Case 5 Flashcards
(101 cards)
1
Q
What are the different antiretrovirals? what are the keys steps in viral replication that they target?
A
- Fusion/entry inhibitors
- Co-receptor blockers e.g. Maraviroc – blocks entry at the CC05
- Reverse transcriptase inhibitors (nucleoside and non-nucleoside)
- Integrase inhibitors
- Protease inhibitors
2
Q
What is Pneumocystis jiveroci (formely P.carinii)? what does it most commonly cause? who do you normally see it in? at what stage is it seen? what does it do? what is pneumonia? what are the symptoms? what is the clinical examination? what is the diagnosis? and what is the treatment?
A
- Yeast-like fungus
- This organism most commonly causes pneumonia (Pneumocystis pneumonia (PCP))
- It is seen among immunocompromised hosts
- Seen when CD4 count falls below 200
- The organism damages alveolar epithelium, which impedes gas exchange and reduce lung compliance
- Pneumonia: inflammation of the lungs caused by infection, in which the alveoli fill with puss and may become solid
- Symptoms: shortness of breath, non-productive cough, fever and discomfort
- Clinical examination: reveals tachypnea (increased respiratory rate), tachycardia (increased heart rate), cyanosis (blue/purple appearance of skin due to lack of oxygen), signs of hypoxia (decreased oxygen levels) and crackling sounds on inhalation
- Chest X-ray: bilateral diffuse interstitial shadowing (alveolar shadowing)
- Diagnosis: PCR amplification of the fungal DNA from blood sample. Silver staining (gram staining). CD4 cell count.
- Treatment: co-trimoxazole (antibiotic)
3
Q
What is Candida? what does it cause?
A
- Candida is yeast
- Causes fungal infections
- HIV: mucosal infections as a result of candida – oral candida is one of the most common conditions (creamy plaques in the mouth and pharynx)
4
Q
What are lower respiratory tract infections? what are the most common ones?
A
- Lower respiratory tract infections – affect the airways and lungs
- Common lower RTIs include:
- flu
- bronchitis
- pneumonia
- bronchiolitis
- tuberculosis – persistent bacterial infection of the lungs
5
Q
What are the main symtoms of lower RTI?
A
- The main symptoms of lower RTI is a cough – usually quite severe and you may bring up phlegm and mucus
- Other possible symptoms are a tight feeling in your chest, an increased rate of breating, breathlessness and wheezing
6
Q
Describe how the infection of the pulmonary system affected the person in the case.
A
Bilateral (affecting both sides) diffuse (spread over a large area) interstitial (affecting the interstitium – the tissue and space around the air sac of the lungs) shadowing (a term used to describe the image on an X-ray – it usually means inflammation – the inflammation could occur due to infections or some inhaled irritant)
7
Q
What is fever? what is triggered by? and what does it do?
A
- High temperature triggered by resetting hypothalamic thermostat
- Trigger by toxins from microbes/cytokines from immune system (e.g. IL-1beta)
- Inhibits bacterial growth
- Speeds up some reactions aiding repair
8
Q
What are the 4 classic symptoms of inflammation?
A
- Redness
- Swelling
- Pain
- Heat
9
Q
When do these 4 symptoms become fever?
A
These are local symptoms but when the inflammation becomes systemic, the symptoms are then called fever
10
Q
What controls temperature? how does inflammation cause a change in temperature? and why does it do this?
A
- Temperature normally controlled by hypothalamus
- What happens in inflammation, is that the microbes causing that inflammation can release toxins or the immune system, seeking to clear up the infection, produces cytokines (particularly LPS and IL-1) – there are receptors on the hypothalamus for these molecules, so when they reach the brain and bind, they reset that thermostat several degrees higher and then you have fever – the idea is that the infection wants to grow at 37 degrees and so by increasing the temperature you are making the environment less habitable – increase in temperature also speeds up a number of immune functions, e.g. phagocytosis, antibody production, production of complements and other proteins – also with fever you tend to rest and that helps you to heel
11
Q
What is HIV?
A
A lentivirus (subgroup of retrovirus) that damages CD4 (T) cells of the immune system: reduces the ability to fight off infections and cancers
12
Q
What are the different types of HIV?
A
- HIV 1 and HIV 2 – within which different subtypes
- HIV-1: origin – chimpanzee found to be positive for HIV-1 antibodies against SIV retrovirus – hunters ate chimpanzee meat affected by SIV – the SIV mutated to affect humans – HIV
- HIV-2: origin – sooty mangabey monkeys – this is rarely found outside of Africa
13
Q
What is AIDS?
