Immunology Flashcards
cells and molecules of the innate immune system
barriers and consequences of barrier dysfunction
how immune system recognises danger
neutrophils and their manipulation
acute inflammation
Anti-TNF-alpha riska and benefits of manipulating cytokine axes
purpose of the immune system 3
maintain tissue homeostasis
keep body free from germs, tissue healing
pre infection: minimise risk/impact - public health: sanitisation, vaccination
What are the two branches of the immune system?
innate and adaptive immune system
the 2 barriers in immune system?
mucus
epithelium
sentinel cells in innate immune system
DC
ILC
(transitional)
What are the characteristics of the innate immune system? And 4 parts/components
pre programmed
no memory
trigerred within seconds
macrophages, phagocytes, dendritic cells, cytokines
What is the first line defence against microorganisms? 2
respiratory system:
pathogen wafted up in mucus along muco-ciliary escalator
cilia produce anti microbial peptides (defensins)
GI system:
Proton pumps on epithelial: K+ in, H+ out
HCl produced to kill pathogens
How are these barriers to pathogens disrupted? (2)
physical disruption
- IV access devices
- catherers
- burns
- skin ulceration (neuropathy/DM/pressure ulcers)
pharmacological disruption
- PPI use: disrupt acidic barrier
- anti-cholingernics: decreased saliva, inc risk of dental caries
can cause urinary retention- inc risk of infection
What molecules compose the innate system?
- cytokines
- complement
- CRP
What cells compose the innate system?
- dendritic cells
- mast cells
- monocytes
What ‘sensing’ cells compose the innate system?
dendritic cells
5 steps to acute phase response?
enter barrier sentinel cells inflammation .. attract granulocytes from blood acute phase response: CRP, SAA, ferritin
3 types of granulocytes in blood?
neutrophils
eosinophils
basophils
increase in infection, inflamm
What cells and special molecules form the adaptive immune system?
- T cells
- B cells
antibodies
What happens in the case of acute inflammation? 2
neutrophils recruited from blood
complement activated
PPI use and CDI (omeprazole, lansoprazole) = pharmacologically disrupt acidic barrier to infection. what may they cause?
norovirus
enterobacter infection
how is the adaptive IS different ot innate?
highly tailored to infection. It takes 4-6 weeks but is then able to rapidly upregulate on re-exposure. It has memory
What do T and B cells derive from?
stem cells in the bone marrow
Where do T and B cells mature?
T: in the thymus
B: in bone marrow/ spleen
2 types of T cells?
- CD4
- CD8
steps in innate immunity ( case of inflammation in detail)
how is homeostatic defended?
1. epithelial breach (tight junctions pull apart- cell signal) bac enter from outside acute inflamm neutrophil recruited from blood complement activated
- selective against where energy used to defend homeostatic.
What are PAMPs? Where are they
immune system is programmed to recognise these - molecular patterns only present on potentially pathogenic organisms (PAMPs)
what is seen with acute inflammation?
Dolor
Rubor
Tumor
Calor
(swelling, heat, redness, pain)
what are receptors for PAMPS like?
compartmentalised
State the three main types of cells part of the innate immune system.gpd
dendritic cells
phagocytes (neutrophils, macrophages)
granulocytes (neutrophils, eosinophils, mast cells)
describe the role of: dendritic cells
in innate immunity
- sentinet, sit below surface and sample environment
- recognises threats via PAMPs/ DAMPs
- primes adaptive immune response by travelling to lymph node
describe the role of: phagocytes (neutrophils, macrophages)
in innate immunity
- recognise pathogen (PAMPs, DAMPs, C3b, antibody),
- phagocytose + destroy pathogen
- resolve inflammation
describe the role of: granulocytes (neutrophils, eosinophils, mast cells, basophils) in innate immunity
recognise pathogen,
granules contain enzymes and peptides to destroy pathogen
How do phagocytes work? 3
- migration
to site which chemokines have been produced (site of inflammation)
e.g. neutrophil migrated blood, down chemokine gradientIL8 interleukins - pathogen recognition
antibody/complement receptors. receptor interactions - phagocytosis and killing
internalisation of pathogen, respiratory burst (dependent of free oxygen radicals) trigger
What does an accumulation of dead neutrophils cause?
pus formation
too many macrophages to clear
What are you at risk of if you have neutropenia?
When does neutropenia occur?
SEPSIS
failure of neutrophils to adequately patrol mucosal barriers
undetectable, neutropenic
neutropenia usually occurs day 7-14 after high dose chemotherapy
What drives neutrophil production?
G-CSF
recombinant
What are the molecules of the innate immune system that cause dolor, tumor, rubor and calor?
mediators (susbstance P) - dolor (pain)
histamine, bradykinin, NO - local vasodilation and fluid leak - tumor (swelling, rubor (redness)
cytokines IL-1, IL-6 - calor (heat)
what drive RBC prodn?
EPO (erythropoetin)
basophil, neutrophil, eosinophil, monocyte (-> macrophage) are all types of what cell?
myeloblast
what drives neutrophil prodn?
G-CSF
what does common lymphoid progenitor differentiate into?
natural killer cell
small lymphocyte -> T and B lymph -> plasma cell
What is histamine?
Produced by and role
produced by mast cells
cause vasodilation and endothelial junction widening (increased permeability)
around perivasculature
What are cytokines and 3 examples? When increased
(IL-1, TNF-alpha, IL-6)
small mols
messengers to drive systemic response
increased DC activation
What is C3a and C5b? Roles?
complements:
C3a - acute inflammation - drives histamine release
C5b - acute inflammation - neutrophil chemoattractant
both = opsonin + enzyme
6 categories of acute inflammatory response? from macrophages
- neutrophil influx (IL-8, C5a)
- cytokines: IL-1, TNF-alpha, IL-6
- lipid metabolites (prostaglanding, leukotrienes)
- complement: C3, C5
- fluid leak oedema
- histamine (mast cells)
role of lipid metabolites (prostaglanding, leukotienes) involved in acute inflamm response?
And derived from what
derived from arachidonic acid
prolong oedema, cause vasodilation and bronchoconstriction
effect of complement in acute inflamm response?
chemotaxis and vasodilation
systemic inflamm response: what do cytokines affect? (4)
- hypothalamus: IL-6, IL-1
- liver: TNF-alpha, IL-6, IL-1
- bone marrow
- fat and muscle
systemic inflamm response: affect of cytokines on hypothalamus
(3)
program:
- fever
- rigors
- anorexia
systemic inflamm response: affect of cytokines on liver?
acute phase proteins!
CRP, complement, transferrin, fibrinogen, SAA
systemic inflamm response: affect of cytokines on bone marrow?
increase mobilisation!
neut- bact
leuk - viral
eosin - parasite
systemic inflamm response: affect of cytokines on fat and muscle?
metabolism change: protein breakdown, cahexia
how is acute phase response monitored?
How’s this inhibited
through acute phase proteins (produced by liver)
inc in response to infection, inflamm stimuli
blocking cytokines can inhibit normal characteristics of this reponse
e.g. tocilizumab (anti-IL-6R) infections w/o fever and CRP rise
Complement cascade
3 pathways possible to lead to C3, C5, TCC release
classical pathway (antibody)
mannose binding lectin pathway
alternative pathway
What is the terminal complement complex?
C5b - C9
membrane attack complex- punches holes through cell membranes killing them
regulatory proteins stop lysis of human cells
Describe congenital and acquired complement deficiency.
congenital: deficiency in C5/6/7/8/9
acquired: eculizumab blocks C5
= membrane attack complex cant assemble properly
= susceptibility to recurrent meningococcal meningitis
how to prevent/treat congenital and acquired complement deficiency
vaccination and prophylactic antibiotics
characteristics of the complement cascade?
And how many arms
What can deficiency lead to
complex,highly regulated proteolytic cascade (C1-C9)
has 3 arms: classical, alternatice, MBL
typically a component is cleaved into a soluble fragment (a) and a bound fragment (b)
consumption of complement - associated with disease which can be measures (e..g SLE)
deficiency of complement/ regulatory proteins can -> infections, angiodema, aHUS
v expensive drugs being used now to target
What are the 5 ways to pharmacologically inhibit the cytokine axes?
- monoclonal antibody to block cytokine
- soluble (decoy) cytokine receptor
- monoclonal antibody to block receptor/s
- mimics of natural antagonist to receptor
- small mol inhibitors of signaling mols (inside)
cytokine receptor -> signalling mols inside -> gene expression
Anti-TNF-alpha benefits and consequecnes?
RA
nail infection
joint deformity and swelling
thin, aged skin
what are anti-TNF-alpha used in treatment of?
rheumatoid arthritis (RA)
plaque psoriasis,
ankylosing spondylitis,
ulcerative colitis (UC)
How does TNF-alpha work for rheumatoid arthritis? (summary of all)
causes endothelila activations: inc inflammation
+ve feedback on inflamm cytokine cascades
systemic effects (sarcopenia, malaise, lipid profiles, atheroma)
causes cartilage destructions via MMPs
causes bone erosion by priming osteoclasts
TNF-alpha inhibition drugs
infliximab (mAb targeted against TNF- alpha)
adalimumab
golimumab
What is a risk for patients on anti TNF?
infections:
TB common and difficult to clear entirely
latent: common with TB containes within granulomas (in macrophages)
- reactivation of latent TB
TNF-alpha = critical in maintaining control over latent infection
whats TNF-alpha critical in?
maintaining control over latent infection
what must all patients starting anti-TNF have to be screened for? 4
- latent TB
- Hep B
- Hep C
- HIV-1
what can (latent) TB reactivation by TNF-alpha, form macrophages lead to? (symptoms of TB reactivation) 4
malaise
weight loss
cough
haemoptysis (coughing of blood)
Part 2: adaptive immunity
- function of immunoglobulin (antibodies)
- therap uses of immunoglobulin - prophylactic, replacement, immunomodulatory
- prodn of monoclonal antibodies and naming
What is the name of the receptor of a B cell?
