immunology Flashcards
what are the key things that the immune system need to be able to discriminate between
self and non self
how do we develop allergies
when the immune system acts on thing that it shouldn’t - it is oversensitive to something that isn’t actually harmful
give a very brief overview of the initial response to infection
- activation of local innate immune cells
- increased permeability of local blood vessels
- migration into tissues of more immune cells and plasma proteins
what are macrophages, dendritic cells and mast cell
- they are all derived from haematopoietic cells
- they are all leukocytes and cause the blood vessels to become sticky and dilate, each has a different effect
- they are all part of the innate immune system and generate an inflammatory response
where in the body and macrophages, dendritic cells and mast cells found
in all parts of the body
what are the first cells that get recruited in the innate immune response
neutrophils followed by monocytes
what do neutrophils and monocytes do in the innate immune response
they stick to the blood vessel wall and migrate through the gaps to the infection site causing an acute inflammatory response
what did Charles janeway predict
the presence of host receptors that recognise conserved patterns on pathogenic molecules - the immune system must do more than differentiate between self and non self
he thought these receptors would probably be germline encoded
what are PAMPs
they are pathogen associated molecular patterns and are what make microbes look different to host cells and this is how the immune system recognises them
what are viral PAMPs
viral surface nucleic acid glycoproteins which are sensed by pattern recognition receptor proteins
what are bacterial PAMPs
bacterial cell wall components are sensed by pattern recognition receptor proteins
what are fungal PAMPs
polysaccharides in the fungal cell wall are recognised by pattern recognition receptors
what are protozoa PAMPs
glycolipids are sensed by pattern recognition receptor proteins
what did polly matzinger propose
the immune system senses damage or danger rather than just non self because some microbes are dangerous and some are not so there would need to be a way to discriminate
what are DAMPs
danger associated molecular patterns
trigger the immune system to respond too danger
what are the differences between host and microbial DNA
there are differences in structure and location
host - located in the nucleus and is ds
microbe - often have nucleic acids that are found in other parts of the cell and some have ss DNA
how can sense cell death from protein abundance
nuclear and cytoplasmic proteins are released from cells when they undergo trauma or death so usually these are present in very low abundance in the extracellular environment so they can be used as a way of sensing death
how can metabolites be used for sensing cell death
extracellular ATP is usually in extremely low abundance and rises due to cell death or damaged tissue which again acts as a signal that the immune system might have to respond
the adaptive immune system attempts to prevent …………………………
re-infection
what are the steps in information transfer from pathogen to adaptive immunity
pathogen - causes some sort of damage or disturbance to host tissue
innate response - activation of dendritic cells, mast cells and macrophages which induce a local inflammatory response which attracts other cells
adaptive immunity - appropriate specific response to pathogen antigens
what gives rise to leukocytes
haematopoietic cells
describe the transfer of information from the innate to the adaptive immune response
- some cells will migrate out of the infection sit and drain into the surrounding lymph nodes
- dendritic cells can carry the pathogenic antigens to the local immune system in adaptive immunity
- adaptive immunity is driven by B cell and T cell activation and is highly specific to defined antigens
what do CD4+ T cells do
they produce soluble mediators called cytokines which direct activation of different parts of the immune system
- they can activate B cells to make antibodies to clear the pathogen
- they can increase the proliferation of killer CD8+ T cells which can kill infected cells
how does adaptive immunity provide protection to reinfection
by providing immunological memory
are wbc and leukocytes the same thing
yes
what are the different types of innate immune cells and what are their functions
- dendritic cells - they engulf pathogens and activate the adaptive immune cells
- mast cells - respond to trauma and infection by releasing toxic molecules and vaso active peptides which drive inflammatory responses and kill pathogens
- macrophages and monocytes - engulf and destroy pathogens - macrophages are tissue resident cells and monocytes are recruited from the blood
- neutrophils - the most common wbc and are attracted very quickly - they are not found in the tissue in the absence of infection but they migrate quickly from the blood when there is an infection and start to phagocytose the pathogens
what do epithelial cells act as
tissue barriers
where are the places that we tend to get infections and give some examples
the places where we have an environmental interface
e.g. GI tract, respiratory tract, genital/urinary tract
what are the cells at the outermost part of our interfaces
epithelial cells
what do epithelial cells express a lot of that is part of the immune system
pattern recognition receptors - they sense invasion by pathogens and help start the immune response
what are fibroblasts
cells that usually form the network right under the tissue barrier and also have receptors which participate in the immune response
which pathogens are better at causing disease
those that can evade aspects of the immune system
how does complement act to control pathogens
when you scratch your arm it does red and raised because the blood vessels become leaky allowing cells and fluid to leak into the site where the tissue trauma has occurred
complement is a series of plasma proteins which act in an enzymatic cascade
it is mainly used in the innate response but can be activated by antibodies in the adaptive response