A
A later stage of HIV infection where someone develops potentially fatal infections and cancers
14
Q
What are the different stages of HIV infection?
A
Acute (acute retroviral syndrome, ARS) Latent (or ‘asymptomatic’ or ‘chronic’) AIDS - Infectious throughout all stages - Use CD4 cell counts or/and WHO clinical staging protocols
15
Q
Describe the HIV virus.
A
- RNA virus
- GP120 envelope protein on virus
- P24 capsule proteins – tested for in 4th generation HIV tests
16
Q
What are the key steps in HIV replication?
A
- Viral entry – binds to CD4 receptor (two types CCR5, CXCR4) – Th cells, monocytes, macrophages, microglial cells
- Reverse transcription – RT transcribes RNA into DNA
- Integration – viral DNA integrates into host DNA
- Viral assembly – genome ‘packaged’ by proteases
- ‘budding’ of mature virus – able to infect other cells
17
Q
What is the pathology of HIV - what does in mainly target?
A
- Innate immune response – non-specific – macrophages, neutrophils, NK cells
- Adaptive immunity – antigen specific – mainly targeted
- cellular – cell mediated
- humoral – antibody mediated
- coordinated by T cells
- dependant on B cells and Th cells
18
Q
What is the natural history of HIV infection? (viral load and CD4 count)
A
- Primary infection – CD4 count dips down quite dramatically
- Then it increases back to near normal levels
- Then it reduces gradually, if not treated
- Within 10 years can do very low levels
- Under 200 cells/mm3 = AIDS
- Primary infection – viral load increases dramatically
- Then dips significantly – may be undetectable
- Then over many years slowly increases
19
Q
What does the risk of opportunistic infection depend on?
A
CD4 count
- Once CD4 count falls below 200 that’s when you become at risk of a number of different opportunistic infections – e.g. pneumocystic pneumonia
20
Q
What is the normal range of CD4 count in someone with HIV?
A
Normal range for CD4 count in someone with HIV = 500 to >1000 cells/mm3
21
Q
At what stage in the history of HIV and TB occur?
A
TB can occur at any stage of the history of HIV, even about 200 CD4 count
22
Q
What are the methods of HIV transmission?
A
- Sexual: increased by STI’s, esp. genital ulcers – immune barrier (the mucosa) is broken down so increases chance of virus crossing the mucosa
- Parenteral: (by some route other than through the alimentary canal, such as subcutaneous, intramuscular, intrasternal or intravenous injection) e.g. PWID (people who inject drugs), blood transfusion (although screen in the UK)
- Mother to baby, breast feeding (to reduce risk of transmission can give mother antiretroviral therapy, can give baby post-exposure prophylaxis with antiretroviral therapy for the first 28 days of life, bottle-feeding only – all of these have greatly reduced transmission and now in the UK only 1% of babies born to HIV-positive women are positive themselves)
23
Q
Describe in detail the replication cycle of HIV.
A
- HIV infects CD4 cells (mainly), monocytes and dendritic cells
- All of these cells express the CD4 receptor
- The gp120 protein binds to CD4 receptor
- M-tropic strains of HIV: the gp41 protein binds to co-receptor (CCR-5) on the cell
- T-tropic stains (only affect CD4 T cells) : The gp41 protein binds to co-receptor (CXCR-4) on the CD4 cell
- Neuclocapsid enters cell and is removed
- Reverse transcriptase copies viral RNA into double-stranded DNA
- Viral DNA integrates into hot DNA, where it lies dormant as a provirus – this is the virus in its latent stage
- Upon activation of the affected cell, viral DNA is transcribed into viral RNA (MRNA)
- Viral RNA is translated into viral proteins
- The viral proteins and viral RNA assemble to form new viral particles (using the host cell’s membrane as its lipid membrane)
- These particles can now infect other cells
24
Q
What are the three stages in the life cycle of HIV?
A
- Infection
- Latent stage
- Development of AIDS
25
Describe what happens during the infection stage.