B cell receptor, antibody or immunoglobulin
There are 2 types of T cells. One type is subdivided. What is this subdivision based on, and what are these subdivisions?
- CD4 is subdivided (CD8 is not)
- based on the cytokines they produce
- Th1, Th2, Th17
CD8 T cells role?
cytotoxic killer lymphocytes.
kill virally infected cells + undertake immune surveillance
How does the innate immune system prime the adaptive response?
innate detects danger signals
antigen presenting cells sends instructions to B and T cells
CD4 T cells produce cytokines
CD8 T cells - cytotoxic
B cells produce antibodies
B cells feedback - complement, ADCC, opsonisation
What do B cells differentiate into?
plasma cells
What do B cells produce? (name the exact names)
antibodies: Ig: M, A, G, E, A
How does the number of human cells compare to the number of bacterial cells in our body?
10 trillion in a human, 100 trillion in bacteria
Describe the T cell receptor.
a and B chain
constant region and Fab (highly reactive)
Describe the B cell receptor
heavy and light chain on outside
constant region and variable region
attaches to antigen
What cells of the innate immune system recognise danger signals? What are these danger signals?
- neutrophils
- macrophages
- dendritic cells
- these danger signals are PAMPs and DAMPs
whats X-linked agammaglobulinaemia?
no immunoglobulin occurred in boys recurrent bacterial: - pneumonia, - sinus infection - ear infections
- enterovirus meningitis
- > resp failure
no B cells so cant produce antibodies!
Once the innate immune cells have recognised the danger signals (PAMPs, DAMPs), what cells of the adaptive system do they communicate to?
first antigen presenting cells have role,…. then
adaptive:T cells and B cells
What do the the B cells do in response to instructions from dendritic cells?
produce antibodies- more specific response to pathogen
What types of innate immune cells can recognise PAMPs?
- macrophages
- neutrophils
- dendritic cells
What do CD4 T cells do in response to dendritic cell instruction- from innate danger signals?
release and coordinate cytokines
What do CD8 T cells do in response to dendritic cell instruction?
they’re activated - cytotoxic lymphocytes
What are the two regions of a T cell receptor?
- constant
- variable (Fab)
Of the two regions of a T cell receptor, the constant region is composed of two what? What are these each called?
- composed of two chains
- one is called alpha
- one is called beta
What is another name for a B cell receptor?
antibody/immunoglobulin
What is the region of antigen called that is recognised by both T cells and B cells?
epitope
How does the epitope recognised by B cells differ from that recognised by T cells? Sketch the difference between the two.
- T cells recognise a linear epitope (9-15 amino acids)
- B cells recognise a soluble, conformational 3D epitope
Where exactly on a T cell receptor must the epitope of antigen have to bind in order to achieve a T cell response?
on MHC (major histocompatibility complex)
group of genes that code for proteins found or surface of cells to help immune system recognise foreign substances
In response to epitope binding on a T cell receptor, what are the T cell responses? 5
- T cell proliferation
- cytokine production
- macrophage activation
- help to B cells/ macrophages
- cytotoxicity
In response to antigen binding to B cell receptor, what are the B cell responses?
- antibody production
- antigen presentation
What must the epitope to B cell be in order to trigger the specific B cell response?
must be able to fit B cell receptor site
How are the variable regions of T and B cell receptors created?
through the shuffling of multiple genes
The variable regions of T/B cell receptors have are very diverse. What are the 3 letters describing the 3 regions of this region, and what do they each stand for?
V (variable)
D (diversity)
J (joining)
Of the variable region, how many genes are there to choose from?
approx 40
Of the diversity region, how many genes are there to choose from?
23
Of the joining region, how many genes are there to choose from?
6
Outline a typical immune response. Make sure you include the following cells: dendritic, T cells, B cells.
- pathogen has PAMPs that trigger activation of dendritic cell
- dendritic cell phagocytoses pathogen, and expresses pathogen peptide on MHC groove
- PAMP also leads to release of costimulatory factors from dendritic cell
- dendritic cell travels to lymph node and presents peptide to T cell
- T cell with receptor that fits peptide is activated
- if CD4 T cell activated, proliferations and releases cytokines (+ costin)
- if CD8 T cell activated, travels to viral infected cells to kill them
- soluble antigen from phagocytosis of pathogen also travels to lymph node to B cell
- B cell that fits antigen is activated
- B cell then communicates w T cell to produce antibody
Summarise a typical immune response. (alternative narrative)
barrier breached - pathogen enters
PAMPs detected - dendritic cells activated - takes them to lymph node
DC travels to lymph nodes, meets T cells
CD8 (cytotoxicity) and CD4 activation (cytokines produced)
in this time, soluble antigens have travelled to lmph node and B cell recognition has occured
B cells present antigen to T cells in MHC II = full activation = high affinity antibodies produced
What are the two molecules that can be used to present pathogen peptide to T cells?
- MHC I for CD8
- MHC II for CD4
Where do CD4 T cells act and what do they do?
MHC II - peptide from pathogen held in place
different cytokines produced
- Th1 - releases IFN-gamma
activates macrophages against intracellular bactera - Th2 - releases IL-4/5
activates eosinophils against worms and parasites - Th17 - releases IL-17
uses neutrophils to target extracellular bacteria
Why is it useful that MHC I + peptide is recognised by CD8 T cell?
- MHC I is expressed on every nucleated cell
- therefore if viral infected, CD8 can detect and kill this cell
What are the two things a B cell can do, once its receptor is engaged by antigen?
- produce IgM antibodies
- interact with T cells to undergo antibody class switch to more higher affinity antibodies
essentially
1. B cell receptor engaged by antigen
2. IgM production (rapid but low affinity)
AND
B cell presents antigen in MHC II to T cells (CD4)
switch to high affinity antibodies (IgG, IgA, IgE)
How do B cells interact with T cells? What type of T cell interacts and why?
- through MHC II + peptide
- CD4’s TCR as this is the type that recognises MHC II
What are the characteristics of IgM? (produced initially in response to antigen engaging BCR)
- released rapidly
- large
- low specificity
- able to agglutinate multiple antigens at once
How do T cells help B cells with their function?
- release cytokines
- these help B cells produce IgG, IgE and IgA antibodies
What are the 2 distinct chains found on antibodies?
- light chain
- heavy chain
What are the two light chain (Fc) types?
kappa or lambda
what do the light chains do?
Fc- IgM, A, G, D, E
binds receptors and determines function
What are the functions of antibodies?
- neutralise toxins
- opsonise pathogens
- aid in antibody-dependent cellular cytotoxicity
- agglutinate antigens
- activate/fix complement
What joins the 2 chains of an antibody?
a disulphide bridge
What part of an antibody tells you what class of antibody it is? (F… region) Which chains are these?
- the Fc region
- heavy chains
What is an example of a toxin-producing genus?
Clostridium
How is antibodies opsonising pathogens beneficial?
allows for macrophages to phagocytose pathogens
Which antibody classes are able to activate/fix complement?
IgG1, IgG3, IgM
How do antibodies help NK cells?
sticks to target and facilitates cytotoxicity from NK cells
How do antibodies block viral entry?
blocks receptor-dependent viral entry
What are the different classes of antibody?
IgG - most abundant
IgA - mucosal, lung/gut
IgM - low affinity
IgE - mast cell affinity, anaphylaxis
why do antibodies agglutinatae to pathogens?
stick to them, stick them together to make immune complexes
What can IgE antibodies drive? Why?
- anaphylaxis
- mast cells have high affinity IgE receptors
What can be appreciated about the different subclasses of antibodies?
they all have different functions
What fragment changes to change antibody class?
Fc fragment
Fab stays the same (antigen binding site)
What is the default immunoglobulin class?
IgM
What is the shape/structure of IgM?
pentameric
what antibody present in
- early B cell response
- later B cell response?
- IgM
- Fc gramnet changes to IgG/ IgE/ IgA
How does IgM act as a link?
- activates/fixes complement
- links adaptive and innate immune system
When an IgM antibody undergoes a class switch, what happens to each region of antibody?
- constant region (Fc) changes class to refine antibody response
- variable region (Fab) - antigen bindig. stays the same
Why is the adaptive system said to be highly specific?
T cell receptor/B cell antibody is highly specific to a pathogen’s protein
- made clone of T cells with a receptor (or B cell with antibody)
Why is the adaptive system said to have memory?
can form memory cells from T cells (pathogen specific clones) which live long and rapidly upregulate the immune response to re-exposure
What are the two types of antibody/immunoglobulin?
- polyclonal (diff B cells, diff specificities)
- monoclonal (same B cell, same specificity- target+func)
What are the 2 in vivo uses of monoclonal antibodies?
- myeloma
- LPD
What is the ex vivo use monoclonal antibodies?
- therapeutic
- diagnostic
What are 3 medicinal uses of monoclonal antibodies according to the region of the antibody?
- conjugatation - drugs, fluorochromes
- Fab region: target specific proteins
- Fc region: generate specific immune functions
What are examples of protein targets for monoclonal antibodies? 4
- cytokines
- cytokine receptors
- surface markers of immune cells
- cellular growth receptors
What immune functions can be generated using monoclonal antibodies?
- cellular depletion via ADCC - IgG1
- target blockade - IgG 4
How are antibodies made?
polyclonal and monoclonal?
antigen we want an antibody against injected into mouse…
a) spleen cells extracted
- cells fused with myeloma to form hybridoma
- monoclonal antibodies selected with best specificity
b) isolate serum
= polyclonal serum with all antibodies in
What is a hybridoma?
a fused myeloma and antibody extracted from the spleen of a mouse
What are two examples of monoclonal antibody blockbuster drugs?
- infliximab
- etanercept
What conditions can anti-TNF alpha drugs be used in?
- rheumatoid arthritis
- ankylosing spondylitis
- psoriasis
- ulcerative colitis
- Crohn’s disease
What 4 conditions can anti-CD20 B cell depletion drugs be used?
