CDL302 Flashcards
define aetiology
the cause, set of causes or manner of causation of a disease
define pathogenesis
the origination and development of a disease
the cellular events and relations and other pathologic mechanisms occurring in the development of disease
what is a respiratory disease?
any disease that affects the airways therefore affecting gas exchange in the air sacs
in asthmatic patients, what component in the airways is affected and how?
the level of mucus in the airway of asthmatic patients is increased
how many diseases are there that can affect the airways?
over 40
how can respiratory diseases be divided?
they can be divided in 4 ways
- obstructive conditions
- restrictive conditions
- infectious, environmental and other diseases
- vascular diseases
what is the difference between obstructive and restrictive lung diseases?
- obstruction leads to a reduction in air flow whereas restriction leads to a reduction in lung volume
- obstructive conditions make it hard to exhale as air remains in the lungs even after full expiration whereas in restrictive conditions, it is hard to inhale as you can’t fully expand the lungs
what is the difference between the cause of obstructive and restrictive lung diseases?
obstructive = due to inflammation, excess mucus, airway narrowing (smooth muscle tightening) restrictive = due to lung scarring, fibrosis and extra-parenchymal problems
what are the symptoms of obstructive and restrictive ling conditions?
they both have similar symptoms:
-difficulty breathing - particularly under exertion i.e. trying to do exercise
what are some examples of obstructive conditions?
COPD, asthma, bronchitis etc
what are some examples of restrictive lung diseases?
interstitial lung disease, sarcoidosis etc
are conditions affecting the lungs life threatening?
many are mild and can be self limiting e.g. cold whereas others are life threatening i.e. pneumonia
the self limiting conditions can become life threatening if they have underlying chronic conditions e.g. COPD
how much air do we inhale a day?
11,000 litres
what is the problem with the fact that we inhale so much air a day?
there are inhalation exposures i.e. allergens (pollen), microbes, aerosolised toxins (tobacco smoke,air pollutants) that can contact our lungs
what kind of people are especially vulnerable to inhalation exposures to our lungs?
spatially (geographically), temporally (age), circumstances (morbidly obese, nutrition, economics, race, gender etc)
what are some genetic influences on how the lungs are affected?
usually rare diseases due to a single genetic defect
what are monogenic diseases?
caused by mutation in a single gene e.g. sickle cell disease, cystic fibrosis etc
what are polygenic diseases?
depend on the simultaneous presence of several genes, not inherited as simply a single-gene disease. e.g. hypertension, CHD, type 2 diabetes
they are associated with the effects of multiple genes in combination with lifestyles and environmental factors
are lung diseases usually due to genetics or the environment?
they are usually not single entities
so are due to a gene-environment interaction
are respiratory diseases caused by genetic factors or environmental factors or both
with examples
genes and the environment can independently cause a respiratory disease but can also combine their effects
- CF = monogenic
- asthma, lung cancer and COPD = polygenic
- carbon monoxide poisoning = environmental
- alpha 1 anti-trypsin deficiency = monogenic but ca be influenced by the environment
is alpha-1 trypsin deficiency caused by genes or the environment?
it is monogenic however the environment can have an effect on it
- main genetic cause of COPD
- if you have this deficiency, you will develop features of COPD but if you smoke, this massively potentates the progression
what is the difference between monogenic and polygenic diseases?
monogenic = rare diseases attributable to genetic variations with large effects. inherited in classic mendelian fashion polygenic = complex diseases controlled by 2 or more genes at different loci or different chromosomes
what are the genes that are seen in both monogenic and polygenic diseases?
TGFB1, TNFA and ADAM33
is smoking a purely environmental cause of lung disease?
no because 90% of COPD patients are smokers and 10-20% get COPD. this shows that it can’t be just environmental
how can genetic be useful in the study of lung diseases?
diagnosis estimation of risk understanding pathological mechanisms ene therapy guidance for new therapies
what are the cells of the immune system? give examples of each
- lymphocytes (T, B and NKC)
- phagocytic cells(monocytes and macrophages)
- granulocytic cells (neutrophils, eosinophils and basophils)
- dendritic cells
what are some barriers that pathogens encounter before reaching the immune system?
there are anatomical and physiological barriers that the pathogens encounter
in the lungs, there are cells that line the airways and produce surfactants, there is ciliary clearance, a low stomach pH and lysosomes in the tears and saliva
what is the function of the epithelial cells that lien the airways in the lungs?
they have a barrier function and are also able to detect and respond to pathogens
what are the cellular and humoral protections of the innate immune system>?
cellular: NKC, dendritic cells, macrophages, eosinophils, neutrophils, mast cells etc
humoral: part of the acute phase response (LPs binding proteins)
what are the cellular and humoral protections of the adaptive immune system?
cellular: T cells and B cells
humoral: antibodies
is there any interaction between the innate and adaptive immune system?
yes, they communicate a lot
the adaptive immune systems progressed from the innate system
what are the cells that sit in the cusp between the innate and adaptive immunity systems?