- Virus infects cells, resulting in high levels of virus in the blood (viraemia)
- Asymptomatic but some people may experience acute retroviral syndrome (ARS) – ‘the worst flu ever’ – this is also called primary infection
- Following infection, the body responds with an immune response:
1. Infected cells, via the endogenous pathway, present viral proteins with MHC-I on their surface – CD8 cells kill these infected cells
2. Antibodies for gp120 (envelope glycoprotein) envelope and p24 (HIV antigen) are produced (complement or opsonisation) – seroconversion
3. Immune response eliminates 99% of the virus
- CD4 cell count begins to decrease
- The detection of antibodies to HIV is used to test for infection
- Following the immune response, the virus enters the latent stage
- The immune system does not clear the virus completely because HIV has a number of features that enable it to survive:
1. It has a very high replication rate
2. It can hide as a provirus where it is not detectable by the immune system
3. It has a very high mutation rate
26
Describe the latency stage of HIV,
- Generally asymptomatic (few patients have swollen lymph nodes)
- Viral DNA lies dormant as provirus
- CD4 cell count decreases slowly
- Individuals with a lower level of viraemia in latency develop slower to AIDS
- The average time from infection to the development of AIDS is about 10 years – the latent stage counts for most of this
27
Describe the development of AIDS stage.
- Emergence of symptoms that indicate progression to AIDS without treatment
- Symptoms: weight loss, night sweats, fever, diarrhoea and swollen lymph nodes
- Symptoms arise as a result of rapid decrease in CD4 cell count and opportunistic infections that attack a damaged immune system
28
What is AIDS defined clinically by?
1. The appearance of major opportunistic infections
| 2. Or by a drop in the CD4 T cell count to below 200
29
What is death mainly caused by in AIDS?
Death is mainly caused by Pneumonia (caused by Pneumocystic jivoreci)
30
How has the treatment of HIV changed? what is still an issue?
- New drugs better tolerated and extremely effective – less awful side effects than previous
- ‘one pill once a day’ – even though may be a combination of drugs in there
- Look at individual and their lifestyle and come up with a regime that suits them and won’t interact with medication that they’re already on
- Some drug interactions (CYP 450) – can be quite serious (if someone on a protease inhibitor)
- Management of HIV now largely out-patient based
31
How is prevention used to treat HIV?
- Virally suppressed PHIV less likely to transmit to others: wider public health significance
- Pre-exposure prophylaxis (PrEP) – currently going through stages to become part of standard care
- Post-exposure prophylaxis (PEP) – e.g. if you get a needle-stick injury
32
How is HIV monitored?
1. Immunological monitoring: CD4 T cell count
2. Virological monitoring: viral load (HIV RNA levels and viraemia)
3. Genotype determination: viral genotype analysis is used to identify strain of HIV
33
What are the different treatments for HIV? and how do they work?
HAART
1. Reverse transcriptase inhibitors: NRTI and NNRTI
2. Protease inhibitors
3. Integrase inhibitors
Reverse transcriptase inhibitors
1. Nucleoside reverse transcriptase inhibitors (NRTIs): need intracellular phosphorylation to be activated
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) : do not need intracellular activation - instead they interfere with reverse transcriptase by direct binding to the enzyme – they are ineffective against HIV-2
Protease inhibitors (PIs)
- Protease: involved in the production of functional viral proteins and enzymes
- Protease inhibitors cause viral maturation to be impaired and immature dysfunctional viral particles are produced
Integrase inhibitors
- Act as competitive inhibitors to integrase by binding to the enzyme, preventing the substrate form binding to it
34
What are the three ways antibodies protect from infection?
- Block binding of pathogens and toxins (immune complexes form – ingestion of these by phagocytes)
- Facilitate phagocytosis by e.g. macrophages/neutrophils
- Kill bacteria by activating complement (through the classical complement pathway)
35
Describe how they block binding of pathogens and toxins. Give examples of which antibodies do this and where.
- Most toxins act by binding to a receptor and then getting inside a cell
- Need an antibody that get can into tissues, and has high affinity so can block binding of toxin
- IgG does this in tissues – forms immune complexes with the toxins that can be phagocytosed by macrophages or neutrophils
- In gut and intestine (to block infection by bacteria), IgA is the main antibody used – more important for whole bacteria than individual toxins
36
Describe how they facilitate phagocytosis.
- Phagocytes not particularly efficient at recognising the bacteria (particularly encapsulated bacteria – can be both gram+ and gram- - they have extra polysaccharide capsule that coats the cell wall)
- Opsonisation – antibody can coat the bacteria and then the macrophages and neutrophils have Fc receptors (receptors for the constant region of the antibody) – so they can coat the opsonised bacteria and ingest it much more efficiency than if the antibody wasn’t opsonised
- Bacteria coated in antibody and engulfed
(opsonisation = the process by which bacteria and other cells are altered in such a manner that they are more readily and more efficiently engulfed by phagocytes)
37
Describe how they kill bacteria by activating complement.
(particularly importnat for extracellular bacteria)
- Opsonisation of bacteria
- The antibodies activate complement
- Complement produces this membrane attack complex that lysis the bacteria
- Then the whole complex can be ingested by phagocytes
38
What is the contribution of antibodies to host resistance?