- vasculitis
- rheumatoid arthritis
- lymphoma/leukaemia
- multiple sclerosis
What is recent NHS push with a lot of monoclonal antibody drugs?
to move patients to less expensive, biosimilar non-patent drugs
What drug/monoclonal antibody targets B cells and how does it do this?
- rituximab
- Fab domains target CD20 on B cells
What is expressed on all B cells? How long until?
- CD20
- until it becomes a mature plasma cell
What does the Fab domain of rituximab target?
CD20
What does the Fc domain of rituximab do once Fab is bound to CD20?
- interacts with Fc receptors
- can directly kill cells expressing CD20
- induces ADCC
What does ADCC stand for?
antibody dependent cellular cytotoxicity
Which store of B cells does rituximab rapidly deplete:
haemopoetic stem cells (bone marrow),
peripheral B cells (spleen/LN)
plasma cells (bone marrow)?
peripheral B cells (spleen/LN)
restored by stem cell pool
In what conditions is the rapid depletion of peripheral B cells by rituximab beneficial?
- lymphoma/leukaemias
- autoantibody producing
What is the dangerous side effect of rituximab?
- due to B cells depletion, body becomes unable to make antibodies
- e.g. for SaRS-CoV-2, patients were unable to make antibodies against virus
What molecule of the adaptive immune system can be used therapeutically?
immunoglobulins
Where is therapeutic immunoglobulin obtained from?
the plasma of blood donors
- expensive
- limited resource
What happens to the plasma in order to obtain therapeutic immunoglobulin?
it’s fractionated, nanofiltered + pasteurised then IgG is isolated
What is the main antibody class found within therapeutic immunoglobulin?
IgG
no IgM, v little IgA
immunoglobulin products are not G_ and largely i_?
NOT generic
largely interchangeable.
What is there a theoretical risk of with immunoglobulin products?
BBV transmission
How can immunoglobulin be administered?
- IV
- IM
- SC
Why is it difficult to obtain immunoglobulin products in the UK?
- it’s not produced from UK blood donors due to new variant Creutzfelt-Jakob disease (nvCJD)
- supply issues in the UK
subject to strict evidence-based guidelines
clinical uses of immunoglobulin (IVIG)
What is the use of immunoglobulin products when in the context of e.g. chickenpox?
- prophylaxis (passive immunity)
- e.g. used as post-exposure prophylaxis (VZIG) against chickenpox
How are immunoglobulin products obtained for prophylactic use?
- a population’s blood donors are taken
- out of the blood donor, an individual has high % of IgG antibody against pathogen
- this is purified
How are immunoglobulin products used in the context of mothers planning to become pregnant?
(anti-Rhesus D) used prophylactically to prevent Rhesus negative mother from making antibodies to Rhesus positive antigens on baby’s RBC surface
stop risk of haemolysis in subsequent pregnancy
What is the most common use of immunoglobulin products?
as replacement therapy for those with antibody deficiencies
What is the dose of immunoglobulins as a replacement therapy?
0.4-0.6g/kg/m
How are immunoglobulins for replacement use obtained?
- general population will be exposed to lots of pathogens
- a pool of polyclonal immunoglobulin will be obtained
- this will be supplied to antibody-deficient individual = get passive protection against pathogens
Why are those needing antibody replacement on lifelong treatment?
the pool of polyclonal antibody mainly contains IgG, (no IgM/A) which has a short half-life (6 weeks)
What are the two forms of antibody deficiency?
- primary
- secondary
What is the cause of primary antibody deficiency?
who does it mainly affect?
usually genetic
- no B cells
- failure of T cell help
- failure to class switch
affects young people
Which antibody deficiency is more common and who does it affect?
secondary
any age, most likely old
What are the causes of secondary antibody deficiency? Which is the most common?
- B cell depletion (due to e.g. drugs) COMMON
- GI loss of IgG
- Renal loss of IgG
- lymphoid malignancy
- immunosuppression
What infections are common for those who have antibody deficiencies?
- sinus infections
- ear infections
- pneumonia
- conjunctivitis
Which therapeutic use of immunoglobulin is subject to strict DoH guidelines?
immunoglobulin as an immunomodulatory product
What are the 3 therapeutic uses of immunoglobulins?
- prophylaxis
- immunoglobulin replacement
- immunomodulation
What is the dosage of an immunoglobulin used as an immunomodulatory product?
1-2g/kg
How do immunoglobulins used as immunomodulatory products work?
- activate inhibitory Fc receptors
- induce T regulatory cells
- modulates inflammatory cytokines
The immune system is programmed to recognise PAMPs. What are these?
pathogen-associated molecular patterns - certain features associated with pathogens found nowhere else in nature so the human immune system recognises these as a threat
Where are the receptors for PAMPs located? Why?
- compartmentalised beneath the epithelial surface (so form 2nd line of defence)
- prevents overstimulation
What does TLR5 recognise?
(toll-like receptor 5 detects) flagellin, a polymer found within the flagellum - a structure enabling bacteria to move
What does TLR4 recognise?
lipopolysaccharide (LPS) - a sugar found in Gram-negative bacteria cell wall
What does MBL recognise?
(mannose binding lectin) detects unshielded mannose residues found in the cell wall of some bacteria
What does TLR9 recognise?
CpG motives - cytosine followed by an unmethylated guanine, a pattern more characteristic of pathogenic nucleic acid than human
What are the roles of dendritic cells?
- sentinel cells: recognise threats
- prime adaptive response by travelling to lymph node
How do dendritic cells recognise threats?
via their receptors, which will bind to PAMPs or D(damage)AMPs
What trigger phagocyte migration?
- a pathogen that has breached an epithelial surface may have complement (C3b) or an antibody attached to its surface
- its breach will cause acute inflammation, which will trigger the release of the chemokine IL8
- the phagocyte will then migrate down the chemokine gradient
How will a phagocyte recognise a pathogen?
it will bind to either complement (C3b) or antibody attached to the pathogen’s surface
How does a phagocyte phagocytose a pathogen and kill it?
it will internalise it, then kill it which is triggered by respiratory burst (dependent on the generation of free O radicals)
What is neutropenia?
low neutrophil count
What is the purpose of titrating a blood cancer chemotherapy regimen?
- to induce neutropenia
- theory is that by killing sufficient neutrophils, you’ve also killed sufficient cancer cells
What is neutrophil production boosted with following an induced neutropenia?
G-CSF
What cards are chemotherapy patients given? Why?
- warning cards
- indicate that if patient gets a fever, need immediate antibiotic treatment
- due to the induced neutropenia
What are the common types of infections neutropenic individuals will acquire?
- invasive extracellular bacterial infections
- invasive fungal infections
- these are due to lack of surveillance at the mucosal barrier
How does G-CSF work?
it’s a recombinant exogenous cytokine that will boost the differentiation of neutrophils from the bone marrow
What substance is released that causes the pain (dolor) of inflammation?
substance P - a neuropeptide that induces pain (can be released by hitting yourself on accident too)
What substances are released that cause the swelling (tumor) and redness (rubor) of inflammation?
- bradykinin
- histamine
- NO
What molecules do macrophages release during the acute inflammatory response?
- cytokines
- lipid metabolites
What cells are involved in the acute inflammatory response?
- macrophages
- neutrophils
- mast cells
- complement molecules
What do the cytokines released by macrophages during the acute inflammatory response do locally?
- IL-8
- causes neutrophil influx
What do the cytokines released by macrophages during the acute inflammatory response do systemically?
- drive the systemic response to inflammation
- increase dendritic cell activation
What do the lipid metabolites released by macrophages during the acute inflammatory response do?
- prostaglandins, leukotrienes derived from arachidonic acid
- prolong oedema
- cause vasodilation
- cause bronchoconstriction
What does the histamine released by mast cells during the acute inflammatory response do?
- causes vasodilation
- causes endothelial cell-junctional widening leading to increased permeability
What systemic inflammatory cytokines are released to the liver and what do they do?
- IL-6, IL-1, TNF-alpha
- cause acute phase response proteins to be released to contain infection in liver
- acute phase proteins include: transferrin, fibrinogen, CRP
What do systemic inflammatory cytokines released to the bone marrow do?
- increase mobilisation of cells to site of infection
- neutrophils: bacterial
- leukotrienes: viral
- eosinophils: parasitic
What do systemic inflammatory cytokines to the fat and muscle do?
- increase muscle breakdown in state of cachexia
- change metabolic programme
During infection, what liver proteins decrease?
- transferrin
- albumin
- this is because the liver is dedicated to producing other proteins
What can we do therapeutically to interfere with the changes in liver protein levels during infection/inflammation? What is an example?
- block cytokines
- this will inhibit the normal response
- tocilizumab blocks cytokine IL-6, so no CRP rise or fever (can block the signs of infection)
What do C3b and C5b act as?
opsonins and enzymes
What do all 3 complement pathways descend on? What complement molecules compose this?
the terminal complement complex (TCC) (ring shaped molecule) - composed by C5b-C9
What does the TCC do?
punches holes through cell membranes killing the cell (complement-mediated lysis)
What bacteria are susceptible to the TCC?
Neisseria menigitidis
How are human cells protected from the TCC?
regulatory proteins stop lysis of human cells
What are 2 types of complement deficiency?
- congenital
- acquired
What does complement deficiency make you susceptible to?
meningococcal meningitis
What 2 fragments are complement molecules cleaved into?
a soluble fragment (a) and a bound fragment (b)
Which cytokine was discovered to be an important one in driving the pathology of rheumatoid arthritis?
TNF-alpha
How does TNF-alpha affect bone in rheumatoid arthritis?
primes osteoclasts to cause bone erosion
How does TNF-alpha affect endothelium in rheumatoid arthritis?
increases endothelial activations, leading to inflammation
How does TNF-alpha affect cartilage in rheumatoid arthritis?
causes joint lining to produce proteases that break down cartilage
How does TNF-alpha affect cytokines in rheumatoid arthritis?
have positive feedback on the inflammatory cytokine cascades
What was the first anti-TNF alpha drug produced?