what are the 3 main effects of complement
amplification of the immune response
opsonisation of pathogens
formation of membrane attack complex
how does complement amplify the immune response
- soluble C3a and C5a are released at infection site and the increased influx of immune cells controls pathogens
- complement proteins in plasma become activated and start to cleave each other into a and b fragments. they act as chemoattractant molecules, diffusing form the infection site towards the local blood vessels
- neutrophils and monocytes sense the chemoattractants and migrate towards the site of infection - hence the response is amplified
how does complement lead to opsonisation of pathogens
- complement fragments bind to the surface of pathogens and some of the tissue cells or neutrophils have receptors for these fragments and recognise the pathogens coded with the complement
- this causes improved phagocytosis, leading to faster clearance and killing of pathogens
- it makes the microbes tastier to the phagocytes
how does complement activate the formation of the membrane attack complex (MAC)
terminal parts of the complement cascade C5-C9 proteins form hydrophobic rings structures which can insert itself into bacterial membranes causing pores to form which leads to death through osmotic lysis
how are our own cells not affected by complement
they are resistant
CD46 protein inactivates C3b
CD59 protein stops the MAC from forming
C1 inhibitor cleaves early complement components to stop amplification of the immune system
what strategies have pathogens evolved to evade the complement cascade
- smallpox virus protein - has protein complex called SPICE which inactivates C3b
- influenza and HIV pick up host complement inhibitors
- e.coli recruits the C1 inhibitor blocking the early activation stages of complement
- Schistosoma and Trypanosoma - gave excess CRIT which blocks early stages in complement activation
bacteria cell wall components are PAMPs, why don’t they change their cell wall components to evade the immune system
their structure is essential
which part of gram +ve cell walls is detected by PRRs
they have very thick cell walls composed of peptidoglycan - the peptidoglycan is detected
what is peptidoglycan
small peptides cross linked into long glycan chains
what other substance is also present in the peptidoglycan of gram +ve bacteria that is recognised by PRRS
teichoic acids
what part of gram -ve bacteria is recognised by PRRs
they have a thin peptidoglycan layer but have an extra membrane called the outer membrane
the peptidoglycan is not so accessible
the outer membrane contains LPS which is recognised by PRRs (TLR4) and is also important for structure
what are TLRs
plasma membrane molecules that mostly recognise PAMPs
what are NLRs
nucleotide binding oligomerization domain like receptors which recognise a range of PAMPs and DAMPs
what are CLRs
C type lectin like receptors that mostly recognise pathogen carbohydrates
what are ALRs
absent melanoma 2 like receptors which recognise bacterial or viral cytoplasmic DNA
what are RLRs
retinoic acid inducible gene 1 like receptors which recognise pathogen ss or ds RNA which is important for sensing viruses
where are bacterial and fungal PRRs (TLR and CLR) found
on the cell membrane
where are viral and bacterial PRRs found (TLRs)
the endosomes - pH change allows viral replication
where are DAMP and PAMP sensing PRR (NLR) found
in the cytosol
where are DNA and RNA sensing PRRs (ALR and RLR) found
in the cytosol
how can pathogens hide from PRR recognition
- the flagellin of helicobacter pylori has evolved to reduce recognition by TLRs - the bacteria have mutated the recognised sequence in flagellin so that it isn’t recognised by PRR
- polio steals RNA host 5’ caps from host mRNA to make it look like host mRNA to hide it form NLRs
- listeria bacteria mutates some of its cell wall components so that is evades NLRs
what is meant by redundancy
we have so many receptors that we have a very good chance of detecting pathogens even if they mutate
are PRR only found on immune cells
no they are found on non immune cells too
what are the consequences of PRR activation
- tells neighbouring cells about the threat - makes inflammatory cytokines
- tells the adaptive immune system - phagocytose the microbe and take it to the draining lymph node
- limits microbe replication - control pathogen
what links PRR activation to altered immune responses
- bacteria activating PRRs results in a kinase cascade which results in NF-kB TF activation as it degrades it inhibitor
- NF-kB translocates into the nucleus and drives altered gene transcription e.g. chemoattractants produced, inflammatory response initiated
- this allows the cell to warn the immune system
how can bacteria reduce NF-kB activation and inhibit the immune system
- e.coli produces virulence factor that injects into cells and degrades NF-kB
- shigella enzyme of gram -ve bacteria causes degradation of an activator of NF-kB
what part of the body does influenza infect
epithelial cells in the respiratory tract
what are the steps in influenza infection
- influenza activates the MyD88/NF-kB pathway
- influenza replicates in the nucleus but puts its nucleic acids back out again to form new virous particles
- during this RNA can be recognised by RIG-1 receptors which can induce apoptosis of infected cells or induces production of type 1 interferons which are recognised by receptors on the surrounding cells which activate an antiviral pathway
- influenza inhibits PRR activation and reduces the immune response by producing NS1 which inhibits NF-kB and blocks RIG-1
is the innate immune system fixed in how it can respond
yes
what are the time scales for innate and adaptive immunity
innate - takes hours to com into effect
adaptive - takes days to come into effect
what do B lymphocytes produce in adaptive immunity
antibodies
what to T lymphocytes produce in adaptive immunity
T effector cells
what are the 2 main types of adaptive immunity
humoral and cell mediated
what happens in humoral immunity
- antibody mediated extracellular attack