- Neutralisation of toxins
- Extracellular lysis of bacteria (with complement)
- Facilitates internalisation for intracellular killing of phagocytes (neutrophils and macrophages)
- Expulsion of parasites via inflammatory reactions (IgE)
- Passive immunity by transplacental transfer (IgG)
39
What is the recommendation for HIV testing?
- Recommendation: universal HIV testing in high prevalence areas (= >2:1000)
- Manchester 5.8 per 1000
- Everyone should be offered a HIV test
40
What are the tissues of the immune system? and what type of lymphoid tissue are they (primary or secondary)?
- Bone marrow – primary lymphoid tissue (immune cells produced & educated)
- Thymus – primary lymphoid tissue (immune cells educated)
- Spleen – secondary lymphoid tissue (highly organised immune tissues)
- Lymph nodes – secondary lymphoid tissue (everywhere where you have vascularised tissue – highly organised immune tissue)
- Lymphatics
- Blood
41
Where do you have lymph nodes? and what do they do?
- Everywhere where there is vascularised tissue, you have lymph nodes draining the tissue
- Lymph nodes filter fluid coming off the tissues, looking for infection and act against it
42
What does the spleen do?
- Does the same but for the blood
- It filters the blood looking for disease, it’s a place of red and white blood cell storage and its place where damaged white blood cells are destroyed
43
What is the anatomy of the lymphatic system?
- Adenoid
- Tonsils
- Thymus
- Spleen
- Lymph nodes
- Bone marrow
- Lymph vessels
- Lymphatic ducts
44
What are the lymph organs? and what do they do?
There are a number of organs that contain lymphatic tissue. They are involved in blood filtering and the maturation of lymphocytes.
- Spleen – functions mainly as a blood filter, removing old red blood cells – it also plays a role in in the immune response
- Thymus – responsible for the development and maturation of T lymphocytes (why don’t need when age??? – because you make a stock of T cells when you are younger)
- Red bone marrow – responsible for the maturation of immature lymphocytes
In addition, some lymphatic tissue is located in the tonsils, appendix, and in the walls of the GI tract
45
What is size of lymph nodes? how many do we have? where are the majority of them?
- Kidney-shaped structures, typically around 2.5cm in diameter
- On average an adult has around 400-500 different lymph nodes spread throughout the body, with the majority located within the abdomen
- They filter foreign particles from the blood (they filter the lymph fluid), and play an important role in the immune response to infection
46
What does each lymph node contain? what happens when they are exposed to fluid? when are they exposed to fluid?
- Each node contains T lymphocytes, B lymphocytes, and other immune cells
- They are exposed to the fluid as it passes through the node, and can mount an immune response if they detect the presence of a pathogen
- This immune response often recruits more inflammatory cells into the node – which is why lymph nodes are palpable during infection
- Lymph fluid enters the node through afferent lymphatic channels and leaved the node via efferent channels
- Macrophages located within the sinuses of the lymph node act to filter foreign particles out of the fluid as it travels through
47
What are antigens usually?
Antigens are usually big molecules:
- Proteins (most common)
- Carbohydrates
- Lipids
- DNA
48
What are the main classes of antibody? what is the structure? and what do they do?
IgG – (standard 4 chains) - main blood and tissue antibody, transplacental transfer, fixes complement, binds phagocytes, neutralises toxins
IgM – (standard 4 chain unit – but 5 of them joined together in a ring – 10 antigen-binding sites – even stronger binding) – other major blood antibody (high avidity), fixes complement, acts as B cell receptor (too large to get into tissue, unless tissue inflamed and damaged)
IgA – (dimer – two 4 chain units together – protein rapped around FC regions) - secretory antibody, protection at mucosal surfaces (resistant to digestion) – highest amount of antibody produced in body overall (a lot of mucosal surfaces)
IgE – (extra-long constant region) - binds to mast cells and basophils, important in worm (multicellular parasite) infections
IgD – (4 chains) membrane receptor (never soluble molecule)
49
What does different heavy chains mean?
Different functions.
50
What is the job of the constant region and variable region?
- Constant region – has the effector function – job of this end is to recruit other molecules and other cells of the immune system
- Job of variable region is to bind to antigen – 2 antigen binding regions per molecule – bivalent – means greater strength of binding – bonds not covalent so antigens can move on and off antibody – so if two sites, there’s greater chance of having at least one bound
51
How is HIV diagnosed (screening and tests)?