Infliximab (Remicade) - chimeric (mouse/human) antibody
What are examples of fully humanised anti-TNF drugs?
adalimumab (Humira) and golimumab (Simponi)
What anti-TNF drug is a soluble receptor protein?
etanercept (Embrel)
What were the 2 positive outcomes of the clinical trial of an anti-TNF drug?
- decrease in the number of swollen joints
- CRP decreased and stayed down for week 8. inflammation reduced
What are latent tuberculosis (TB) infections?
where the tuberculosis infection is kept within macrophages within granulomas in the lungs - TNF-alpha plays a role in maintaining this
Patients who were treated with anti-TNF were followed up for 20 years and some developed active tuberculosis infections. Why is this?
- they may have had latent TB infections
- the anti-TNF drug would have removed the TNF that was containing the TB infection within the granuloma of the lungs
- this would lead to reactivation of the latent TB
Part3: vaccination
Overview of immunological memory
How vaccination can exploit immunological memory to generate long lasting protection
Different types of vaccines - their advantages and disadvantages
Role of the pharmacist in vaccination
4 roles of pharmacist in vaccination
clinical advice
- who can/cant have vaccine
- who not to give to and when
demand management/prioritis
- e.g. Hep B vaccine shortage
public health + commun
- why you should have it
service delivery and saftey monitoring
Vaccination involves the administration of what material?
antigenic material
What does antigenic material stimulate in human beings?
an immune response that develops the adaptive immune system (adaptive immunity to a pathhogen)
What is vaccination?
administration of antigenic material to stimulate an immune response that develops the adaptive immune system and immunological memory
What aspect of the immune system is exploited by vaccines?
immunological memory
What is meant by a ‘naive immune cell’?
an immune cell that has matured but not yet been exposed to antigen
Which naïve immune cells can go on to develop immunological memory?
- CD4 T cells (CTL)
- CD8 T cells (Th)
- B cells
What process occurs in order for a naive immune cell to develop immunological memory?
clonal expansion + contraction
What is meant by clonal expansion + contraction?
T and B cells are stimulated to proliferate, some die off, and some survive and go on to develop immunological memory
How do the affinities between IgG and IgM antibodies compare?
- IgG is high affinity
- IgM is low affinity
Sketch a graph showing the response from IgM antibody and IgG antibody comparatively. Label the axes, the point of primary inoculum and the re-exposure to the inoculum.
…
Memory responses from the immune system are said to be…
qualitatively and quantitatively superior
Name the 4 different types of vaccine.
- live attenuated
- killed/inactivated
- toxoid
- subunit
What is meant by an attenuated pathogen?
one that is still able to replicate but not cause full blown disease in individual
What are examples of live attenuated vaccines?
- intranasal immune virus
- BCG
- MMR
- VZG
- Zostervax
How has the intranasal flu vaccine been engineered?
the virus can only replicate at 34 degrees which is the temperature inside the nose
Why are live attenuated vaccines useful?
they produce strong immune responses
What patient group are live attenuated vaccines contraindicated in?
immunocompromised !!
Patients on what class of medications cannot have live attenuated vaccines?
immunosuppressants
State some examples of immunosuppressant medications.
- azathioprine
- ciclosporin
- chloroquine
- hydroxychloroquine
- prednisolone
- methotrexate
What type of vaccine is: rotavirus, Zostervax, VZV, BCG, MMR?
live attenuated
Name some examples of killed/inactivated vaccines.
- hepatitis A
- SALK polio
- hep B
- rabies
Why are killed/inactivated vaccines useful?
they produce a potent immune response
What patient group are killed/inactivated vaccines safe in?
immunocompromised
What is the state of pathogen in killed/inactivated vaccines? How is this achieved?
- unable to replicated
- inactivated via heat, radiation or chemicals
What type of vaccines are hepatitis A, SALK polio, and rabies vaccines?
inactivated/killed
What is found within a toxoid vaccine?
toxins produced by pathogens
What are examples of toxoid vaccine?
- diphtheria
- tetanus
- DTP (has other components too)
How does a toxoid vaccine stimulate an immune response?
the immune response needs to produce antibodies to neutralise the toxin
this is the vaccine target
What is DTP?
a vaccine combined with heat killed pertussis, diphtheria toxin and tetanus toxin
What types of vaccine are tetanus, diphtheria and DTP?
toxoid vaccines
What is the target of the immune response within a subunit vaccine?
the subunit of a virus e.g. a surface protein, polysaccharide or polysaccharide conjugate which can be made by recombinant protein tech
What are examples of subunit vaccines?
- hepatitis B
- pneumococcal
- meningococcal C
- HiB
- HPV
What type of vaccines are hepatitis B, pneumococcal, meningococcal C, HiB, and HPV?
subunit vaccines
What are the brand names of the meningococcal vaccine?
- Prevenar
- Pneumovax II
What aspect of immunity do vaccines attempt to replicate?
the correlates of natural immunity to pathogens e.g. encapsulated bacteria such as S. pneumoniae
What protection does S. pneumoniae have against the immune system?
polysaccharide cell wall
- stops complement binding and neutrophil killing
How do we know that the natural correlates of bacteria are antibodies?
those with antibody deficiencies are unable to mount a sufficient immune response to encapsulated bacterial infections
What do the antibodies bound to S. pneumonia do? What are vaccines designed to facilitate?
- enhance neutrophil killing by opsonisation
- designed to facilitate the production of anti-polysaccharide antibodies
What are the two types of B cell responses?
- T-cell dependent
- T-cell independent
antibodies target polysacc capsule and do whta?
bind and help activate complement cascase and facilitate neutrophil killing via opsonisation
What type of B cell response recognises conformational protein epitopes (e.g. shapes)?
T-cell dependent
need T cell help to fully activate
What type of B cell response recognises repetitive pattern of sugars (can cross link the B receptors)?
T-cell independent
can do so without and produce antibody
What is an example of a macromolecule from a pathogen that has lots of repetitive patterns?
polysaccharide
How is the repetitive pattern of polysaccharide recognised by B cell receptors?
the repetitive pattern is able to crosslink multiple B cell receptors
What are examples of encapsulated bacterial infections?
- pneumonia
- meningitis
- conjunctivitis
- sinusitis
- otitis
How does age compare between the two types of B cell response?
T-cell dependent: any age
T-cell independent: only efficient after 2 years of age !!
How does antibody quality compare between the two types of B cell response?
T-cell dependent: high affinity antibody
T-cell independent: low affinity antibody
How does class-switching compare between the two types of B cell response?
T-cell dependent: yes
T-cell independent: limited
How does immunological memory compare between the two types of B cell response?
T-cell dependent: yes
T-cell independent: limited
How does antigen-type recognised compare between the two types of B cell response?
T-cell dependent: protein
T-cell independent: carbohydrate, lipid, nucleic acid
What age groups do encapsulated bacterial infections affect? Why?
- the very young and very old
- in the very young, the T-cell independent response is not very efficient yet
- this response is used to recognise polysaccharide in encapsulated bacteria and produce antibodies`
What does Pneumovax II (PPV23) contain?
capsular polysaccharide derived from 23 serotypes of diff pneumococcal bacteria
What does Prevenar (PCV13) contain?
capsular polysaccharide derived from 13 diff serotypes of pneumococcal bacteria CONJUGATED TO carrier protein + adjuvant
What age group is Pneumovax II (PPV23) used in? Why?
- > 65 and >2 years if at clinical risk
- able to mount a T-cell independent response to the polysaccharides within the vaccine that normally make up the bacteria’s cell wall (subunit)
How does Prevenar work? (hint: what type of B cell response?)
- generates T cell dependent response
- APC presentation to T cell, leading to B cell activation
... joined to carrier protein, picked up B cell activation + antigen presentation to cognate T cell < - -> APC with antigen presentation to T cell
What age group is Prevenar (PCV23) used in? Why?
- routine immunisation at 2, 4 and 12 months of age
- able to mount sufficient T-cell dependent B cell response
ligating B cell
Adjuvants help the local release of what?
chemokines and cytokines
to augment immune response to protein target
What do adjuvants facilitate?
the activation of recruitment of APCs
What do adjuvants depot?
antigen
What do adjuvants do? (3)
- help local release of cytokine and chemokine
- facilitate recruitment of APCs
- antigen depot
What are the two types of adjuvants?
- live attenuated
- artificial
Why are live attenuated adjuvants naturally immunogenic?
they contain PAMPs
What are 2 examples of artificial adjuvants?
- alum
- emulsified squalene
What is alum? artificial adjuvant
hydrated double sulphate salt of aluminium
What is emulsified squalene? artificial adjuvant
naturally occurring compound found in shark liver oil, olives, vegetable oils, rice bran
why artifical adjuvants better?
= more potent immune repsosne
= long lasting immunity ☺
What is herd immunity?
when enough of the population is vaccinated against a pathogen
What factors affect herd immunity?
- susceptibility of hosts
- nasopharyngeal carriage
- vaccine effectiveness
- coverage rates
- force of transmission
- crowding
If 1 person with measles spent time with 100 unvaccinated people, how many would: a) get infected b) get infected w complications and c) be unaffected
- 90 would get infected
- 7 would get infected w complications
- 10 people would be unaffected
How many people will a single person with measles infect on average in a susceptible population?
12
How does effectiveness compare between vaccines? Give an example.
- some vaccines can be more effective than others
- tetanus>pneumococcal
Apart from efficacy, what else can vary between vaccines when considering vaccine effectiveness? Give an example.
- the length of effectiveness
- e.g. pertussis needs a catch-up vaccine
At what percentage coverage are vaccination programmes most effective? Why?
- > 90%
- the pathogen prevalence is significantly reduced
A percentage vaccine coverage lower than what is ineffective? Why? Give two examples.
- <90%
- the pathogen is still present and can be transmitted
- Nigeria polio virus, MMR uptake in UK
What are the major proteins found in influenza A?
- haemagglutinin (H)
- neuraminidase (N)
What combination of influenza A protein was responsible for the swine and Spanish flu?
H1N1
What combination of influenza A protein was responsible for the bird flu?