NKT cells and dendritic cells sit on the cusp of the 2 systems
describe the innate immune system
it is important in not getting us sick initially
involves a rapid host defence against invading pathogens
it is evolutionarily conserved
involved in the recognition of invading pathogens and activation of anti-microbial response
is emerging as a critical regulator of human inflammatory disease
implicated in the development of some diseases e.g. asthma
what is the significance in the fact that the innate immune system never changes?
this means that it will always respond to a pathogen in the same way i.e. if you inhale a bacteria today and again the same bacteria in 6 years, it will respond in the same way and take the same amount of time. this is because the quicker second response is by the adaptive immune system
how does the innate immunity deal with the fact that pathogens are able to evolve much quicker than our cells are?
our genetic attributes are much slower than the pathogens ones and this means that we would struggle to keep up. so, in innate immunity, they recognise very conserved structures within bacteria and also across different sets of pathogens.
they have also evolved to recognise some of the biological consequences of infection
what does the action of the innate immune system rely on?
they rely on a limited number of genetically predetermined receptors called pattern recognition receptors
these are highly conserved structures that are expressed by a large group of pathogens
they are common biological consequences of infection
what are the 3 broad strategies that the innate immune system utilises?
2 of the 3 strategies utilise pattern recognition receptors
- microbal non-self = pathogen associated molecular patterns (PAMPS) e.g. TLRs, RLRs, NLRs and collecting family
- consequences of damage/injury = damage associated molecular patterns (DAMPS) e.g TLRs, RLRs, NLRs and RAGE family
- missing self = MHC class 1 specific inhibitory receptors - these cells are on the cell surface and inordinacy health, they would be presenting host cells to the immune system and NK cells recognise these as host cells and cause an inhibitory signal so that they don’t attack themselves
how does the innate immune system function using PAMPs
it recognises the PAMPs that are found on pathogens but not usually on host cells
PRRs either act to directly bind PAMPs or interacting with other receptors that are bound to PAMPs
bacteria, fungi and viruses are all recognised by their PAMPs
what is the good thing about using a pathogens PAMPs to recognise it?
they are not easily mutated and they are very crucial to the cells function and so this would be something easy to recognise a pathogen by
how does the immune system function using DAMPs?
they are endogenous molecules that are created to alert the host to tissue injury and to initiate repair
can be intracellularly or extracellularly
intracellular: molecules released by cell necrosis/activation following injury
in the extracellular metric, molecule fragments are released/up-regulated in response to tissue injury
these prime the immune system to be ready to attack
what kind of cells are released by DAMPs intracellularly?
proteins = heatshock proteins (TLR2 and 4), high mobility box1 protein (TLR2 and 4)
self nucleic acids: mRNA (TLR3), ssRNA (TLR7 and 8), DNA (TLR9), IgG-chromatin complexes (TLR9)
what kind of cells are released by DAMPs extracellularly?
proteins: fibrinogen (TLR4), fibronectin (TLR4), tenascin-c (TLR4)
proteoglycans and glycosaminoglycans: billycan (TLR2&4), version (TLR2), hyaluronic acid fragments (TLR2&4)
how could DAMPs cause pathogenesis?
harmful stimuli e.g. pathogens, injury, heat, auto-antigens, tumours and necrotic cells can all trigger damage leading to release DAMPs.
this will activate TLRs and lead to the release of pro-inflammatory mediators which then can feedback and cause an increase tissue damage.
if this loop is allowed to propagate and lead to the release of more and more DAMPs, it can have a detrimental effect and cause pathogenesis
what kind of diseases are associated with high levels of DAMPs?
associated with many inflammatory and autoimmune diseases swell as atherosclerosis and cancer
- although endogenous signals can be good (to prime the host if your under attack immunologically), if they are allowed to propagate and not checked it can do more harm
how many TLR receptors are in humans?
10
how can TLRs be divided?
can be broadly divided into those who recognise bacteria which are on the cells surface and those who recognise viruses which are contained within endosomes
what is the difference between TLRs on the cell surface and those in endosomes?
TLRs in endosomes generally can’t recognise host molecules where as those on the cell surface recognise any kind of DNA or RNA
give 2 examples of TLRs - 1 in humans and 1 in a model organism
TLR10 - cell surface, ligand undetermined in humans
TLR11-13 = expressed in mice
what can TLR4 recognise and what can it do?
TLR4 can recognise bacterias e.g. lipopolysaccharide and mannan , also Repiratory Sinsitual Virus and a lot of host proteins including Tenascin-C
– this will trigger an inflammatory response to all of these different ligands
how are TLRs different to normal receptors?
they are very different to normal receptors as they have the ability to recognise a wide range of ligands
they sometimes use co-receptors to do this e.g. TLR2 can work with TLR1 and 6 which is a way to expand the repertoire of proteins that they can see/recognise
describe TLR signalling
- using TRL4 as e.g.
the TIR domains of TLRs interact with TIR domains of the adaptor proteins
TLR4-TRIF signalling = initiated within endosomes
(in bacteria): phosphorylation cascades activate NF-kB and MAPKs allowing entry to the nucleus to drive expression of cytokine genes - predominantly in response to bacteria
(in viruses): phosphorylation of IRFs lead to localisation of the nucleus to drive expression of type 1 interferon (IFN) genes to help control viral infections
-in response to TRIF, IRF activation happens
-cross talk an occur i.e. TRIF activating NF-KB
which TIRs can interact with MYD88?
all TIRs except TLR3.
what are the TIR adaptors and how many are there?
there are 4 main TIR adaptors: MYD88, TRIF, TIRAP/MAL & TRAM
what does TLR4 need to bind to Myd88?
it needs a bridge i.e TRF1 as it can’t directly bind to Myd88
what is the difference between TLRs and NLRs?
NLRs detect bacteria from the cytosol
TLRs detect bacteria from the endosomes and cell surface
how many NLR genes are present in humans and in mice?
