous
* in an attempt to be thin
* It gives rise to alveolar ducts, chains of
connected alveoli.
118
What is the structure of the alveoli?
intralveolar septum?
* chaotic network of little cells
* simple squamous epithelium
* walls contain the respiratory capillaries
* there are pores between alveoli which connect alveoli. Through the hole gas can permeate
* Between alveoli are the **intralveolar septum**
* Intralveolar septum contain elastin fibres which keep alveoli from collapsing
* positive pressure that intermitently occurs keeps the alveoli open
119
What are Type I pneumocytes?
* Epithelial cells present in the alveoli are called pneumocytes
* Type I pneumocytes are the flat squamous ones which are those which form the majority of the surface area of the alveoli (95%) and provide exchange surface
* Have tight junctions to prevent extracellular fluid leakage and sit on basal lamina
120
What are Type II pneumocytes?
* Type II pneumocytes are more prevelant that type I but are only about 5% of the area-so tightly packaged in together
* sit at angles between alveolus septa and they produce surfactant which again prevents collapse of the airways due to how the surfactant reduces surface tension
121
Type II pneumocytes can also be called _____ cells
* stem cells
* as they can regenerate into either type I or type II pneumocytes.
122
What doe the blood-gas barrier comprise of?
* Consists of surfactant, type I pneumocyte, basal lamina, connective tissue, basal lamina endothelial cell plasma
*
In thinnest barrier, two basal lamina can fuse and there is no connective tissue
so in thinnest part the endothelial cells and the type I pneumocytes can share a basal lamina
123
What is the role of the intra-alveolar macrophages?
* sometimes dust particles can make it into the alveoli
need macrophage to deal with the dust
* Macrophages have techincally left body and enterred alveoli
* When “full”, they migrate up to the airways until they are carried off by the ciliated cells
* Some macrophages end up in interalveolar septum
loaded with particles