H5N1
What is the evasive mechanism that means we need a flu vaccine every year?
antigenic drift
What evasive mechanism can cause a pandemic by entering an animal host? Use the example of influenza A.
- antigenic shift
- if two strains (one human, one animal) infect an animal, that could generate a new strain
- nobody will have immunity to this new strain
What patient groups receive the annual flu vaccine?
- healthcare workers
- > 65 years old
- > 2 years old
- pregnant
- at risk groups (asthmatics, COPD, DM, etc.)
Flu vaccines have a protein found in a substance people have an allergy to. What is this protein, and can vaccines be safely administered to patients with this allergy? Why or why not?
- ovalbumin
- yes, if no history of severe anaphylaxis due to the low ovalbumin content
- if history of anaphylaxis, must be done in hospital setting
annual flu vaccine- caution with what patients?
egg allergic patients
- most can be vaxxed safely in general practive woth low ovalbumin content vaccs unless prev anaphylaxis to egg
What is the key component of SARS-CoV-2 that mediates its infection? How does it do this?
- spike protein
- permits entry into respiratory epithelium by binding to ACE2
What do COVID-19 vaccines target?
the spike protein on SARS-CoV-2
What do the Pfizer and Moderna vaccine contain?
mRNA for the spike protein
How do the Pfizer and Moderna vaccines work?
- the mRNA for the spike protein from the vaccine is translated by ribosomes in the deltoid muscle
- macrophages then pick up the spike protein and present it to the adaptive immune system
What does the Astrazeneca virus contain?
DNA coding spike in modified chimpanzee adenovirus
How does the AstraZeneca virus work?
the DNA is transcribed and translated into spike protein
What patient vaccine history should be considered before giving vaccines?
- any previous vaccination
- any previous reaction to vaccine (rare)
- any allergy
- any immunosuppression or whether they’re immunocompromised
- any close contact to an immunocompromised as live vaccines can shed
Why is vaccine history important to consider for the pneumococcal vaccines?
PPV23 cannot be given within 5 years as it can reduce the response
What is the main information source to consult for vaccines?
the green book
Part 4: Autoimmunity
Basis of immune tolerance
Immunopathogenesis of autoimmune disease
Basis of treatment of autoimmune disease
Drugs predisposing to autoimmunity
Where do T cells come from?
derived from the bone marrow
What is the precursor of a T cell?
a myeloid cell
What stem cells are harvested for bone marrow transplants (BMT)?
CD34 haemopoetic stem cells
- After differentiating in the bone marrow, where do T cell precursors go?
to the thymus to mature
- After maturing in thymus, where do T cells go?
to the lymph node
the naive CD4 and CD8 T lymphocytes
T cells only recognise antigen when presented…
in the context of MHC
i.e. antigen presenting cell with MHC and antigen attached
connect to
T cell receptor on T cell
how do stem cells become matute cells i.e. steps they change to
stem cells -> multipotent progenitor cells -> comitted precursor cells -> mature cells
How do TCR of CD4 cells recognise peptide?
recognise peptide presented by _professional APC (B cells, DC, macrophages) _ in the context of MHC II
How do TCR of CD8 cells recognise peptide?
recognise peptide presented by nucleated cells in the context of MHC I
What class of MHC is presented on all nucleated cells? What T cell recognises peptide bound to it?
- MHC I
- CD8
What class of MHC is presented on professional APCs? What T cell recognises peptide bound to it?
- MHC II
- CD4
What are examples of professional APCs?
- dendritic cells
- B cells
- macrophages
MHC is said to be highly…
polymorphic
What does HLA stand for?
human leukocyte antigen
What 3 proteins make up MHC I?
HLA-A, HLA-B, HLA-C
What 3 proteins make up MHC II?
- HLA-DP
- HLA-DQ
- HLA-DR
How many alleles are there for the proteins that make up MHC (both classes)? Why?
- 6
- 1 allele from mother, 1 from father
- 3 diff HLAs for each MHC class
With tissue typing, what must be ensured regarding the donor and the recipient?
the haplotype matches between the two
What geographical correlation is found for a specific MHC II allele? State the allele, and the correlation.
- HLA-DR4
correlation between autoreactivity for this allele and autoimmune conditions:
type 1 diabetes,
rheumatoid arthritis
multiple sclerosis
The cost of diversity is…
autoreactivity
What is the estimated recognition capacity of 1 TCR?
can recognise >1 000 000 peptides
_ + _ = autoimmune disease.
autoreactivty
+
environmental/genetic/epigenetic factors
= autoimmune disease
_ alone is not enough for autoimmune disease.
Autoreactivity alone is not enough for autoimmune disease
How do we know that autoreactivity is not enough for autoimmune disease?
20% of health individuals in a study had titre positive for ANA yet don’t have autoimmune disease
What has to happen before we get an autoimmune disease?
- autoreactivity
- other checks need to break
ANA link with age?
prevalence increases with age
What is central tolerance and where does it occur?
- the thymus
- thymic epithelial cells delete autoreactive T cells
What special cells help in positive thymic selection?
thymic cortical epithelial cells
What do thymic cortical epithelial cells have on their surface?
MHC II
What are the 2 stages of thymic central tolerance?
- positive selection
- negative selection
positive thymic selection: what is being checked for between MHC II and TCR?
is there enough contact between them to allow binding?
if so: T cell gets survival signal and can progress ☺
What is necessary for positive thymic selection?
the progenitor T cell must be able to bind to the MHC II of the thymic cortical epithelial cell with its TCR
What is the result of positive thymic selection?
survival signals are sent from the thymic cortical epithelial cell to the progenitor T cell
Following positive thymic selection, where do progenitor T cells go?
to the thymus medulla
Where does negative thymic selection occur?
thymic medulla
What special cells help in negative thymic selection?
thymic medullary epithelial cells
What do these special cells (-ve selection) have on their surface?
MHC II + self-antigen/peptide
When is a T cell killed (and potentially autoreactive cell is purged) during negative thymic selection?
if it binds too tightly to the MHC II (with TCR) + self-antigen/peptide on the surface of the thymic medullary epithelial cell
When is a T cell considered safe in negative thymic selection? What happens to it?
- when it binds loosely to MHC II + self-peptide presented on the thymic medullary epithelial cell
- it can leave the thymus and enter the circulation
When does a T cell have the potential to produce a regulatory T cell?
when it binds neither tightly nor loosely to MHC II + self-antigen/peptide presented by thymic medullary epithelial cells
Summarise the possible outcomes of negative selection.
The progenitor T cell could:
- bind too tightly to thymic MHC II + self-peptide = killed/deletion
- bind loosely to MHC II + self-peptide, = leaves thymus, released to periphery (circul)
- bind neither too loosely or too tightly = potentially becomes a regulatory T cell
What steps occur before positive selection (in cortex)?
autoimmunity
- T cell progenitor/precursor enters thymus
- TCR arranged B chain first = rearranged B chain (VDJ)
Where in the thymus does positive selection occur?
the thymus cortex
What occurs in positive selection?
autoimm
- the rearranged beta chain is bound to a generic alpha chain + tested to see whether it can bind to MHC II on the thymic cortical epithelial cell
What happens involving the TCR if a T cell successfully passes positive selection?
alpha chain is also rearranged to produce a complete TCR
What happens in negative selection in medulla?
autoimm
progenitor T cell’s receptor is tested to see how tightly it binds to MHC II + self-peptide
Where does a T cell go once it passes negative selection?
enters the circulation
Summarise what central tolerance in the thymus.
autoimm
- progenitor T cell enters thymus cortex
- beta-chain’s VDJs are rearranged and paired to generic alpha chain
- TCR tested to see if it can bind to MHC II on thymic cortical epithelial cell
- if it can, alpha chain VDJ genes rearranged to produce complete TCR
- T cell then enters medulla
- TCR tested to see if it binds too tightly to MHC II + self-peptide
- if binds tightly, naïve T cell released into circulation
When a CD4 T cell arrives at the lymph node, what can it do?
differentiate into different Th cells:
Th1/2/7
What does a CD4 cell that differentiates to a Th1 cell release? What immune cell does this activate and what does it do?
- releases IFN-gamma
- activates macrophage against intracellular bacteria
What does a CD4 cell that differentiates to a Th2 cell release? What immune cell does this activate and what does it do?
- IL-4/5
- activates eosinophils against worms and parasites
What does a CD4 cell that differentiates to a Th17 cell release? What immune cell does this activate and what does it do?
- IL-17
- activates neutrophils against extracellular bacteria
What happens when a CD8 T cell enters the lymph node?
recognises MHC I on virally-infected cells and kills them
CD8 killing virally infected cells is an…
MHC-I dependent process
What do natural killer cells do?
kill virally infected and tumour cells
that have lost expression of MHCI ‘missing self’
How do virally infected and tumour cells hide from CD8?
downregulate MHC-I on their surface
What class of cytokines (and what of them specifically) help upregulate MHC I on cell surfaces?
- interferons
- IFN-alpha and IFN-beta
What T cells regulate peripheral tolerance?
regulatory T cells
What do regulatory T cells have on their surface?
- potentially autoreactive TCR
- FOXP3+
- CD25
What do regulatory T cells upregulate when their receptor is engaged?
immunosuppressive molecules
What is an example of an immunosuppressive molecule and what does it do?
- CTLA-4
- strips APCs of CD80 and CD86 (costimulatory factors) reducing their ability to activate T cells
What are CD80 and CD86?
costimulatory factors
What do regulatory T cells directly do and how?