2. B lymphocyte secretes antibody
what happened in cell mediated immunity
- intracellular attack
2. T cells activate response
where do B cells mature
the bone marrow
where do T cells mature
the thymus
what are the 2 types of T cell response in cell mediated immunity
phagocytosed microbes –> helper T lymphocyte - activation of macrophages
microbes replicating in infected cells –> cytotoxic T lymphocyte - kills infected cells
describe T cell receptors
different on each T cell - unique specificity
describe B cell receptors
they are antibodies - surface immunoglobulins
they are different on each B cell - unique specificity
what is the clonal selection theory
the process by which an antigen selectively binds to and activates only those lymphocytes bearing receptors specific to the antigen. The lymphocytes proliferate into a clone of effector cells and memory cells for that antigen
what are the steps in clonal selection
- a single progenitor cell gives rise to a number of lymphocytes each with different specificity
- removal of self reactive immature lymphocytes by clonal deletion
- left with a pool of mature naiive lymphocytes
- recirculation to peripheral secondary lymphoid organs
- proliferation and differentiation of activated specific lymphocytes to form a clone of effector cells
- effector cells (helper T, cytotoxic T, B cell) eliminate antigen
what are our secondary lymphoid organs
spleen and lymph nodes
what causes lymphocyte activation
when a foreign molecule and a lymphocyte receptor bind with high affinity
what are the receptors on the effector cells the same as
the parent cells receptor that was activated and proliferated by clonal selection
what causes autoimmunity
because lymphocyte receptors are generated randomly some might recognise self
what are the basic phases of the adaptive immune response
- antigen presenting cell (naiive T/B lymphocyte)
- clonal expansion
- differentiation
- lymphocyte activation (antibody producing cell, effector T lymphocyte)
- humoral and cell mediated immunity (elimination of antigens)
- apoptosis
7 surviving memory cells
what does the need for proliferation and differentiation in adaptive immunity result in time wise
a 4-7 day delay
what do helper T cells do in cell mediated immunity
they help B cells
they help cytotoxic T cells
they direct innate immune responses
describe the T cell receptor complex
it is on the surface of the cell
CD3 allows recognition and identification of these cells
how are T cells subdivided into 2 groups
they either have CD4 surface molecule or CD8 surface molecule
which type of T cells have CD4 and CD3 surface molecules
T helper
which type of T cells have CD8 and CD3 surface molecules
cytotoxic T cells
what do helper T cells recognise antigens presented as
they recognise antigens presented in MHC II on the surface of antigen presenting cells and help them
what do cytotoxic T cells recognise antigens presented as
they recognise antigens presented in MHC I on many cells types and can be induced to kill
what is the key link between innate and adaptive immunity
antigen presenting cells (APCs)
give 2 examples of antigen presenting cells
macrophages
dendritic cells
what is the link between humoral and cell mediated immunity
antigen presenting B cells
what are antigens presented in the context of and what is this known as in humans
MHC which is HLA in humans
what signals do T cells require to activate
- antigen presentation in the context of MHC
- surface molecule Costimulation
- soluble molecules - cytokines
what are the 3 kinds of signal that APCs deliver to naïve T cells
- activation - APC in MHC context
- survival - Costimulation
- differentiation - cytokines
what are the difference between MHC I and MHC II
MHC I - presented on all nucleated cells apart from rbc and present to CD8 T cells (cytotoxic)
MHC II - restricted to professional APCs (e.g. dendritic cell) and present to CD4 T cells (helper)
what do helper T cells do
they help antigen driven maturation of B and T cells
- Th interacts though antigen specific and antigen independent mechanisms
- undergoes differentiation
- mature Th interacts with plasma or T effector cells
why do we need different subsets of Th cells
to be able to deal with different types of pathogens
how are we protected form mycobacterium tuberculosis
IFN gamma and activated macrophages - macrophages kill things better if they are activated by IFN gamma
how are we protected form leishmania
IFN gamma and activated macrophages - macrophages kill things better if they are activated by IFN gamma
how are we protected form schistosome
mast cells activate the innate immune response
IgE mediates mast cells
what are the two Th subsets
Th1 and Th2
in initial T cell activation are T cells divided into subsets
no they appear uncommitted and make transcripts associated with both subsets
differentiation requires continued activation and sustained differentiation signals
what happens to immature dendritic cells in the periphery when they encounter a microbe
- immature DC express PRRs which respond to PAMPs
- ligation of the PRR causes DC activation and migration to draining lymph nodes
- activated DC express high levels of pMHC and costimulatory molecules to engage with specific T cells
- activated DC make soluble mediators that influence Th cell differentiation
how are Th 1 cells made
activated DCs produce Il-12 (cytokine) which drives NK cells to produce IFN gamma (cytokine). the presence of both of these drives commitment of a Th cell to a Th 1 cell
how do Th1 cells protect against extracellular and intracellular pathogens
by producing IFN gamma, TNF alpha (cytokine) and IL-2 (cytokine)
what are the effects of Th1 cells
- induction of ROI in macrophages which are toxic to pathogens (TB, leishmania)
- help doe long lived protective CD8 T cells
- induce chemokine release to attract immune cells to infection site and increase vascular permeability to aid access
- help to B cells
- enhance APC activity and MHC II expression
- cause apoptosis in infected cells
- coordinate granuloma formation to wall of pathogen
production of IFN gamma and IL-12 push those cells to become cells that make ……………….