22 in humans
34 in mice
what is the role of NLRs?
they are involved in sensing intracellular bacterial pathogens and DAMPs, and in the regulation of inflammatory and cells death responses
what are NLRs characterised by?
by the presence of conserved nucleotide-binding and oligodimerisation domain (NOD) motif that activates the signing complex
how many structural subfamilies of NLR are there and what are they?
there are 5 NRLA - acidic domain NRLB - BIR domain NLRC - CARD domain (NOD1, NOD2) NRLP - Pyrin domain (NRLP3) NRLPX - no known homology
how many functional subfamilies of NRLs are there?
there are 2 functional NRLs
- NRL C(NOD1 and NOD2) - inflammatory and antimicrobial signalling
- NRLP3, NRLP6 and NAIPs - inflammasomes
what do NOD1 and NOD 2 sense?
NOD1 and 2 sense bacterial molecules produced during the synthesis, degradation and remodelling of peptidoglycan (PGN) - which is a major component of bacterial cell walls
NOD1 recognises mess-diaminopimelic acid(mess-DAP) containing PGN fragments (MAINLY GRAM NEGATIVE)
NOD2 senses muramyl dipeptide (MDP) found in the PGN of nearly all GRAM POSITIVE and GRAM-NEGATIVE organisms
what does the NOD family result in the singling of?
NOD family results in the signalling of NFK-6, MAPKs and the release of pro-inflammatory cytokines
how are inflammasomes different from NODs?
they are different as they also can recognise the microbial products in the cytoplasm and also cellular/metabolic stress which can trigger activation of the inflamasomes which are involved in cleaving/activating cytokines e.g. IL-1B and IL-18. this is an additional control mechanism
what are RLRs and what can they detect? what members are there?
RLRs = rig like receptors
there are 3 members that detect viral RNA in the cytoplasm
RIG-1, MDA-5 and LGP2
describe RIG-1
RIG-1 = retanoic acid inducible gene 1
short dsRNA (up to 1kb)
s’ triphosphate (5’ppp) cas (ss or ds RNA)
influenza A and RSV
describe MDA-5
melanoma differentiated gene 5
long ds RNA (over 2kb) with no end specificity
replication intermediates
rhinovirus
describe LGP2
laboratory of genetics and physiology 2
very high affinity for any dsRNA
describe RLR signalling
ligand binding induces conformational changes and oligomerisation of RLRs to activate the signalling partner IPS-1 on mitochondrial membranes
IPS-1 activates signalling cascades leading to activation of IRFs and NF-kB an the expression of interferon and cytokine genes
LGP2 functions as a positive regulator in RIG-1 mediated and MDA5 mediated virus recognition
what cells are involved in the innate response to infection? what are there roles?
cytokines, chemokine and others (e.g. acute phase response, adhesion molecules)
these have 2 roles: immediate defence and direct adaptive immunity
how many cytokines are involved in the inflammatory response? what are the main functions of the cytokines and how do they work?
5 main cytokines
1 of the main functions is to recruit the inflammatory cells to the site of infection.
could be through effects on the vascular endothelium to make it more leaky so that the cells can get out
could upregulate adhesion molecules on these cells allowing them to bind to the endothelium and pass through into the area where the pathogen is
what is the role of adhesion molecules?
they are induced on circulating immune cells and endothelial cells
they work to co-ordinate movement of cells into infected tissues where phagocytosis and killing takes place
what can be triggered during the systemic effects?
the acute phase
describe the acute phase response in the liver
cytokines can activate hepatocytes in the liver to generate acute phase proteins
describe the acute phase response in the hypothalamus
they are endogenous pathogens and so act on the hypothalamus to raise the body temperature (fever)
describe the acute phase response in dendritic cells
TNF-alpha stimulates migration to lymph nodes and maturation
why advantage is there to inflammation causing a fever?
because bacteria and viruses find it more difficult to replicate at a high temperature whereas our adaptive immune system works much better at these high temperatures
give an example of a condition which can occur where the acute phase response system goes wrong
- stats
sepsis is a condition that occurs when the acute phase response goes wrong
affects ~200000 people in the UK every year and ~40,000 people die
many of these are avoidable but this condition can be very hard to diagnose
its usually detected in the latter stages, making it difficult to stop
how does sepsis develop and how does it cause damage to organs?
starts with an infection from insect bites/cuts etc
immune response responds to this in a normal way
for some reason, wither the body can’t control the spread of infection around the body or because the immune system is in overdrive leads to sepsis. this can cause damage to organs
what does the release of interferons lead to the activation of in the anti-viral response to infection?
release interferons will then act on interferon receptors (IFNalpha and IFNbeta) activating the STAT pathway
has 3 main effects on our cells
what are the 3 main effects on our cells caused by the activation of STAT pathway in the anti viral response to infection
1 = induce resistant to viral replication.
activates genes that cause the destruction of mRNA
inhibits the translocation of viral proteins and some host proteins
interferons tend to communicate to neighbouring cells that viral attack is underway thereby priming them for an attack
2 = increases MHC class 1 expression and antigen presenting of viral proteins
facilitates recognition and susceptibility to cytotoxic t cells
3 = activates NK cells to kill virus infected cells
as well as activating dendritic cells and macrophages + include chemokine to recruit lymphocytes
how can you target an over active immune system?