- Informed consent: anyone can do this – most people happy to be tested – routine test – not just high-risk people – opt-out testing for HIV with pregnant women
- Screening: HIV antibody – serum sample sent to lab, point of care test (not as good for early diagnosis as can take a while from there to be enough antibody)
- If positive: repeat, check HIV RNA (PCR) (make sure no human error)
- CD4 count and HIV RNA: assess need for treatment (WHO advocates test for all positive people – NHS England says treat if CD4 count is less than 350 and treat if symptomatic (can be psychological)) – very important to stick to treatment in terms of preventing antiviral resistance
52
What is seroconversion illness?
- Acute HIV infection
- 6-week mark following exposure
- Seroconversion is the period of time during which HIV antibodies develop and become detectable
- Seroconversion generally takes place within a few weeks of initial infection
- It is often, but not always, accompanied by flu-like symptoms including fever, rash, muscle aches and swollen lymph nodes – these symptoms are not a reliable way to identify seroconversion or to diagnose HIV infection
- Triad of lymphadenopathy, mouth ulcers and maculopapular rash
- A lot of people asymptomatic
53
What are the different ways of testing/screening for HIV?
1. Screening for anti-gp120 antibodies through ELISA (screening)– a positive ELISA result doesn’t always mean that the patient has HIV – Western Blot confirms HIV (analytical technique used to detect specific proteins) (positive test: presence of 24 antigen and gp41 (envelope glycoprotein) antibodies and either gp120 or gp160 antibodies)
2. Detection of p24 antigen: useful indicator of active viral replication as 24 antigens appear before anti-gp120 antibodies are produced
3. CD4 cell count: treatment started if CD4 cell count is <350
4. Viral load (before seroconversion)
54
What does the innate immune system consist of?
- Macrophages
- Neutrophils
- NK cells
- Inflammatory mediators
- Dendritic cells
55
What are the physical barriers in the innate immune system?
```
Respiratory tract
- Mucus
- Ciliated epithelium
Eyes
- Tears
- Lysozymes/lactoferrin
Gastrointestinal tract
- Stomach acidity
- Intestinal pH
- Normal flora
- Mechanical flushing (vomiting/defecation)
- Lysozyme
Skin
- Barrier, sweat, sebum
- Antimicrobials (e.g. lactoferrin)
- Low pH
- Commensal bacteria – good bacteria – crowd out the bad bacteria
- Shedding
Genitourinary tract
- Washing by urine
- Vaginal secretions
- Urine acidity
- Lysozyme
```
56
What are the antimicrobial factors in innate immunity?
- Complement – bunch hole in bacterial membranes
- Iron-binding proteins (e.g. lactoferrin) – natural antimicrobial proteins
- Anti-microbial peptides (AMPs) – produced by innate immune cells, e.g. platelets
- Cytokines e.g. interferons
57
What is an important cytokine? what produces it? and what are its two actions
IFN
- Cells infected with virus produce IFN
2 actions:
- IFN acts internally - protects infected cell by preventing viruses from replicating further
- Secreted IFN binds to receptor in nearby cells and triggers anti-viral response
58
What do cytokines serves as?
Cytokines serve as molecular messengers between cells – they are small proteins that are produced by cells – cytokines interact with cells of the immune system in order to regulate the body’s response to disease and infection, as well as mediate normal cellular processes in the body
59
How are cytokines diverse?
They are diverse, meaning, they are not all alike – they serve various functions in the body: colony stimulating factors, growth and differentiation factors, immunoregulatory and proinflammatory cytokines
60
How do cytokines work?
How they work – cytokines are released by cells into the circulation or directly into tissue – the cytokines locate target immune cells and interact with receptors on the target immune cells by binding to them – the interaction triggers or stimulates specific responses by the target cells
61
What are the cellular vectors in innate immunity?
- Natural killer cells – type of lymphocyte
- Monocytes – become macrophages
- Eosinophils
- Neutrophils
- Basophils
62
What is something suprising that these cells can do, considering that they're part of the innate immune system? and how do they do this?
Although these cells aren’t particularly clever as they are part of the innate immune system, what they can do is pattern recognition – they can discriminate between viruses, bacteria, gram negative, gram positive, and flagellated bacteria, and multicellular parasites
Sense organisms through:
Pattern Recognition Receptors – PRR
They recognise:
Pathogen Associated Molecular Patterns – PAMPs
Receptors: 4 of the main PRRs
TLRs, NLRs, CLRs, RLRs
63
What are TLRs? and what do they do?