IFN gamma
Th1 increase …… activity making them more likely to present to them so they get even more ……
APC
IFN gamma
give examples of autoimmune diseases that Th1 are involved in
- coeliac disease - autoimmune response to gluten - T cells activate macrophage in the gut causing inflammation
- rheumatoid arthritis - T cells activate macrophages in joint causing sustained inflammation
- multiple sclerosis - immune response against the CNS
- Inflammatory bowel disease - immune system attacks the gut
autoimmune diseases occur due to differentiation of Th cells in the wrong ………….
context
how are Th2 cells made
- DC are exposed to Th2 stimuli e.g. damage at epithelial surfaces
- DC produce lower levels of activation molecules (pMHC, costimulatory) than those exposed to Th1 stimuli
- Basophils PRR are activated by PAMPs and basophils produce IL-4 which drives commitment of Th cell too Th2
how do Th2 cells control helminth infections
Th2 cells produce IL- 4, 13, 5, 9, 25 and parasite specific IgE to control helminth infections
what are the effects of Th2 cells in parasite proteciton
- mast cell degranulation causing release of mediators to enhance parasite expulsion
- IL-13 promotes mucous production to enhance expulsion of eggs/worms in response to injury
- IL–4 and 13 act on macrophages involved in tissue repair and angiogenesis
- Il-5 induced eosinophilia releases cytotoxic cationic proteins that damage parasites
- collagen production for wound repair and encapsulation of parasite egg (IL-13)
give examples of how Th2 cells cause allergy and asthma
- collagen/fibrosis driven by Il-13 in airways of asthmatics
- mast cell degranulation releases many inhibitors that causes smooth muscle constriction, vascular permeability e.g. in asthma and allergic dermatitis
- IL-13 promotes mucous production in allergy/asthma response
- IL-5 induced eosinophilia release cytotoxic cationic protein that cause tissue damage
- IL-4 and 13 act on macrophages
what do the 2 types of Th cells differentiate from
naïve CD4 T cell in response to environmental cues
Th1 are characterised by the production of …..
IFN gamma
Th2 are characterised by the production of ……..
Il-4
why don’t we have Th1 and Th2 cells of every specificity
because that would be too costly - we have the ability to switch T cells into one form or another instead
the immune system must adapt to compete in the ………… ……..….. with pathogens
arms race
what is humoral immunity dependent o
B cells and antibodies
what are antibodies
immunoglobulins
how many classes of antibodies are there
5: IgA, D, E, G, M
what is indicated by antibodies being found at very high levels in serum and give an example of on that is
indicates they are important - IgG1
what are B cells helped by
T cells
how do T cells help B cells
- antigen recognition induces expression of effector molecules (memb bound molecules (Costimulation) and cytokines) by the T cell which activates the B cell
- B cells proliferate
- differentiation of B cells to resting memory cells and antibody secreting plasma cells
how do T cells and B cells get together
- activated T and B cells move towards opposite areas and they meet at the edge of the follicle
activated T cells migrate towards the ………………….
follicles of the lymph node
activated B cells migrate towards the ……………..