1 way to target to detrimental effects on over active immune system is to inhibit the response using antagonists
what are the 2 main strategies of immunomodulation
antagonists: block binding of ligands/protein ligands complexes to receptors/ interfere with intracellular adaptor molecules of common signalling pathways
antagonists developed to date = small molecules, proteins, oligonucleotides, antibodies and peptides
agonists: adjuvant effect (used with a primary treatment) promoting protective responses e.g. interferes with anti viral, vaccines
what are side effects of antagonists and agonists as strategies of immunomodulation?
Antagonists - side effects = potentially repress protective mechanisms
Agonists - side effects = potentially enhance inflammation
what are the respiratory tracts mace of?
cartilaginous rings
what part of the body is the respiratory tract attached to?
joined to the middle ear cavity and this is why when you get a cold, your ear is sometimes blocked
what are the functions of the lungs split into?
respiratory and non-respiratory
what are the respiratory functions of the lungs?
ventilation and gas exchange CO2, O2, pH, humidifying
what are the non-respiratory functions of the lungs?
- making, activating and inactivating of vasoactive substances, hormones and neuropeptides
- lung defence: compliment activation of host defence proteins, recruitment of leukocytes, cytokines and growth factors
- speech, vomiting, defacation and child birth
how are lungs a major biosynthetic organ?
they are highly vascularised
why are respiratory infections so rare in comparison to the amount of air we inhale?
we inhale ~10,000 litres of air every day and lots of pathogens could potentially come in and infect our lungs but our host defence system can prevent pathogens from coming in and establishing an infection
what is epithelial tissue composed by?
cells that line the cavities and surfaces of structures thouhout the body
what tissue are glands formed by?
epithelial cells
what are connective tissue and epithelial tissue layers separated by?
basement membrane
what is the primary role of respiratory epithelium?
to line the airways and moisten them. also to protect them by acting as a barrier to prevent potential pathogens or foreigners from infecting the lungs
how does the respiratory epithelium work to prevent pathogens and foreign particles etc from entering the lungs?
by work of the mucociliary escalator
what are the chemical epithelial barriers?
- anti-proteases: SLP-1, lysozyme and phospholipase A
- these are to protect the lungs from proteases that could be left behind after an inflammatory response etc - anti-fungals
- anti-microbial peptides
- surfactant A and D - opsonise pathogens for enhanced phagocytosis
- interact with the surface of pathogens and then link the phagocytosis mechanism within the lungs and they mark these pathogens for uptake by professional phagocytosis
give an example of a non specific defence mechanism in the lungs
bacterial flora - provide a low level induction system that keep the defence system primed
what evidence is there to show that different parts of the respiratory tract have different functions?
different parts of the tract have different airway epithelium i.e. bronchioles = ticker than in the alveoli
as you go down the tract, cells get more cuboidal/columnar and alveoli gets more squamous
are mice and human epithelia similar? what are some differences?
they are similar
human airways are more cartilaginous and have a greater number of mucosal glands
the epithelial cell population is about the same
what is the name of the junction where bronchioles move into alveolar gas exchange regions?
the bronchioalveolar duct
what are neuroendocrine cells?
basal cells which are progenitor cells for repopulation of airways following injury in the trachea and bronchi
what is a pericellar lining fluid? where is it
there is cilia with pericellar lining fluid above it which is thin watery fluid that the airways secrete
on top of this is a mucin layer
what cell types are there in the submucosal gland?
there are 2 types of secretory cells.
- goblet cells which produce mucus
- serous cells which produce a different series of proteins
what cells are specialised to help with the gas exchange in the alveolar epithelium?
type 1 and type 2 cells in the alveoli are very thin cells that have a huge surface area with a nucleus that sticks out. they allow reasonably for gas exchange between the capillaries and internal surface of the alveolar structure
-surfactant = a lipid based material that serves to lower the surface tension of the respiratory tract
what is mucus made of and what secretes it?
airway mucus is a viscoelastic gel containing water,carbohydrates, proteins and lipids.
it is the secretory product of the mucous cells (goblet cels and submucosal glands)
what is the gel - brush hypothesis?
it describes the mucus on top of cilia which brushes it
what is the mucus gel layer made by?
created by huge proteins- MucSAC/SB
where is mucus transported to and how is this done?
mucus is transported from the lower respiratory tract into the pharynx by air flow and mucociliaryy clearance
what does mucus protect the epithelium from?
mucus protects the epithelium from foreign material and from fluid loss
how does the mucociliary escalator work?
- encapsulate foreign particles then the cilia beat in organised waves
the cilia beat in directional (synchronised) waves to move the mucus up the airways
this happens all the time in the body to prevent being clogged up
is the mucus clearance via the escalator a period thing or contents?
happens constantly - its innate
what is a cough?
an expulsive reflex that protects the lungs and respiratory passages from foreign bodies
what are the causes of coughs?
irritants - smokes, fumes, dusts etc
diseased conditions e.g. COPD, tumours etc
infections (influenza)
what is a sneeze?
an involuntary expulsion of air containing irritants from the nose
what are the causes of sneezes?
irritation of nasal mucosa
excess fluid in airways
what kind of cells do infections target and what is the consequence of this?
they target airway epithelial cells
a conséquence of this is damage
in most cases, what happens to airway epithelium following an insult?
a complete repair
what is the cycle that happens after epithelial cells suffer insult?
there is a cycle of differentiation, damage, spreading an d migration, proliferation then differentiation again
why are epithelial cells able to change their phenotype?
they have a degree functional plasticity which is what allows it to change its phenotype
what are the principle progenitor cells in the epithelium?
basal cells
there is no evidence that in different regions, basal cells have been able to form different cells
what happens if there is an epithelial abnormality in the lungs?
pulmonary disease
what underpins many obstructive long diseases?
abnormal epithelia responses to insult/injury
why are mucus plugs/inflammation associated with severe disease?
when there is mucus and inflammatory cells blocking the airways, mucus plugs can completely obstruct the airways. this can be coughed up by a patent during an asthmatic attack
does cancer or respiratory diseases kill more people?
respiratory diseases kill more people than all cancers combined
what does the failure of adaptive immunity cause?