- directly kill other immune cells
- Granzyme/perforin dependent process
What do T regulatory cells produce?
give 2 examples
immunosuppressive cytokines
- TGF-beta
- IL-10
What is CTLA-4?
an immunosuppressive molecule that suppresses APCs ability to activate T cells
What does IL-2 do?
necessary for expansion of T cells
What are IL-10 and TGF-beta?
immunosuppressive cytokines
Summarise the actions of centrally generated T regulatory cells
- release immunosuppressive molecules (CLTA-4) which act on APCs
- release immunosuppressive cytokines (IL-10, TGF-beta)
- directly kill other immune cells (Granzyme/perforin-dependent process)
- upregulate CD25 to deprive T cells of IL-2, necessary for expansion
Normally, an APC will recognise and present pathogen peptide. What happens that can trigger the peripheral generation of a T regulatory cell?
an APC accidentally expressing a self-antigen and presenting that in the context of pMHC
What happens when an APC accidentally presents self-antigen (without DAMPs and PAMPs)?
if a naive CD4 T cell recognises it, it can be induced to become a peripherally generated regulatory T cell
(sim job to thymic T cells)
What are two ways to describe the way T regulatory cells are generated?
- thymic generated (bind not too tightly or not too loosely to self-antigen on MHC II)
- peripherally generated (by accidental presentation of self-antigen by APC in context of pMHC)
Autoimmune disease is _, self-directed _ caused by autoreactive _ and _ _ responses, ultimately arising from a _ of _ _ to self _.
autoimmune disease is inappropriate, self-directed inflammation caused by autoreactive B and T cell responses, ultimately arising from a failure of immune tolerance to self-antigens.
What are Witebsky’s postulates?
a set of criteria to define autoimmune conditions
Witebsky’s postulates require direct evidence of what?
autoantibody or autoreactive T cells that can transfer disease (e.g. transplacentally)
Give an example of direct evidence provided for Witebsky’s postulates.
A pregnant mother with Grave’s disease can pass on her autoantibodies to her baby which will have the disease for the half-life of the autoantibodies
Witebsky’s postulates require indirect evidence following what?
reproduction of disease in an animal model
Witebsky’s postulates require clinical clues from…
disease presentation, genetics (e.g. strong MHC association) and response to immunosuppressive treatment
What is required within Witebsky’s postulates?
- clinical evidence of autoreactive T cells or autoantibodies that can transfer disease (e.g. transplacentally)
- indirect evidence following reproduction in an animal model
- clinical clues from disease presentation, genetics (e.g. strong MHC association), and response to immunosuppressive treatment
Why are clinical clues from the response to immunosuppressive treatment criteria included in Witebsky’s postulates?
all autoimmune diseases should respond to immunosuppressive treatment
Autoimmune disease is caused when what goes wrong?
central and peripheral tolerance
5-7% adults affected
2/3rds women
What are the 3 categories of things that can break tolerance?
- genes
- environment
- immune regulation
Give examples of gene-related factors that can break tolerance.
- MHC II (alleles)
- twin studies
- signalling genes
Give examples of environment-related factors that can break tolerance.
- smoking (risk factor for rheumatoid arthritis)
- microbiome (antibiotics, IBS)
- vitamin D
Give examples of immune regulation-related factors that can break tolerance.
- hormonal effects
- C. jejuni - GBS
- Coxsackie virus - T1DM
?? unsure still
mechanism 1 of autoimmunity:
How does the beta cell mass progressively change in type I diabetes? Why does this occur?
- decreases
- CD8 T cells kill pancreatic beta cells
When do type I diabetics become symptomatic? What are they said to totally be at that point?
- when 30% of the beta cell mass remains
- insulin dependent
What autoantibodies cause myasthenia gravis?
- IgG1
- IgG3
How do autoantibodies cause myasthenia gravis? (2 effects)
after binding to the ACh receptor on the posynaptic membrane on the neuromuscular junction, they can:
(endocytosis+ degradation)
- cause complement cascade activation-> MAC formed by ac5-c9, allows free ion movement + messes up electrical polarity of memb
- if divalent, crosslink receptors causing internalisation of receptor and delaying synaptic transmission
What are the clinical consequences of myasthenia gravis?
- when patient is asked to look up for a long period of time, ptosis occurs where eyelids will progressively droop
- when patient asked to close eyes for a maximum of 10 seconds, muscle fatigue will be noticed in the eyelids when opening
What is a pannus?
an extra growth on a joint in rheumatoid arthritis
Which immune cells drive rheumatoid arthritis?
CD4 T cells
What does the pannus produce in rheumatoid arthritis? (3)
- antigen
- proinflammatory cytokines
- growth factors
What enzymes are involved in the autoimmunity mechanism of rheumatoid arthritis?
matrix metalloproteases (MMPs) –> tissue destruction
What can occur specifically in antibody positive rheumatoid arthritis?
immune complexes can deposit in inflammation site and perpetuate inflammation
- Describe the autoimmune mechanism behind rheumatoid arthritis.
- CD4 T cells release inflammatory cytokines IL-17 and IFN-gamma
- pannus on joint produces antigen, proinflammatory cytokines and growth factors
- MMPs lead to joint tissue destruction
- immune complexes perpetuate inflammation
What are the 2 strategies for treating autoimmune diseases of the endocrine system?
- replace hormone
- block hormone
Give 2 examples of replacing the hormone as a strategy for treating endocrine autoimmune disease.
- thyroxine in autoimmune hypothyroidism
- insulin in type 1 diabetes
Give an example of blocking the hormone as a strategy for treating endocrine autoimmune disease.
(if too much hormone)…
carbimazole in Grave’s disease (anti-TSH-R autoantibodies)
What are the 4 immune suppression strategies?
- generic
- cell-specific
- pathway-specific
- molecule-specific
Give an example of a generic immune suppression strategy.
steroids
Give an example of a cell-specific immune suppression strategy.
calcineurin inhibitors (CNIs)
Give an example of a pathway-specific immune suppression strategy.
Janus kinase inhibitors (JAKi)
Give an example of a molecule-specific immune suppression strategy.
anti-cytokine monoclonals
What are the advantages of the generic immune suppression strategy?
- older so side effects well established
- cheaper
What strategy of immune suppression do glucocorticoids fall under?
generic - steroids
How do glucocorticoids work?
bind to glucocorticoid receptor in cytoplasm then trafficked to nucleus, where it modulates gene expression
Why is steroid use limited?
it causes broad toxicity
What portion of autoimmune/inflammatory conditions are responsive to steroids?
the vast majority
What do steroid-sparing agents do?
reduce the need for steroids
Give examples of the toxicities produced by steroid use.
- steroid-induced diabetes mellitus
- hypertension (mineralocorticoid)
- dyslipidaemia
- weight gain
What drug is first used to suppress cancer?
methotrexate
How do antimetabolites work?
block the pathway of nucleotide synthesis
What is the theory concerning lymphocytes in autoimmune disease that explains why antimetabolites work?
lymphocyte turnover predicted to be significantly higher in autoimmune conditions
so by depriving cells of metabolites needed for DNA synthesis they will enter cell arrest/ death
What class of drugs is methotrexate?
antimetabolites
How does methotrexate work?
inhibits difolate reductase (necessary for thymidine synthesis)
What class of drugs is azathioprine?
antimetabolite
How does azathioprine work?
converted to 6-MP (inhibits purine synthesis)
What class of drugs is MMF?
antimetabolite
How does MMF work?
inhibits inosine 5-monophosphate dehydrogenase, necessary in de novo purine synthesis
What is MMF selective for? Why?
lymphocytes, as these depend on the de novo purine synthesis pathway as opposed to the salvage pathway
Give 2 examples of calcineurin inhibitors.
tacrolimus, ciclosporine
Explain the pathway involving calcineurin.
- complex TCR signalling cascade involves PLC, calcineurin and NFAT (trans factor)
- NFAT is translocated to nucleus leading to increased expression of IL-2 receptor, necessary for T cell proliferation
What is a key side effect of calcineurin inhibitors?
chronic renal toxicity
What is the target of anti-TNF-alpha?
TNF-alpha
What conditions can anti-TNF alpha be used to treat?
rheumatoid arthritis, ankylosing spondylitis, IBD, psoriasis, psoriatic arthritis
What does anti-TNF alpha increase the risk of?
reactivated TB
What is the target of tocilizumab?
IL-6 receptor
What conditions is tocilizumab used to treat?
rheumatoid arthritis, JIA, cytokine release syndrome
What infection does tocilizumab increase the risk of?
straphylococcal skin infection, infections w/o fever or CRP
What does rituximab target?
CD20 (B cells)
What conditions is rituximab used to treat?
rheumatoid arthritis, lymphomas/leukaemias, various autoantibody mediated conditions
What infection does rituximab increase the risk of?
hypogamma, PML
What does eculizumab target?
C5
What is eculizumab used to treat?
atypical HUS, PNH
What infection does eculizumab increase the risk of and why? (think about its target)
meningococcal, as it targets C5 which is responsible for complement-mediated lysis against meningitis
What are 3 examples of JAK inhibitors?
- baricitnib
- tofacitinib
- ruxolitinib
target downstream signaling kinases
What state can cancer induce in the body?
immunosuppression
How do tumour/cancer cells induce immunosuppression?
- release CTLA-4 which can bind to CD4 T cells
- release PD-1 ligand which can bind to CD8 T cells switching them off
- encourage regulatory T cells to suppress natural immune responses
What drugs interrupt the way cancer dodges the immune system?
immune checkpoint inhibitors
What is ipilumumab?
an anti CTLA-4 Ig1
What immune cells does ipilumumab deplete, and what immune cells does it kill?
- depletes T regulatory cells that express CTLA-4 via ADCC
- kills immune cells expressing protective CTLA-4
immune related adverse effetcs: effect of blocked CTLA-4?
enhances anti tumour activity
What condition can people treated with ipilumumab develop? Why?
- pan hypothyroidism
- immune cells in the pituitary stalk express protective CTLA-4 which is blocked by ipilumumab
What are CD8 cells also known as?
CTLs = cytotoxic T lymphocytes
What are pembrolizumab and nivolimuab?
anti-PD-1 drugs
How do pembrolizumab and nivolimuab work?
block intra-tumour PD-1 ligand which normally switches off CD8 cells
What is the autoreactive consequence of pembrolizumab and nivolimuab?
break is removed from potentially autoreactive T cells
Summary of all the immune-related adverse events when people treated with immune checkpoint inhibitors?
thyroiditis, hyperthy/hypothy rash, vitiligo anaemia, thrombocytopenia myocarditis vasculitis colitis ...