paracortex of the lymph node
what happens when T and B cells meet
they meet at the edge off the follicle and interact
- B cells returning to the follicle undergo rapid proliferation and form a GC
- the T cells influence GC output to produce
- affinity matured memory B cells - increasing affinity
- long lived high affinity plasma B cells - provide protection
what is the other Th subset other than 1 and 2
T follicular helper cells
Thf cells are close/distant form other CD4 T cell lineages
distant
Thf cells have a unique collection of effector molecules with high levels of what
SURFACE MOLECULE SIGNALS THAT ARE COSTIMULATORY
ICOS
CD4DL
STABILISE INTERACTION BETWEEN T AND B CELLS
SLAM family e.g. DC84
SAP - slam associated protein
what are important molecules in T-B cell interactions (cell-cell contact)
- TcR - recognition of cognate pMHCII on B cell
- BcR - acquisition of Ag and B cell activation
- MHC II - presentation to Thf - critically important
- CD28/86 - maintenance of Thf phenotype
- CD4OL/CD40 - promotes B cell survival and proliferation
- ICOS/ICOSL - T cell entry to follicle, promotes Tfh cytokine production
- SLAMF and SAP - critical in stabilising T-B cell contact
what are important molecules in T-B cell interactions (soluble) - cytokines
- preventing death - IL-4
- aiding maturation and differentiation - IL-5,6,21 TGF beta
- promoting proliferation - IL-2,4
- enhancing processing and presentationIL-4 increases MHC II expression
- promoting isotype switching - IL-4, IgG1, IgE. IFN gamma, Ig62c, TGF beta, IgA
what is the germinal centre
sites of lymphocytes undergoing division in follicles of secondary lymphoid tissue
the main site where high affinity antibody secreting plasma and memory B cells are generated
the germinal centre is associated with .. cell dependent antibody responses
T
describe the structure of the germinal centre
can be split into 3 sections
1 - mantle zone
2 - light zone
3 - dark zone
describe the mantle zone of the GC
contains non specific B cells
describe the light zone of the GC
contains follicular DCs and T cells
describe the dark zone of the GC
contains proliferating B cells
how do B cells combat rapid bacterial growth
they proliferate very quickly and randomly mutate the antibody variable region
what id affinity maturation
when the average affinity of serum antibodies to its target antigen increases over time
it occurs due to somatic hypermutation (SHM) of the antibody variable region
B cells in an individual GC are usually ………… related but the GC is a specialised site that supports events required for ………… …………..
clonally
affinity maturation
describe the Darwinian selection pressure in the GC
we get random generation of new receptors which could have better or worse affinity for the antigen it is trying to recognise
we want optimal recognition and get rid of any intermediate, low or self recognition
Darwinian selection makes this happen
after somatic hypermutation we have antibodies with different affinities - describe the 3 possible fates
high affinity - adequate BCR signal - adequate T cell help - survival
intermediate affinity - adequate BCR signal - inadequate T cell help - apoptosis
low affinity - Inadequate BCR signal - apoptosis
the GC supports affinity maturation through which 3 processes
clonal proliferation
somatic hypermutation
affinity maturation
newly mutated receptors are selected against the antigen held by the ……… …….. ………. and require continued help to survive the selection process
follicular DC
proliferating GC B cells accumulate in the ……… ……….. and SHM preferentially occurs here
dark zone (centroblasts)
proliferating B cells migrate from the dark zone to the ……..……. ……….
light zone (centrocytes)
what happens to B cells in the light zone
- they moves along FDC network
- higher affinity B cell receptors able to bid Ag on FDC
- now process and present Ag on MHC II
- presentation of pMHC II to cognate GC Tfh elicits help
- higher affinity BCR - better Ag capture - more Ag presentation
what does dysregulation of T-B cell interaction result in
immune diseases and disorders
what are some immune diseases and disorders caused by impaired T-B cell interaction
- HIGM - CD4O/L cannot isotype switch - cannot make IgG so get lots of infections
- overabundance of Thf in murine models and patients with autoimmune disorders (too much T cell help –> too many antibodies)
- CD4OL, ICOS mutations producing reduced Tfh results in severe defects in protective humoral immunity (B cells secreting antibodies impaired without T cell help)
how can we use T cell help for vaccines
we can take an antigen and put it onto a protein to make a conjugate vaccine
e.g. haemophilus influenza type b vaccine - polysaccharide and tetanus toxoid - vaccine elicits T cell help and we get a much better antibody response
what parts of the adaptive immune response do we get memory from
all of them
- CD4 T cell responses
- CD8 T cell responses
- B cell and antibody responses
how is the secondary response different to the primary response
it is faster and bigger due to immunological memory
what is the basis of vaccination
protection form reinfection
what are therapeutics for infection, allergy, autoimmunity, cancer and transplantation
vaccine and immunomodulatory drugs
approximately how many microbes are in the body and where are most of them found
10^14 and most of them are found in the colon
what % of microbes found in the body are non culturable
80%
what do we use to identify bacteria since many of them are non-culturable
16S sequencing and whole genome sequencing
what is 16S sequencing
it uses the 16S region of rRNA which is conserved between all bacteria so primers can be made to sequence that section and amplify it using PCR
the sequence shows minor differences between bacteria and this is what is used to identify them
what is whole genome sequencing
when we sequence the entire genome and compare it to sequences of other bacteria
compare the advantages and disadvantages of 16S sequencing and whole genome sequencing
16S sequencing only uses a small region of DNA so it is relatively cheap and quick
whole genome sequencing is more expensive, slower and computation intensive
whole genome sequencing provides a more detailed description of the bacteria and can identify their functions but a bacteria can only be identified is it has already been sequenced
what are maternal factors that determine the human microbiome
gut microbiota
vaginal infection
periodontitis
what is periodontitis
information in the genes
what are birth factor that determine the human microbiome
vaginal or caesarean delivery
what are postnatal factors that determine the human microbiome
antibiotics
breast feeding
host genetics and environment
(these influences all occur before 3 yo - after that the bacterial community is stable for 60-70years)
bacteria live on cells that have a layer of ………. on them. this requirement is seen in …………, ……………. and ……………… as these organisms have co-evolved with bacteria for thousands of years
mucous
humans, corals and plants
what is a normal population of bacteria
the regular distribution of bacteria that most healthy people have in their body
those who have inflammatory bowel disease or obesity have a different population of bacteria
what is the most common genus in the colon
Bacteroides
bacterial communities are complex, stable and …………….. and are affected by many factors, especially …………..