Failure of adaptive immunity leads to recurrent respiratory infections, specific to the cell affected
what are the internal and external defences in the innate immune system?
internal:
- phagocytic cells
- antimicrobials
- inflammatory cells
- natural killer cells
external:
- skin
- mucous membrane
- secretions
what are the defences are in adaptive immunity?
humoral response (antibodies) cell mediated response (cytotoxic lymphocytes)
what is the difference between an antigen and a pathogen?
an antigen is a molecule capable of inducing an immune response
a pathogen is a molecule (bacteria or fungi) that are covered in a myriad of unique receptors)
what are the key properties of the adaptive immune system?
specific - ability to mount a specific immune response to a huge range of antigens including pathogens
self-recognising - recognition of self antigens and eliminate of attractive clones
memory - development of immunological memory and so is able to remember long lived B and T cells
how do lymphocytes recognise antigens?
- T cells and B cells express different unique antigen receptors
- The variable region determines the receptor specificity
how many different antigen receptors are there? why is this a problem for DNA?
~10^18
DNA can’t encode all those receptors
describe how there is diversity and specificity in adaptive immunity
• Early in lymph development, diversity comes from DNA recombination
• Generation of pathogen specific variable regions in lymphocyte receptors is the basis of diversity and specificity
• Much diversity is generated early in development via DNA rearrangements (VDJ recombination)
o VDJ lays the blueprint of DNA
• Exposure to relevant antigen, triggers replication and somatic hyper-mutation generating further diversity
what is affinity maturation?
Selection for higher affinity
how do we get millions of unique t cells?
• Multiple variable and diverse joining regions
• More looping mechanisms which are excised
o Very random excision of regions then they are put back together
• Random recombination events occur between about 50 Variable (V) 27 Diversity (D) and 6 Joining (J) segments in both heavy and light chains
• Recombination (splicing) is not precise (nucleotides inserted or deleted) greatly increasing diversity
• Further mutations occur on pathogen exposure (somatic hypermutation)
• with selection of higher affinity clones (affinity maturation)
in adaptive immunity, what regions does recombination happen (V,D,J)
50(V), 27(D), 6(J)
what is immune tolerance?
what are the different types of immune tolerance and what can they cause?
¥ A state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response
¥ Tolerance can be to self, but also to the fetus in pregnancy, or it can develop to pathogens (chronic infections) or cancers
what happens if there is a failure to establish tolerance?
¥ Failure to establish tolerance leads to autoimmune disease, where our immune system attacks our own body. An example is rheumatoid arthritis
what are the 2 types of tolerance?
central and peripheral
- Central tolerance – way to distinguish cells that are self to those that are non self – most in early life
- Peripheral tolerance – way to prevent over-reactivity of the immune system to environmental entities — continues throughout life
where do the 2 types of immunological tolerance occur? and what happens?
Central tolerance
In the thymus, lymphocytes that react with self-antigens are deleted or develop into suppressor ‘Tregs’
Peripheral tolerance
In lymph nodes, autoreactive clones escaping central tolerance are deleted or suppressed by Tregs
what are t-reg cells?
• T cells that react to an autoantigen (antigen from normal tissues which are targeted by humoral or cell mediated immune system) become t-reg cells
o They migrate to migratory tissue and are established there and then mediate peripheral tolerance
what is the advantage of immunological memory?
¥ Allows rapid immunological response on subsequent exposure
in what aspects are memory b cells better than naive cells?
¥ Following activation, a small proportion of high affinity B and T cells differentiate into long-lived memory cells, residing in lymph nodes or tissues
¥
Memory B cells are distinguished from naive B cells by an increased lifespan, faster and stronger response to stimulation and expression of high affinity immunoglobulin (IgG)
describe the process of antigen presentation
- APCs that have interacted with Th are licensed to activate cytotoxic T cells (CD8 +ve) kill virus-infected or tumour cells
- Cytotoxic T cells form pores in their target cells which ‘explode’
how do t helper cells help other immune cells?
- Following APC-Th cell interaction, governed by MHC and co-stimulatory receptor interactions, cytokines are produced
- Cytokines activate different T cell transcription factors leading to differentiation into different Th cell subsets
describe the interaction between T helper cells and B cells
- B cells can interact with antigen directly
- In some cases, they can produce antibody without ‘help’ (T-independent)
- Mostly B cells need input from Th cells (Th2 and Tfh cells)
what do activated B cells become?
plasma cells
what happens in isotype switching?
¥ In isotype switching (class switch recombination or CSR) the ‘variable’ antibody region is unchanged but becomes attached to a different constant region, altering its properties.
what do naive B cells express initially and what does this change to upon maturation?
initially express IgM and IgD
after maturation - IgM = switched to IgG, IgA or IgE
what are IgM, IgG, IgA, IgE and IgD for?