What is lupus?
butterfly rash
Give examples of drugs that can induce lupus.
antiarrhythmics:
- promacainamide
- quinidine
antihypertensive
- hydralazine
What is meant by slow acetylators?
i.e. metabolism slower
How is drug-induced lupus caused?
- occurs in slow acetylators
- drug reacts with reactive oxygen species (ROS)
- leads to product binding to nuclear protein
- produces neoantigen, which is not recognised by immune system
- leads to rash (lupus- ANA+ histone+ DNA-)
How is drug-induced lupus cured?
withdrawal of drug
Part 5: allergic disease + immunotherapy
immunopathogens of allergic disease
drugs to trwat
allergen immunotherapy
allergy mimics
establishing immunological tolerance: 2 types?
thymus
periphery
mucosal surfaces help establish what?
tolerance to antigen
How do mucosal surfaces help establish tolerace to antigens?
mucus blocks contact epithelium and tight junctions intraepithelial lymphocytes sentry cells (DC/ILC) lymphatic system MALT (mucosal associte lymhoidal tissues) - generates IgA preventing allergen uptake
3 types of unwanted allergen that mucosal surfaces help establish tolerance to?
commensals
aeroallergens
food
what do DC cells do (establishing tolerance to antigen)
DC on the surface
high dose antigen at mucosal surface -> anergy/deletion
or
chronic low dose stimulation of immune system at mucos surface -> Treg (IL-10, TGF-beta)
what do B cells do (establishing tolerance to antigen)
Dimeric IgA prevents allergen uptake (B cells)
spectrum: What are the different types of allergy? and how are they each mediated?
type 1 hypersensitivity - IgE mediated
type 4 hpersensitivity - T cell mediated
non IgE mediated diseases
others + adverse reactions
examples of each types of allergy on spectrum?
type 1 hypersensitivity - IgE mediated - anaphylaxis, true food allergy, hayfever, venom allergy
type 4 hpersensitivity - T cell mediated - contact dermatitis
non IgE mediated diseases - food induced enterocolitis, eosinophilic, oesphagitis
others - SJS-TEN spectrum, NSAID hypersensitivity, urticarias
Describe type 1 hypersensitivity.
B cell producing antigen specific IgE after T cell hep and Th2 cytokines (L-4) (class switches to produce antigen specific IgE)
IgE receptors on mast cells containing histamine
antigen binds to high affinity IgE receptors = mast cell degranulation = histamine released within minutes as mediators already preformed
innate IS
Describe type 1 hypersensitivity.
B cell producing antigen specific IgE after T cell hep and Th2 cytokines (L-4) (class switches to produce antigen specific IgE)
IgE receptors on mast cells containing histamine
antigen binds to high affinity IgE receptors cross linked = mast cell degranulation = histamine (tryptase lipid mediators cysLT, PGD2_ released into circ within minutes as mediators already preformed
innate IS
how is type 1 hypersensitivity assessed? (2)
sudden rise in histamine -> immediate symptoms
most type 1 hypers. recs happen wothin mins of allergen exposure
can measure histamine(in mins) ot mast cell tryptase: inc over 24 hrs, highest at approx 2-3 hrs - NICE)
What does histamine cause? (5)
vasodilatation
(endothelium releases NO - hypotension)
(fluid leak - angiodema)
sneezing (via neurostimulatory effects)
regulates sleep/wake (antihistamines cause drowiness)
mucus secretion (direct effect on glandular tissues = hypersecretion)
expulsion of digested food from GI tract - plugs up lungs in asthmatic, casing nasty mucus plugging up = hypoxia
What drugs are used to manage type 1 hypersensitivity?
antigen = densensitisation
anti IgE =blocks
mast cell stabilisier = stops granulation eg steroids/ sodium chromoglycate
HISTAMINE RECEPTORS: antihistamines
physiolgical instabilitiy = fixes effects of histamine eg adrenaline
example anti-IgE drug used to treat type 1 hypersensitivity
Omalizumab
How can you test for type 1 hypersensitivity? in lab
measure allergen specific IgE
measure mast cell tryptase and histamine- less reliable
Why do we need IgE mediated immunity?
neutrophil cant engulf some infection eg parasitic worm infection - IgE bind to antigens, bind to eosonophils causing degranulation
(hygiene hypothesis)
Why is there hypothetically an increase in allergic disease?
reduced early pathogen exposure which woud lead to increased default Th2 differntiation
basis of anti parasite immunity?
too big for phagocytes
igE attaches to helminth
eosinophils bind to IgE -> degranulated
Helminth killed w toxic granules and O2- and N radicals
IL-14 inc goblet cell mucus prodn to expel parasite
What factors make someone less like to get allergy?
pets
live in countryside
youngest child
Why does eczema cause failure of tolerance?
barrier dysfuction + S. aureus colonisation more likely
cutaneous exposure to innocuous antiges through broken sskin rather than the normal mucosal routes
leads to a failure to establish norml tolerance
failure of tolerance = allergy
in through skin
What factors cause allergic disease?
- environment early life exposure to antigens infections (RSV) hygiene antibiotics maternal smoking diet air polluiton chlorine genetics
- genes
polymorphisms (IL4 receptor or FceR0
filaggrin (barrier)
…but probab a combination
What type of allergy is allergic rhinitis and what are the types?
seasonal - pollen: tree/grass/weed
perennial rhinitis - house dust mites, pets, molds (all year)
type 1
What are the steps of treatment for allergic rhinitis?
- PRN non sedating AH, allergen avoidance (close windows, dont dry laundry outside when mowing lawn) 1M before season
- regular OR non-sedating AH - during problem season
- add topical intranasal steroid eg fluticasone
- increase non sedating AH to BD, try dymista/ montelukast if asthmatic
- antigen desensitisation
topical treatments dont work for allergic rhinitis when?
if mucus already present
- start treatment early (1m before season)
- saline nasal washes
How do you use nasal spray?
shake well with cap on for 10 seconds hold upright and spray away from you gently blow your nose shake an take cap off tilt head forwards a little bit point nozzle slightly outwards block other nostril with finger spray and breathe in gently take nozzle out and breathe out via mouth repeat in other nostril wipe nozzle and replace cap
Why may there be treatment faiure with allergic rhinitis?
right diagnosis?
unilateral symptoms - pain, discharge, crusting = refer ENT
non-allergic rhinitis? exercise, food, cold
treated too late?
try nasal washes
start treatment 1M before allergen season
compliance
inhaler technique
dymista tastes disgusting - try Avamys (but no local AH)
try immunotherapy?
role of allergist:
What are the different types of type 1 hypersensitivity? 3
true food allergy - sensitised to highly stable storage proteins within nut - high risk of anaphylaxis
oral allergy syndrome - primary sensitisation to aeroallergen (pollen). cross reactivity with ubiquitious and unstable plant proteins = oral tingling and itchines only
LTP allergy = sensitised to lipid transfer proteins- cross reactiviy w other LTP in plant based products (eg apple) moderate risk of systemic reaction
What is childhood-onset asthma?
T2 type asthma
- allergic asthma - anti IgE treatment -exercise induced
- late onset eosinophilic asthma - aspirin exacerbated respiratory disease
What is adult-onset asthma?
NON T2 type asthma
- obesity associated asthma
- smooth muscle mediates paucigranulocytic asthma
- smoking related neutrophilic asthma
whens desensitisation therapy recommended as tretament?.
when standard optimal therpay failed
desensitisation therapy not suitable for ?
patients w poorly controlled asthma/ CVD - small risk of systemic reaction with SC IT
types of desensitisation therapy.
SC vs sub lingual
depends on area.
cost and resources - NHS and allergy unmet need
desensitisation timeline + symtpoms?
antigen dosing…. induction 12 weeks
maintenance 3-5 years..
symptoms reduce over time
What are the 3 mechanisms of antigen desensitisation?
- minute doses of antigen -> mast cell undergoes piecemeal degranulation -> allergen specific IgE replaced by other IgE increaising activation threshold
- antigen, DC - bocks Th2 -> reduced IL4
and induces Treg-> inc IL-10
(expansn of allergen specific Tregs and redn in Th2) - B cell
reduced IgE
inc IgG4
block uptake of antigen
what immunotherapy is available?
SC
- common for venom (bee/wasp)
- v effective
- small risk of systemic reac and death
- pollinex (grasS) licensed but most other allergens not
- very labour intensive
sublingual
- equally efficacious
- cheaper, 1st dose in hospital, then daily sublingual tablet at home
- granax licensed in uk for allergic rhinitis
what is primary prevention of allergy?
children 4m-11m of age w severe eczema, egg allergy / both
gievn 6g peanut a week until reach 5 y/o
what is type IV hypersensitivity?
contact dermititis
mediated by T cells -> inflamma nd oedema in skin
symptoms happen 24-72hrs after exposure to caustaive agent
different to
- type 1 (IgE mediated)
- irritant response
- eczema
e..g localised form jewellery
What is patch testing?
done by dermatologists
5d test w variable sensitivity + specificity
What is acute/chronic urticaria?
must be distinguished from what?
looks like hives
often triggered by infections (common in), stress
must be distinguished from allergy
how does acute/chornic urticaria occur?
into basophil:
- BAC INFECTIONS
- VIRAL INFECTIONS
- allergens
- neuroendocrine axis
- autoantibodies (IgE/IgG)
- cytokines (IL-4)
->
basophil produces/releases:
- platelet activating factor (PAF)
- IL-4, GM-CSF
- histamine
- pre-formed lipid mediators (PGD2, LTC4)
- chrondriotin sulphate, elastases
Part 6: drug allergy + anaphylaxis
What are consequences of penicillin allergy? (5)
- significant restriction in available antibiotics (when resistance is increasing) and inc use of fluoroquinolones, clindamycin, vancomycin
- potential harm from other drugs
- longer inpatients stays
- higher incidence of antibiotic resistant infections
- higher associated health care costs
How can you improve communication to patients by
improve accuracy of drug allergy documentation + of referrals to allergy service
How do you confirm a penicillin allergy? (4)
- retake history, timing of drugs, symptoms and other concurrent medical issues
symptoms on day doesnt equal anaphylaxis
type 1 symptoms are immediate and reproducible - SPT/ID testing
put small amount on skin and compare to a + control (pure histamine) and - control (saline) - specific IgE (sIgE)
looking for the antibody against the drug - drug challenge
look at risks vs benefits, monitor symptoms for an hour after administering
what is the role of the pharmacist in allergy?