interdependent
diet
bacteria metabolise complex carbohydrates from plants and produce what
short chain FA
what vitamins do bacteria produce
B3, 5, 6, 12
biotin
tetrahydrofolate
Vit K
how do bacteria limit pathogen colonisation
they outcompete them and may protect against epithelial injury if you have ingested something scratchy and damaging
what are the functions of the short chain FA
they are the main energy source for epithelial cells and they directly affect the immune system
there presence results in the production of Treg cells and inhibits DCs
they have an anti inflammatory effect on intestinal epithelial cells which reduces the risk of autoimmunity
why is there little evidence of efficiency when it comes to probiotics
host bacteria are already stable so outcompete the probiotics but there is no harm in taking them
give 6 examples of diseases associated with changes in microbiota
acne rheumatoid arthritis obesity IBS inflammatory bowel disease multiple sclerosis
are diseases associated with changes in microbiota caused by changes in microbiota or are the diseases what causes the change in the microbiota
it is unclear
what are the 2 branches of inflammatory bowel disease
colitis and crohn’s disease
what are the 3 factors that cause inflammatory bowel disease
host genetics
microbiota
innate and adaptive immune response
what are the steps in development of inflammatory bowel disease
- lesions generated by the immune response against microbes cause inflammation
- bacteria that thrive in inflammation then grow driving further inflammation creating a cycle
what bacteria is often found in hospitals and id generally resistant to antibiotics
Clostridium difficile
what does clostridium difficile cause
it enter the body and multiplies in the GI tract causing inflammation over the normal intestinal bacteria
they release toxins that damage the colon and may lead to pseudomembrane formation
what is a treatment for c difficile
faecal transplants which replaces c difficile with a normal bacterial community from a donor
what are the risks of a faecal transplant and how do we minimise this
exposure to unknown pathogens and transfer of illness so donors and samples must be carefully matched
what does a break in the immune system’s tolerance to self result in
autoimmunity
there are multiple chechpoints in the education of lymphocytes to remove those that react to ………..
some autoreactive lymphocytes are kept but regulated by ……………. mechanisms so that they can’t drive disease
if these mechanisms fail it can lead to ……………..
self
tolerogenic
autoimmune disease
regulation of lymphocytes in the thymus involves …………… and ……………. selection
positive and negative
what is positive selection
it destroys lymphocytes that cannot recognise MHC II
what is negative selection
it destroys lymphocytes that recognise self peptides in MHC II
what does peripheral regulation include
- regulatory T and B cells
- DCs sensing danger
- Costimulation
- ignorance
- privilege
what does a lack of regulation of lymphocytes result in
broken tolerance and pathological events from autoimmunity
can innate and adaptive immune cells both be involved in autoimmunity
yes
how do Treg cells regulate the immune system
they reduce the response one the infection has cleared
how are treg cells important in the autoimmune response
if they are deficient this helps drive the autoimmune response
what are autoantibodies
antibodies produced by B cells in the autoimmune response
……. …….. specific for autoantigens may help generate the anti host response by helping to produce antibodies
T cells
T cells in graves disease are ……. …………. …….. …….