¥ IgM Produced early in immune response
¥ IgA Mucosal immunity (gut and lung)
¥ IgG >80% circulating antibodies are IgG
¥ IgD Found on the surface of all B cells
¥ IgE Binds mast cells, mediates allergic reactions
what does the variable region and constant region of antibodies bind to?
• Variable region binds target antigen and constant region interacts with effectors
what are IgM ad IgG especially good at ?
• IgM are good at neutralising and agglutinating, IgG are good at opsonising and fixing complement
How can we manipulate the adaptive immune response therapeutically?
for vaccination, immune suppression,MAB?
also in infection, inflammatory diseases and malignant disease?
¥ Vaccination – augment the adaptive response
¥ Immune suppression – reduce the adaptive response
¥ Monoclonal antibodies (’biologic therapy’)
¥ Varied applications including
¥ Inflammatory disease (suppress immune system)
¥ Infection (additive to immune system)
¥ Malignant disease (augment immune system)
what are pathogens derived from? and what can they do?
¥ Vaccines are derived from pathogens or toxins (e.g. dead or attenuated bacteria, capsular polysaccharide, viral proteins)
¥ Vaccines can prevent infection or reduce morbidity in individuals, and also generate ‘herd immunity’ - need to vaccinate 75-95% (disease-specific)
how can vaccinations be administered?
¥ Can be administered by injection, nasally, orally etc.
describe the problem with the influenza vaccination
¥ Annual outbreaks of influenza A lead to massive strains on health services and many deaths
¥ Major antigens are neuraminidase (N) and hemagluttinin (H)
¥ Mutations (antigenic drift – all flu viruses) mean protection is reduced, and genetic re-assortment with viruses affecting other species (antigenic shift – Influenza A only) may lead to pandemics
¥ Influenza A is classified by its expression of N and H e.g. H1N1, H3N1 etc. As influenza A affects other species, antigenic shift can occur
¥ Influenza B causes less severe disease and is less variable (antigenic drift only)
how is an influenza vaccine manufactured?
- WHO selects ‘likely’ flu strains for next year in February (2 flu A and 1 flu B). Don’t always guess correctly.
- Manufacture low pathogenicity virus to express the relevant H and N
- Mass produce virus in eggs and kill virus to generate vaccine
- Targets – elderly, chest diseases, diabetes. Immune responses may be insufficient Patients who can’t make antibodies derive limited benefit
what are the typed of immunosuppressants?
describe each
¥ Corticosteroids – modulate transcription and suppress both innate and adaptive responses. Multiple side effects
¥ Antimetabolites – suppress DNA synthesis – mainly T cells
¥ Methotrexate inhibits dihydrofolate reductase and prevents synthesis of folic acid
¥ Purine analogues e.g. azathiaprine
¥ Mycophenolate – inhibits guanosine synthesis
¥ Calcineurin inhibitors (cyclosporin, tacrolimus) – prevent G0-G1 cell cycle progression – T cells
¥ Monoclonal antibodies - wide range of targets and applications e.g. rituximab (antiCD20) targets B cells
how are MABs made? how has this process become advanced?
¥ Clonal antibodies engineered to specific targets for scientific and medical applications
¥ Fuse myeloma cells with spleen cells from immunised mice (Kohler and Milstein)
¥ Can now be made by recombinant technology using viruses or yeast and made chimeric and even ‘humanised’ to reduce allergic reactions
how do tumour cells evade checkpoint receptors?
¥ Presentation of tumour antigen with MRC and co-stimulation should lead to an activated T cell response
¥ T cells express inhibitory checkpoints receptors e.g PD-1 (Programmed Death 1). Tumours may express ligands eg PD-L1 to engage these checkpoints, inhibiting the immune response
what has been proposed as a way to stop tumour cells from evading checkpoints?
¥ Monoclonal antibodies have been engineered to prevent this, enhancing recognition and immune responses to tumour cells
what is asthma?
A chronic inflammatory disorder of the airways causing recurrent episodes of wheezing, breathlessness, chest tightness, and cough. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.”
what kind of cells does asthma involve?
both innate and immune cells
what are the different causes of asthma?
o airway inflammation
o bronchial hyper-responsiveness
o recurrent reversible airway obstruction
what is the burden of asthma in the UK?
♣ 5.4m in the UK receiving treatment. 1.1m children (1:11), and 4.3m adults (1:12)
♣ 1,246 asthma deaths in 2012 (358 males, 888 females)
- 21 aged 0-14 years
- 204 aged 15-64 years
- 1,021 aged >65 years
♣ 1 person dies from asthma every 7 hours
♣ 60% of asthmatics report significant persistent symptoms or symptom burden
♣ 31%said asthma symptoms prevent them doing things in spare time
♣ 65% of asthmatics report severe attacks (exacerbations)
- excessive mucus clogs up airways in asthma patent
why is it difficult to treat asthma with drugs? what is used instead?
- difficult to treat severe asthma attack with drugs because the airways would be clogged up and so taking drugs wouldn’t work as they can’t get access
- use systemic drugs to open up the airways instead
how much does asthma cost the NHS per annum - what is the breakdown of the costs?
♣ £1.1bn per annum costs to the NHS
- 6.3m primary care consultations (74% costs)
- 93,000 hospital in-patient episodes
- 1800 intensive-care unit episodes
- 36,800 disability living allowance claims (13%)
♣ 1m lost working days per annum
why is asthma becoming more common?