understand the difference between side effects and allergies
What are normal side effects of penicillins?
nausea
diarrhoea
transaminitis
candida
What are the use and normal side effects of macrolides?
promotes gastric motility
abdominal pain
nausea
diarrhoea
What are normal side effects of opiates?
urticarial rash
itch
sedation
hallucinations
What type of reaction is NSAID hypersensitivity?
non IgE mediated reactions
not a true allergy (just side effect of drug)
What is the pharmacology of NSAIDs?
block COX-1 enzymes which inhibits the production of PG (widespread homeostatic funcs) from arachidonic acid = antiinflammatory effects
arachidonic acid builds up and 5-LO produces LTC4 and LTD4
effects = angiodema, urticaria, bronchoconstriction (normal hypersensitivity)
What are alternatives to NSAIDs? 2
analgesic - paracetamol
COX–2 inhibitors
What is red man syndrome?
vancomycin hypersensitivity
dependent on infusion rate (slow <10mg/min and add AH) want not given too quick
can happen on first dose
direct mast cell degranulation (not IgE mediated, vancomycin binds to mast cell)
What is red man syndrome by vancomycin made worse by?
opiates - more mast cell degranulation
What is rituximab, the side effect of first dose rituximab and how can you reduce it?
monoclonal antibody from mice targetting B cells so it binds to CD20
inflammation in human body; fever, chills, rigors, angiodema
give first dose with hydrocortisone and piriton to reduce inflammation
rituximab MoA (for CD20 and B cell lymphoma)?
Nk cells -> ADCC to B cells, classical complement cascade
???
What is Steven Johnson syndrome?
severe cutaneous adverse rxn idiosyncratic (hard to predict) in early SJS: target lesions if not stopped: mucosal desqumification progresses to toxic epidermal necrolysis early skin blistering late widespread epidermal necrolysis
What is SJS/TEN caused by and symptoms?
drug related: malaise, fever, feeling like skin on fire w/out obvious signs initialls
antibiotics (penicillins, sulfa containing drugs)
aromatic anticonvulsants (lamotrigiine, phenytoin, carbamazepine)
antiretrovirals (nevirapine)
allopurinol
NSAIDs
type 4 hypersen rxns
What is SJS/TEN associaated with?
MHC-1 genetic linkages; implicates CD8+ T cells in pathogenesis
What do you do if SJS is suspected?
stop the drug !!!
transfer to ITU or burns unit to look after lesions
What is anaphylaxis?
acute, severe, life-threatening allergic reaction in a pre-sensitised individual, leading to a systemic response caused by the release of immune and inflammatory mediators from basophils and mast cells involving at least two organ systems (such as angiodema [around airway], vomiting [GI tract])
What is the ABCDE management of anaphylaxis?
Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach
stop obvious triggers - remove drug etc.
bee sting may potentially lead to what reactions?
- airway compromise
- wheeze, breathing difficulties
- rapid CV collapse
urticaria, angioedema
distributive shock (2 effects of histamine)?
hypotension
- histamine increases NO
tunica media relaxation
vascular leak (oedema and erythema) - hist alters capillary permeability (tight junctions)
4 effects of histamine?
distributive shock
1. hypotension
- hist increases NO
tunica media relaxation
- vascular leak (oedema + erythema)
hist alters cpaillary permeability (tight juncs)
…
- bronchoconsticiton/ spasm (wheeze)
- direct + indirect effects on bronchial smooth muscle - mucus secretn (diarrhoea in GI tract)
- direct effect on goblet cells of resp mucosa
causes of anaphylaxis?
food
tatrogenic (dk but cause but inc w age)
insect sting
7 cofactors for anaphylaxis?
drugs: NSAIDs, ACEi- inc bradychinin, opiates- mast cells affected exercise EtOH infections hormones route of delivery antigen dose
Why does injection of drugs hve the shortest time to arrest?
goes right into circulation as opposed to food/stings/oral drugs
most important risl factors for cardiac arrest and death form perioperative anaphylaxis?
older patients
obese
asthma in young
differential diagnosis of anaphylaxis?
syncope/faint anxiety induced hyperventilation hypotension due to MI, blood loss, sepsis scombroid poisoning mastocytosis carcinoid syndrome vocal cord dysfunc chronic urticaria + angioedema C1-esteras inhib deficiency exercise induced direct mast cell activators- opioids
4 AIRWAY danger signs?of anaphylaxis
persistent cough
vocal change (hoarse)
difficulty swallowing
swollen tongue
4 BREATHING danger signs?of anaphylaxis
wheezy
noisy breathing
stridor
high RR
4 CIRCULATION danger signs?of anaphylaxis
loss of consciousness
pre-syncope
confusion
impending doom
What should you do if you have an anaphylactic reaction in terms of position?
lie flat w legs slight up
elevate feet- fluid
What do you give to someone having an anaphylactic reaction?
oxygen
nebulised salbutamol
IV fluids
IM Ad (o.5mg 1:1000IM) repeat at 5 mins if needed
How does adrenaline act?
↑ peripheral vasoconstriction
↑ peripheral vascular resistance
↑ BP + coronary artery perfusion
↓ vascular permeab + angioedema
-> bronchodilatation
↓ inflamm mediator release
stabilising physiologyu deranged by action of histamine
3 types of IM Ad and when given?
Epipen
Emerade
Jext
give if any danger sign present- delay if risk factor for death
What other drugs can you give for a anaphylxis rxn?
adjunct therapies:
- antihistamines
- steroids (200mg hydrocortisone)
cetirizine (non-sedating) - helpful if not given early
sedating AH not recommended e.g. piriton
timeline of symtpoms for anaphylaxos (Ad)
after antigen exposure:
initial symptoms = mast cell degranulation
1-8 hrs…
second phase symptoms = de novo mediator sythesis
when to admit patients after anaph and what to check?
admit patient for monitoring (12 hrs) check tryptase (0,2,24 hrs)
What is included in the follow up for anapnhylaxis?
do they need Ad autoinjector to take home?
whats the risk of future allergen exposure?
refer to appropriate local allergy clinic
How do you use an adrenaline autoinjector?
4 steps…
How many allelles does MHC II have and what do they do?
HLA-DP
HLA-DQ
HLA-DR
one from father, one from mother
each bind to a different peptide
why is Type 1 hypersensitivity symptoms reproducible?
as the Ig antibodies dont go away
what is the difference between side effects and allergies?
with allergies your immune system dictates the response to the allergy but does not for side effects
how do NSAIDs stop arachidonic acid from accessing catalytic site?
the NSAID will block both Cox1 and Cox2 inhibitors by binding at an arginine molecule halfway up the channel inhibiting the access of arachidonic acid and so inhibiting synthesis of prostaglandins PGI2 and PGE2, thromboxanes TGA2
what symptoms will occur with patients with urticaria and angioedema?
urticaria: airway compromise
angioedema: rapid CV collapse
how does histamine cause hypotension?
histamine increases NO release and so the BP will decrease
this causes organs to not be able to perfuse properly
how does histamine cause vascular leak (oedema)?
histamine will alter the permeability of tight junctions and so these will open and fluid leaks out and eventually causes angioedema
how does histamine cause bronchoconstriction/spasm?
it has direct and indirect effects on bronchial smooth muscle
- opens up the blood vessels and constricts airways and causes wheeziness
how does histamine cause mucus secretion?
histamine has a direct effect on goblet cells of respiratory mucosa
- histamine can cause mucus plugging in the lungs and there is difficulty recruiting alveoli to ventilator capacity so adult cant breathe properly
what can mucus plugging cause?
can cause patient to become rapidly hypoxic
what is the purpose of the drug adrenaline?
- increases peripheral vasoconstriction
- increases peripheral vascular resistance
- increases BP and coronary artery perfusion
- decreases vascular permeability and angioedema
- maintains bronchodilation
- decreases inflammatory mediator release
how often should you administer an adrenaline after first dose? how should it be administered
5 mins after first dose if needed
and should be given IM
Inflammation key points.
think of it like a network of cells
- all immune cells secrete cytokines of various sorts
- chemokines= mols generally responsible for chemoattraction of other immune cells. cytokines generally direct cellular func rather than migration; they are not interchangeable but there is overlap.
- most complement proteins are made by the liver (C3, C4). C1q which initiates the classical cascade is produced by myeloid lineage cells.
describe consumption of complement?
means it is being used up - whole C3 and C4 is being turned into cleavage products as part of the activation of the complement cascade; clinically you can measure C3 and C4 - as it gets used up, levels in the blood go down in certain diseases. Low C3 is a marker of alternative cascade activation, low C4 is a good marker of classical cascade activation
does both positive & negative selection occurs before forming the naive CD4/CD8 T Cells.
Or is it the naive T cells that undergo positive/negative selection?
thymocytes enter the thymus and undergo positive and then negative selection within the thymic cortex and medulla respectively. The final goal of this process is to produce a naive T cells.
difference between monoclonal and polyclonal immunoglobulins
providence of polyclonal immunoglobulin
there are two broad therapeutic uses for polyclonal immunoglobulin - immunomodulation and immunoglobulin replacement and appreciate there is a strict governance process over the use of Ig in the NHS
broad array of monoclonal antibodies used for different therapeutic purposes; some target cells (e.g. CD20 - B cells), some target cytokines (e.g. anti-TNF), some target complement (e.g. eculiziumab). You will find more details about certain monoclonals in the lectures to illustrate how they cause a secondary immunodeficiency - you will be expected to understand that there are potential immunological toxicities of administered these medicines.