anti-thryroid follicular epithelial cells
how are innate cells like macrophages and neutrophils implicated
- through cytokine release
- through destructive enzymes
- effector pathways e.g. ROIs
- netosis leading to autoantigen presentation
most autoimmune diseases are monogenic/polygenic
polygenic
why is GWAS a key area of study for autoimmune diseases
because there are lots of risk alleles to be found
which genes are important in the immune system and what do mutations in these gens result in
AIRE FOXP3 LRBA STAT1 STAT3 mutations in these genes result in increased risk of autoimmune disease
a mutation in one gene can lead to many different phenotypes - give an example of this
mutation in STAT1 can lead to hyperthyroidism, eczema or chronic mucocutaneous candidiasis
why does autoimmunity lead to increased infections
because the immune system is impaired
how does the environment influence autoimmunity
environmentally induced changes in the microbiome induce changes in the immune system
how can smoking lead to autoimmunity
it can trigger a pulmonary mucosa response
is there a cure for autoimmune diseases
no, treatment can only lower symptoms
describe rheumatoid arthritis
predominantly affects joints and gets worse over time
the adaptive and innate immune system and tissues cause an inflammation response which damages cartilage and bone
angiogenesis and lymphangiogenesis leads to increased infiltration of inflammatory molecules
what leads to the transition event and break in tolerance in rheumatoid arthritis
genetic risk
environmental risk
epigenetic modifications
post translational modifications
……..………. may have a positive effect against autoimmunity
antioxidants
what is a vaccination and what is its purpose
it is a means of producing immunity against pathogens by the introduction of live, killed or altered antigens that stimulate the body to produce antibodies against more dangerous forms
what did Edward jenner do
he routinely practiced variolation
found the potential for the cowpox vaccinia to protect against smallpox and performed the first protection trial
what are the only 2 diseases to have been eliminated by vaccination
smallpox
rinderpest - cow disease
what do vaccines induce in the immune system that is important for protection
memory - memory cells make the secondary response much stronger an efficient
what are the advantages of memory cells over naïve B lymphocytes
they are long lived increased frequency rapid proliferation produce more antibody produce higher affinity antibody IgA and IgG have better effector functions - class switching
how is the secondary antibody response different the primary one
faster stronger response
isotype/class switched
higher affinity
IgG has a higher/lower affinity than IgM in the secondary immune response
higher
why are the secondary responses better than the primary responses
- the GC reaction drives affinity maturation and class switching of memory B cells and long lived plasma cells
- B cell expresses antigen on MHC II and the T cell recognises this complex. B and T cells communicate - cognate interaction
how do most vaccines work
by inducing long lived plasma cells and plasma antibody responses
what happens to serum antibody levels after vaccination
they increase and remain relatively constant throughout life
what are the live attenuated UK immunisations
MMR
rotavirus
Influenza (LAIV)
shingles (herpes zoster)
what are the killed UK immunisations
inactivated polio (salk) influenza (split virion)
what are the subunit UK vaccinations
DTP
Influenza surface antigen
Men C
Men quadrivalent (ACWY)
what are the recombinant subunit vaccinations
HPV
Men B
give an example of how an attenuated virus is made
- pathogenic virus is isolate and cultured on host (human)
- virus is incubated on cells of another host (monkey)
- virus spontaneously mutates and grows on other host (monkey) dues to them providing a selective environment - doing this repeatedly causes further mutation
- virus can now be used as a vaccine as it can no longer grow on human cells
why did polio patients have to be put in an iron lung
due to paralysis of the diaphragm
intubation hadn’t been invented yet
which of the polio vaccines was produced first
salk (killed)
sabin (live attenuated)
only 40 cases of poliomyelitis occurred in the UK between 1985 and 2002 - what were their causes
- caused by live sabin vaccination
- wild virus infection acquired overseas
- unknown but wild virus wasn’t detected
why shouldn’t children swim after having the polio sabin vaccination
because they can poop out live virus
why wasn’t the salk vaccine produced earlier
because the sabin vaccine was easy to give and more effective
how are killed vaccines made
- usually use chemicals or heat to kill them
- this kills the organism rendering it completely uninfective
- killed organism can induce immunity
e. g. whole cell pertussis vaccine
how are subunit vaccines made
toxins are the pathogenic fragments of bacteria that make us feel ill
antibodies to toxins can prevent infection
subunit vaccines are purified down to just the antigen
e.g. acellular pertussis vaccine
what are chemically inactivated toxins called
toxoids
describe the carrier protein and hapten use in immunisation
carrier proteins - e.g. toxoid recognised by B and T cell
hapten - e.g. polysaccharide (no peptides - only recognised by B cells)
1 - use same carrier protein and hapten for both immunisations then we get a secondary Ab response to hapten
2. different carrier protein but same hapten - no secondary Ab response to hapten
3. carrier protein on its own then same protein with hapten - we get a very strong secondary Ab response to hapten