♣ Epidemiological data over the last 50 years shows a steep increase in allergic conditions e.g. asthma and immune disorders i.e. Multiple Sclerosis
♣ During this time, there has been a decline in infectious diseases i.e. measles mumps etc.
why has the occurrence of infectious diseases gone down?
Could be due to successful drugs/therapies for these infectious diseases
what is the 2 theories that explain why asthma happens?
- Biodiversity hypothesis shows that proposes that reduced contact of people with natural environmental features and biodiversity, including environmental microbiota, leads to inadequate stimulation of immunoregulatory circuits.
- Hygiene theory describes the protective influence of microbial exposures in early life on the development of allergy and asthma,
what is the link between th1 phenotype and getting asthma?
• Exposure to microbial components early in life skews immune response
Th2 Th1
o At birth children have a th2 immunology
o Exposure to microbial infections drive it to a more th1 phenotype which protects it
• Decrease in prototypical Th1-stimulating infections e.g. measles, mumps, tuberculosis
why is it suggested that a decline in biodiversity and better hygeine can drive asthma? what is the family link to this?
• Declining biodiversity, urbanisation and associated changes to diet and lifestyle
♣ Decrease in infection in early childhood
♣ Elder siblings would be passing on all germs and infections to child earlier than when they would get it so youngest in family would be less likely to get asthma etc
♣ The number of children per family has reduced so this is less of the case
♣ Better hygiene standards and mean that its less common to transfer germs
♣ Children that grew up on farms are more exposed to more microbes and unpasteurised milk etc.
what are the risk factors for developing asthma?
♣ Development of asthma and triggering exasabtions o Allergens o Genetics o Food additives o Smoking o Repiratory infecions o obesity o Medication o Occupational exposures o Pollution ♣ Involved in triggering exasterbations o Temperature change o Exercise o Gastric reflux o Stress and emotions o Cold air o Strong odours
what is the genetic link to asthma occurrence?
♣ Heterogeneous & genetically complex (polygenic) ♣ >100 genes identified ♣ Close relative with atopic disease ♣ 1 parent = 25% risk ♣ 2 parents = 50% risk
what have twin studies shown about the link of asthma to genetics?
♣ twin studies used to compare between people with either 100% identical genetic makeup (monozygotic) or 50% of the same genetic makeup (dizygotic)
♣ Twin studies - genetic factors account for:
♣ ~70% variation in disease susceptibility
♣ ~24% variation in overall asthma symptom severity
♣ High heritability does not preclude important contribution of environmental factors
what is epigenetics?
♣ Epigenetics - the transcriptional dynamic alterations leading to changes in gene expression
what genes have been most linked to asthma?
Chemokines expressed in epithelial cell layer
Spink5 and flag involved in tight junction formation
what are the physiological aspects inked to asthma?
Physiological (e.g. obesity and diet)
-overweight’ higher asthma risk’
nitrites = involved in preserving meat e.g. bacon and they have been linked to asthma
Vitamin D – show to reduce colds etc. the cold virus = key trigger of many asthma exacerbations
what are the environmental disease is linked to asthma?
• Respiratory Virus Infections (Respiratory Syncytial Virus –RSV)
- 33.8m RSV infections worldwide per annum in children <5 years
- Small proportion develop severe disease
- Severe disease = fourfold incidence of asthma
- Major trigger of exacerbations
- High number of children can develop bronchitis
what environemntal factor links to asthma?
♣ Tobacco smoke
- Pregnancy
- Parental smoking in childhood
- Genetics (ORMDL3; PCDH1)
♣ All these mean there is an increased risk of asthma in childhood and adulthood
♣ Can cause epigenetic changes
♣ These genes are more closely related to children whose parents smoke
what are the phenotypes associated with asthma?
• Asthma has evolved from a term describing a single disease to one encompassing multiple subgroups or ‘phenotypes’
• Asthma used to be associated with only th2
• There are other phenotypes that are eosinophilic
• Non-eosinophilic – associated with neutrophils
o It tends to be corticosteroid refractive – don’t respond to inhalers
describe the eosinophilic and non-eosinophlic phenotypes of asthma
♣ Th2 (eosinophilic)
- Early- and later-onset disease over a range of severities
- Associated with allergy (atopy – the tendency to develop IgE mediated reactions to common aeroallergens)
- Non-allergic variants (late onset, exercise-induced)
♣ Non-Th2 (non-eosinophilic)
- Obesity, smoking, neutrophilic
- Associated with more severe disease
describe eosinophilic asthma including the genes that are involved and what it causes
♣ Eosinophilic asthma
o Environmental allergens
o Dendritic cells which are APC
o Takeup allergen, process it and present tem in lymph nodes oto t cells. This drives a th2 phenotype of the th2cells
o Allergic info = driven by the t clls
o Cytokines: il4,5 and 13 =key processes
o Il4 – eosinophilic
o Il4- and 13 – effects on epithelial layer and smooth muscle cells
o Mast cells =key as they nind the ag specific IgE leading to degranulation
o Tryase – proinflammatory
o X – pro fibrotic
o Release bronchoconstriction
o Causes SM to contract leading to bronchio-hyperactivity
descibe non-eosinophilic asthma including the genes involved
• Non-eosinophilic asthma o More theoretical so less I known o Key triggers – pathgens o Toll like receptors o Smoke etc. o Act on epithelial cells and macrophages releasing il8 o Neutrophils cause airway o T cells have a key role o Th1 and th17 cells – drive epithelial cell to produce il8 o Release if Gamma – act on mast cells etc o Known defects – o Interferons
what is the main pathology of asthma?