- We express 9 of these
- They can bind different ligands and can discriminate between different type of infections
- Recognises double-stranded RNA, which is only produced by viruses, recognise CpGDNA (50% of bacteria’s DNA), recognise flagellin from flagellate bacteria, LPS from gram -ve bacteria, bacterial lipoporteins/PGN from gram +ve bacteria
- Some are extracellular and some are intracellular (recognise organisms that infect inside the cells)
64
What are phagocytes? and what are the different types of phagocytes?
White blood cells and tissue dwelling cells able to digest and kill microbes
- Monocytes in blood
- Tissue macrophages (most efficient phagocytic cell)
- Neutrophils in blood (not particularly efficient – they eat one bacteria and then they die – but make up for it by their shear number)
65
What are natural killer cells?
White blood cells and tissue dwelling cells able to recognise and kill infected cells
66
How do NK cells work? and what is the positive of this?
- Kills recognised infected host cell by apoptosis (programmed cell death – cell closes in on itself, forms an apoptotic body, which is then digested and destroyed by macrophages)
- Tidy way of killing cells as the other way is lysis where the virus is spread as the cell explodes
67
Describe the process of inflammation.
- Organisms gets in to tissue, usually through cuts and abrasions
- Proliferates
- Which causes tissue damage
- Which results in the release of chemokines (attracts or repels cells), cytokines (messengers of the immune system), histamine
- Histamine diffuses down to local blood vessels and increases permeability of vessels because it’s vasodilatory – so now vessels are leaky
- Neutrophils and macrophages normally move through the blood vessels without stopping, but when you get increased vascular permeability and release of cytokines (such as IL-1 and TNF) from the immune cells in the local tissue, these cytokines change the adhesion molecules on the surface of macrophages and neutrophils so that they no longer roll along, and instead they get stuck on blood vessel wall and because it’s holey, they squeeze through into the local tissue
- They’re attracted up to the point of infection by the cytokines and there they can clear the local infection (migration of inflammatory cells, fluid (causes swelling), red blood cells and leakage of clotting proteins)
- (inflammatory cell = a neutrophil, macrophage, monocyte, eosinophil, or basophil that participates in the inflammatory response to a foreign substance = any cellular component of inflammation)
- Next stage would be wound healing
68
Give a summary of inflammation.
- Vasodilation and increased permeability
- Accumulation of blood
- Leakage of clotting proteins/clot formation
- Chemotaxis of neutrophils/macrophages and engulfment of microbes
- Death of phagocytes (formation of pus)
- Initiation of tissue repair
69
What do dendritic cells do?
- Provide bridge between the innate and adaptive immune system
- They’re the only cell that can present antigens to a naïve T (first time a T cell sees an antigen, it has to be a dendritic cell that presents that antigen to the T cell)
70
What's their role in innate immunity?
- ‘sentinels’ of immune system – continually looking for danger – they’re present (in small numbers) at every site where we come into contact with the external environment (skin, gut, lungs) – they’re very motile cells, they have dendrites fingers that move around
If they sense danger: (they endocytose foreign material)
- Antigen uptake
- Antigen transport (from the external environment to the lymph node)
- Antigen presentation (once they reach the lymph nodes, they’ve matured from an antigen-up-taking cell to an antigen-presenting cell – present antigen to T cell in the paracortex)
71
What's their role in adaptive immunity? and what are the signs of danger?
- Dendritic cells process and present peptide antigens to T cells (signal 1)
- Dendritic cell expresses costimulatory molecules (CD80, CD86) (CD = cluster of differentiation) – their function is to bind CD28 and CTLA-4 on the T cell (signal 2)
- Dendritic cell producing soluble cytokine mediators (signal 3)
Signal 1 is saying that they found something foreign, and signal 2 is saying that it could be dangerous (many foreign but good bacteria in gut, this would only produce signal 1 because you don’t want to get rid of this)
Require ‘danger signals’ for productive immune response – dendritic cell will produce signal 2 and 3 if when taking up the antigen, it saw danger
Danger can come from two ways:
- Microorganism itself – has PAMPs (pathogen associated molecular patterns) (if dendrite recognises a PAMP when it’s taking up its foreign antigen, then it stimulates that there’s danger)
- Damage to own host cells – produce molecules like uric acid and ATP, heat shock proteins, which act as danger signals = DAMPs (danger associated molecular patterns)
If they recognise danger the signals 2 and 3 will take place
Then the T cell will proliferate and go down clonal expansion
72
What are the 3 cardinal characteristics of adaptive immune responses?
- Memory
- Specificity
- Discrimination between ‘self’ and ‘non-self’
73
What cells are involved in adaptive immunity?