4. same carrier protein and hapten but deplete T cells between immunisations - no secondary Ab response to hapten
we want to direct AB against the carbohydrates on the surface of the bacteria but why is this a problem
the immune system cannot mount secondary immune responses to carbohydrates because there is no T cell B cell help because T cells don’t recognise carbohydrates, only proteins
we need a protein for the T cell to recognise B cell presentation
carrier protein + hapten = …………. vaccine
conjugate
what is the secondary response driven by
T cells - they drive class switching and affinity maturation of B cell response to the carbohydrate/polysaccharide in the GC reaction
Men C was controlled very well by its vaccine but Men B wasn’t - what has been developed to control Men B
Men B, C, W, Y bacillus strain is accelerating the demise of Men B
what is herd immunity
where the unvaccinated proportion of the population can be protected by those who are vaccinated - the ratio of vaccination required for this to be effective depends on the infective organism - all based on probability
we need 95% vaccination for measles, why is this
because it is a very good virus - it takes a while to die whereas other diseases are much less robust
what is the problem with anti vaccine communities
they create a niche that is very susceptible to infection
how can vaccination be an altruistic measure
it can protect vulnerable people who you are closely associated with
what are recombinant subunit vaccines
some viruses/bacteria are very hard to grow because they grow in cells that are difficult to cultivate
- we isolate genes that encode the protective antigen against the virus - for HPV it is a surface antigen called L1
- the gene for L1 is cloned into insect or yeast cells which are easy to grow and culture - make lots of the vaccine protein
- we get self assembly of VLPs which are then purified and used as a vaccine
what is a VLP
virus like protein - no live RNA/DNA - surface of virus assembled into a particle
how is the live attenuated flu virus made
- start off with highly attenuated virus which is cold adapted so can’t replicate lower down in the respiratory tract because it is too warm
- some of the virulence genes of the virus are removed to make it more acceptable
- we have isolated genes for 4 seasonal surface proteins (HA/NA)
- new vaccine made every year and it can be administered intra-nasally since it is a live virus
what are the known limitations of the LIAV
it is ineffective in over 50s
issues with safety in children with asthma
not for the immunocompromised
what is meant by vaccinating to control the transmission agent
children are big transmitters of infection - by controlling them we can prevent transmission to vulnerable people in the community
what dies the T cell recognise an antigen through
its T cell receptor recognises MHC with antigen peptide
what are the 3 steps in T cell activation
- MHC with antigen peptide presents to T cell receptor. cognate signal tells T cell that it’s the antigen specific T cell - this alone causes T cell anergy
- Costimulation - DC tells the T cell to activate
- cytokines - cytokines from the DC tell the T cell what kind of T cell it should become
all of these signals turn the anergic phenotype into an activated phenotype
what is T cell anergy
a regulatory state of the T cell - no immune response
whole organism vaccines (…………………, ………………) supply the 3 signals of T cell activation - MHC, Costimulation, cytokine and drive really strong T cell response
attenuated and killed
how are attenuated recombinant vaccines made e.g LAIV, malaria, TB, HIV - mainly viruses
- inset protective antigen genes into attenuated pathogen to act as a carrier
what are adjuvants
agents which act non-specifically to increase the specific immune response or responses to an antigen
what are the clinical uses of adjuvants
aluminium precipitates used as adjuvants and are a component of many vaccines - they induce Th2 responses
what is the problem with aluminium precipitates as adjuvants
it only drives antibody responses of B cells, no other responses like increased phagocyte activity
which vaccines require Th1 immunity
bacterial - TB, leprosy
viral - HIV, influenza
parasite - malaria, leishmania
give examples of adjuvants
liposomes/virosomes VLPs monophosphoryl lipid A QS21 MF-59 ASO3 esoteric - household items
adjuvants may act directly via …….
DCs - we are trying to make adjuvants that activate DCs e.g. flagellin, LPS, dsRNA
what are other new approaches to vaccine production
DNA viruses
genetically attenuated vaccines
what are DNA vaccines
- inject plasmid DNA encoding protective antigen into host
- host takes up DNA and expresses protein
- host immune response to protein enhanced by CpGs in prokaryotic DNA
what are genetically attenuated vaccines
- take existing pathogen and delete essential genes
- GM pathogen now unable to proliferate effectively in host but does generate immune response (delete genes involved in adverse effects and keep genes you want to conserve)
provide a basic statement on how to make each type of vaccine
- attenuated - find/make attenuated pathogen using culture methods
- killed - kill the pathogen using heat/chemicals
- subunit - kill the pathogen and isolate its protective antigens (toxoids)
- recombinant subunit - clone genes for protective antigen and express in e.g. yeast and isolate antigen
- live recombinant - clone genes for protective antigens and express in vaccine vector e.g. LAIV
- genetically attenuated - knock out virulence genes with recombinant technology
- DNA vaccine - clone genes into expression vector and inject construct –> proteins made