Decrease in diameter of the airways
what is a condition linked to the airway inflammation caused in asthma? are they linked?
Bronchial hyper-responsiveness (BHR)
• Hallmark of asthma – degree of BHR correlates with asthma severity
• Caused by airway inflammation
• A dynamic and reversible process
• Inappropriate and excessive contraction ‘bronchoconstriction’ of smooth muscle
♣ In response to allergen, rapid decrease in lung function within 15 minutes of lung insult
♣ Reversed to normal baseline soon (ACUTE)
♣ In 50% patients, time after that allergic insult, they get a late asthmatic insult 6-24 hours after initial insult
♣ It’s much more severe and prolonged than the initial insult
describe the acute and late airway allergen response in bronichial hyper-responsiveness condition
♣ AAR = triggered by binding of allergen to membrane bound IgE on mast cells
o Release of mediators (histamines, cysteinyl leukotrienes, PGs)
o bronchoconstriction
♣ LAR = due to influx of inflammatory cells (especially eosinophils)
o Influx of inflammatory cells, mainly eosinophils
o Airway oedema
o Bronchoconstriction
♣ If people have a modest asthma attack and don’t use their inhalers, could get the prolonged attack later which would be much more damaging to the airways
what is airway remodelling?
• Airway Remodeling - The development of specific structural changes in the airway wall in asthma accompanying long-standing and severe airway inflammation
what happens to the airway smooth muscle in airway remodelling?
o Hypertrophy and hyperplasia (proliferation) of airway smooth muscle cells in response to growth factors (PDGF, endothelin-1) released from inflammatory or epithelial cells = further narrowing of airway lumen
o Release of inflammatory mediators = maintained inflammation
o Irreversible ‘fixed’ airflow obstruction
what happens to the blood vessels in airway remodelling?
♣ Blood vessels
o Increased mucosal blood flow
o Angiogenesis in response to growth factors (VEGF)
o Microvascular leakage from post-capillary venules = oedema & plasma exudation into lumen
what causes mucus hyprsecretion in airway remodelling?
• Mucus hypersecretion
o Hyperplasia of submucosal glands & increased epithelial goblet cells
o Mucus plugs that occlude asthmatic airways – especially fatal asthma
o IL-13 & neutrophil elastase are potent inducers
what causes fibrosis in airway remodelling?
o Aberrant repair to persistent epithelial injury
o Basement membrane thickened due to sub-epithelial fibrosis
o Type III and IV collagen depositions below basement membrane
♣ Triggered by myofibroblasts
♣ Mucus gland = much larger
♣ Thickened SM
♣ Lymphocytes in the airway
o Release of pro-fibrotic mediators (TGFβ) from epithelial cells - associated with eosinophil infiltration
o Persistence of fibrosis = asthma would be irreversible due to the airway narrowing
what is a potential treatment for asthma to treat airway remodelling?
o Bronchial thermoplasty = potential treatment for asthmatic patients – burning SM off the airways which could benefit patients
- Epithelial layer shedding
- Goblet cell hyperplasia
- Collagen deposition beneath basement membrane
what are treatments for asthma?
♣ Usually controlled using inhaled corticosteroids (ICS) and bronchodilators - long-acting β2-agonists (LABA)
♣ Use both in combination
why do some patients not properly adhere to inhaled corticosteroids as an asthma treatment and what does this cause?
♣ Could be due to poor adherence of treatment
♣ Compliance increases when a patient has exacerbations
♣ the younger you are, the less likely you are to comply
-could lead to the asthma being more severe
♣ poor communication with healthcare professional –
♣ i.e. not using inhalers right etc.
what is the biggest problem of severe asthma to the economy and why can it be hard to treat?
♣ Severe asthma accounts for 5-10% patients, but consumes >50% medical expenditure
♣ Different phenotypes of asthma with different patterns of inflammation may benefit from specific therapeutic targeting
♣ different phenotypes require different medications
what is COPD and what does it usually result from?
A chronic and progressive disease that is characterized by the development of airflow limitation that is not fully reversible and by an accelerated decline in lung function. This usually results from an abnormal inflammatory response of the lungs to noxious particles or gases.
what are 2 main conditions that COPD encompasses?
• COPD – encompasses several conditions
o Chronic bronchitis - affects bronchi
o Emphysema – affects alveloli
who is most effected by COPD?
the elderly
but can also happen in young people
what is the burden of COPD in terms of the economy and its prevalence in the world and the deaths its caused
• Major global healthcare issue
• Predicted to become 3rd leading cause of death worldwide and ranked 5th for disease burden.
• 1.2m in the UK living with COPD, 2% population (4.5% people >40) = 2nd most common lung disease in the UK
• 2nd highest contributor to respiratory mortality (lung cancer 31%; COPD 26.1%; pneumonia 25.3%)
• 29,776 COPD deaths in 2012 (15,245 males, 14,531 females)
o 2,719 aged 15-64 years
o 27,056 aged >65 years
what is the difference in epdemiology of COPD in developing vs developed countries?
- In developing countries, use biomass fuel which contributes to COPD deaths more so in these countries than smoking which is more prevalent in developed countries
- Risk factors vary according to geographical area