- T lymphocytes
- B lymphocytes
- Antibodies
- Dendritic cells
74
What does it mean that lymphocytes are clonally distributed with respect to antigen specificity?
- Million million lymphocytes in body have specificity for 100 million different foreign molecules
- So, these lymphocytes are said to be clonally distributed with respect to antigen specificity
- Only lymphocyte with specific receptor for antigen with divide in daughter cells – proliferation
75
Specific interaction with antigen induces what?
Activation, proliferation and differentiation.
- Selective clonal expansion provides for a) immunological memory and b) differentiated effector cells for antigen elimination
76
What is the same about T and B cells?
- Are specific
- Distinguish self from non-self
- Provide immunological memory
77
Describe humoral immunity .
- Not cell-mediated – mediated by molecules i.e. immunoglobulin (=antibodies)
- resistance against extracellular pathogens
- specific receptor is antibody
- (when antibody is on membrane it’s the receptor, when its released in soluble form it’s the effector mechanism)
78
Describe the activation and differentiation of B lymphocytes.
- B cells undergo clonal expansion
- Some of B cells form memory cells
- Effector cell of the B cell = plasma cell
- Plasma cell is the terminal differentiation step of the B cell
- Plasma cell has the synthetic/secretory machinery for manufacture and export of large amounts of specific antibody
79
Describe the activation and differentiation of T lymphocytes.
- Differentiation leading to memory cells and various types of effector cells
- Must bond to antigens on antigen presenting cell not soluble antigens
- MHC (major histocompatibility complex) molecules (class I or II) are expressed on antigen-presenting cells and they present the antigen
- The T cell binds to the antigen and this triggers it to divide and differentiate
80
What must the TCR (T cell receptor) have affinity for?
Both peptide and MHC
- TCR not only binds the foreign molecule but also the MHC molecule
81
Describe the major histocompatibility complex (MHC) system.
- Either class I or class II
- All nucleated cells express class I
- Only antigen-presenting cells (e.g. dendritic cells, macrophages, monocytes) and B cells express class II
- Polygenic – more than one gene is producing an MHC molecule – multiple copies of MHC
- Polymorphic – 2000 amino acid sequences for each individual type of gene – molecules vary hugely
- Codominant – gene from maternal and paternal lines are both expressed
82
Describe the heterogeneity of T lymphocytes. What makes a T cell a T cell? What are the other types of T cells? and what class of MHC are they restricted to?
- All T cells, by definition, express this cluster of differentiation molecule CD3
- CD3 is another name for the T cell receptor
- CD4+ T helper (Th) cells (help activate Tc cells, activate macrophages, help antibody response) – MHC class II restricted – the only see antigens on antigen-presenting cells
- CD8+ T cytotoxic (Tc) cells (kill virus-infected cells) – MHC class I restricted - they can see all host cells
83
What do cytotoxic T cells do?
They kill virally infected cells.
- Job similar to that of the Natural Killer Cell (kill virally-infected cells)
- However, unlike them, cytotoxic T cells recognise the specific viral antigen being expressed by the viral host cell – recognise antigen being expressed on a MHC class I molecule
- Cytotoxic T cells send death signal to cell to undergo apoptosis (not lysis because they’re virally infected)
84
Where does the activation of cytotoxic CD8 cells occur?
In the lymph nodes
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What is necessary for the activation of Tc cells?
1. Peptide-MHC class I presentation by dendritic cell
| 2. Peptide-specific help from CD4 T cells (without CD4 cells, CD8 cells are ineffective)
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What do CD4 T cells do in terms of CD8 T cells?
They promote the proliferation of CD8 cells.
1. Antigen-specific T cells are activated by dendritic cells (they arrive in lymph nodes) in the lymph nodes (and expressed peptide antigen)
2. Activated CD4 T cells secrete IL-2
3. Activated T cells proliferate and become effector T cells (CD8 cells)
4. Effector T cells leave the lymph node and migrate to the site of infection where they destroy the virally infected cells
IL-2 is essential for proliferation of activated T cells – therefore CD8 cells only grow in presence of IL-2
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What is one of the main functions of a T helper cell?
One the main functions of a T helper cell is to tailor the quality of the immune response depending on the pathogen (parasite compared with virus)
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How to T helper cells shape immune responses for specific threats?
By producing different hormones and cytokines
89
What do Th1, Th2 and Th17 produce in response to what as part of which response?
Th 1 -> produce IFN-gamma & IL-2 - Cell-mediated immunity (delayed type reactions) -> viruses, intracellular bacteria
Th17 –> produce IL-17 & IL-22 -> cell-mediated immunity -> fungi
Th2 -> IL-4, IL-5, IL-10 & IL-13 -> B cell responses and inflammation -> multicellular parasite
90
What is necessary for macrophages to kill intracellular micro-organisms?and why is this necessary?
Activation by Th1 cells
Mycobacteria have a defence mechanism where they hide inside macrophage’s lysozymes – they’re resistant to digestion
1. Infected macrophages express surface membrane MHC class II and pathogen peptides
2. TCR on activated Th1 cells binds MHC class II + peptides
3. Th1 cells secrete IFN-y which activates macrophages (& activated lysosomal compartment) and helps them to kill the pathogen
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What is essential for the removal of intracellular micro-organisms (such as mycobacteria)?
IFN-y (gamma)
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What does failure to remove intracellular organisms result in?
chronic inflammation
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What helps antibody responses? and how does this help?
Th2 cells
‘help’ B lymphocytes respond to antigen – they produce a 2nd signal which helps B cell to differentiate and produce antibodies
- Influences the quality of B lymphocyte differentiation and isotypes of antibody produced
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Describe the derivation and differentiation of T and B lymphocytes.
- Lymphocyte precursor differentiates into pre-T cells and pre-B cells
- Pre-T cells released from bone marrow and go to thymus where they are educated (which means that T cells that would react with self and cause harm are eliminated)
- Pre-B cells stay in bone marrow and are educated there
- They’re both released as mature antigen-sensitive lymphocytes
- They circulate through the blood, spleen, lymph nodes, blood, spleen, looking for their antigen
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What are T lymphocytes involved in?
- Kill virus-infected cells
- Help provide resistance against intracellular pathogens
- Activate macrophages
- Help antibody responses
- Immunoregulatory function
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What is compliance, concordance, and adherence?
Compliance – degree to which patient follows the advice of a medical professional (no longer use this word as much)
Concordance – doctors and patients making decisions together
Adherence – extent to which a person’s behaviours are aligned with treatment / management plans agreed with medical professional
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What is the COM-B framework?
Capability and opportunity -> motivation – behaviour
- In UK, people generally have capability – the money and the knowledge
- Opportunity – depends on time and social support (how people around the act)
Focus on ‘motivation’
- Important to differentiate general from moment-to-moment
Reflective (social cognitive models, decision, conscious, beliefs, thoughts)
Automatic (habit, response to impulse)
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What is the health belief model? why was it developed? what is it used for? what does it assume? what are the negatives?
Demographic variables will shape the following:
- Susceptibility – how susceptible do people think they are to an illness/outcome
- Severity – how serious do they think an illness that they have or could get is
- Costs – money, time
- Benefits
- Cues to action – e.g. public health campaign, something happened to a friend
- Health motivation
- Perceived control – how much control do you think you have e.g. stopping a cold
- -> Likelihood of behaviour
- Developed to explain uptake of TB screening i.e., predicting a health protective behaviour
- Model used to predict / explain / change variety of behaviours (health threatening, health protective, adherence etc.)
- Assumes that humans are rational information processors
- No emotion / little focus on habit
- Focuses on beliefs about a future illness, but in context of illness might be related to symptoms
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What is the self-regulation model (/common sense model)?
```
Illness representation
- Identity, timeline, cause, control/cure, consequences
Coping behaviour
- For control of illness
Appraisal of coping – how did I cope
- Outcomes
Representation of emotional reaction
- E.g. fear, distress
Coping behaviour
- For control of emotion
- E.g. ignoring symptoms
```
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What are rational models? what is the problem with them?
- People are probably not rational in all their decision making
- Rational models tend to explain only about 50% of behavioural intention and even less of actual behaviour
- There is a difference between what you intend to do (intention) and what you do (volition)
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What is PRIME theory? and what 4 assumptions is it based on?
- Incorporating motivation, emotion, impulse and cognition into one model
- Prime theory tells us that when an impulse arises in somebody, they can be easy to understand and difficult – e.g. may have something to do with childhood – they can be from your internal environment (percepts, drives, emotional states, arousal ideas, frame of mind) or external environment (stimuli, information)
- If we have motives that are stronger than the impulse, then we won’t do what the impulse tells us to do
- Based on four assumptions:
- we need to understand moment-to-moment control of behaviour (instead of asking someone what influenced them to do it after it happened) in order to influence it
- system can be modified
- self-identity in the form of motives (e.g. if you say you are a non-smoker, you are less likely to start smoking) and plans are crucial
- system is complex but elements are simple
- Relatively new model and so evidence is sparse
- Can still be used to understand behaviour especially if an individual expresses high motivation to change but is finding it difficult
