Immunology And Infection Flashcards
How is shigella transmitted
Faecal oral transmission
How does shigella infect cells
Uses actin from host to move from cell to cell - to invade neighbouring cells
What does shigella cause
Damages GI tract causing bloody diarrhoea
How can neisseria meningitis is cause infection and what effects can it have
It is a commensalism bacteria in the nasopharynx, but can become harmful and move into blood, affecting body
Can lead to septic shock, septicaemia, meningitis and death
Non blanching rash is a sign of which bacterial infection
Neisseria meningitidis
Name 2 nosocomial infections
C diff
MRSA
What causes TB
Mycobacterium tuberculosis
What can helicobactor pylori cause
Is a bacteria which can cause
Peptic ulcer disease
Gastric cancer
Why are mutations more frequent in bacteria if the mutation rate is the same in bacteria and humans
Bacteria reproduction rate is much greater than humans do the speed of mutations and change is greater in bacteria
Describe 2 Protozoa
1) Malaria - plasmodium virus
Vector = female anopheles mosquito
Location = tissue and blood parasites
Replication = trophozoites inside cell
2) leishmaniasis
Vector = sandfly (often on dogs, or bite dogs and then dog bites human)
Location = blood and tissue parasites
Replication = trophozoites inside cell
Manifestation = cutaneous and visceral disease (major swelling of organs)
How do Protozoa replicate?
Either by binary fission or by formation of trophozoites (the activated feeding stage in the life cycle of a Protozoa)
What are Protozoa
Unicellular eukaryotes
Can be blood, tissue or intestinal parasites
Describe the transmission of Protozoa
Unusually have 2 hosts (primary and secondary) eg mosquito Is first host of malaria and human is second
What are the routes of transmission of viruses
Air borne
Blood borne
Faecal oral
Vectors
How do viruses replicate
Budding or cytolysis (host cell explodes, releasing viruses) , use host cells machinery
What are viruses
Obligate intracellular parasites
What kind of viruses is HIV
a retrovirus ie has RNA and uses reverse transcriptase to convert it to DNA and integrate to insert that DNA into the host cells DNA
What virus causes small pox
Variola virus
What kind of cancer is HPV linked to
Cervical
What is the cell wall of bacteria made of and what does it determine
Peptidoglycan
Determines shape of bacteria and whether the bacteria is gram positive or negative
What colour will be atria stain if it’s gram positive or negative
Gram positive = blue
Gram negative = pink
How do bacteria divide
Binary fission
Describe DNA of bacteria
Singular circular chromosomes
What are bacteria
Unicellular prokaryotes
What are fungi
Unicellular eukaryotes
What are helminths
Macroscopic Multicellular eukaryotes
What fungi causes allergic reactions
ABPA (allergic bronchopulmonary aspergillosis)
What fungi causes mycotoxicosis
Aflatoxin
How can fungi replicate
Bud/divide (unicellular fungi like yeast)
Or
using their filaments/hyphae - cross wall and septa, spreading them into neighbouring cells and fragment and divide this way
Different types of mycoses (fungal infections)
Superficial (on surface of skin)
Cutaneous
Subcutaneous
Deep/systemic
Targets for anti fungal therapy
Cell wall (human cells have no cell wall) Cell membrane (fungal cells use egosterol to stabilise membrane whilst human cells use cholesterol) DNA replication (fungi activate certain molecules involved)
Which infections agent causes white spots on tongue
Candida albicans (a fungi)
3 types of helminths
1) Tape worm
2) Flat worm (fluke) eg causes schistosomiasis- vector is a snail, helminths burrows into soles of feet and enters blood stream, resides in liver causing fibrosis and cirrhosis (liver hardening)
3) round worm eg Ascaris
Treatment/protection for helminths?
There is treatment but no vaccine
Helminths transmission
Faecal oral - lay their eggs in gut so eggs are present in faeces - contaminates water
which method to activate the complement cascade does not rely on antibodies
Alternative pathway
2 functions of complement cascade
Large number of proteins react with one another to
Opsonise pathogens
Or
Directly kill pathogens using MAC (membrane attack complex)
What are complement proteins produced by
Liver
Macrophages
Monocytes
3 ways to activate the complement cascade
1) classical pathway - antibodies and antigens
2) MBL (mannan binding lectin aka mannose binding protein) pathway - MBL binds to pathogens surfaces to initiate complement cascade and is produced in liver
3) alternative pathway - uses no antibodies, instead uses bacterial surface to initiate complement cascade
Describe the complement cascade briefly
1) initiation
2) production of C3 convertase
3) production of C5 convertase
4) MAC formation
4 ways bacteria can disrupt the complement cascade
Inhibit complement convertases
Inhibit complement proteins
Degrade/cleave complement proteins
Activate host-derived regulators
S Aureus - complement evasion
1) produces SCIN protein which binds to C3bBb and prevents formation of C3 convertase and C5 convertase. This prevents C3b deposition, C3a formation and C5a formation
2) produces Efb protein which binds to C3d part of C3 and induces a conformational change in C3. This prevents factor B binding to C3 and C3dg binding CR2
3) produces SSL7 which binds to C5 and prevents formation of MAC
Other bacterial complement evasion strategies (other than inhibit complement convertases, inhibit complement proteins or products)
1) proteases cleave complement components
2) acquired host derived complement regulators
Eg
- C3 is inactivated by fH on bacterial surface
- C4BP is associated with fI and degrades C2a from C3 convertases
Main ways microbes eg staph aureus evade immune responses
Evade opsonisation
Evade complement
Evade actions of neutrophils
- evade chemotaxis
- evade phagocytosis
- kill neutrophils
What is Staph aureus
Commensal bacteria living in the nose of 30% of population
Is opportunistic - can become harmful
Is gram positive
What is opsonisation
Opsonins (could be antibodies or complements) bind/tag bacterial antigens
This allows
1) deposition of complement in the classical complement pathway
2) neutrophils and other phagocytes to detect invading microbes
How does staph aureus evade opsonisation
1) expression of capsule -stops opsonins binding by hiding antigens
2) inhibits antibody opsonisation - SpA (staph aureus surface protein) binds to Fc region of IgG antibodies
3) inhibits detection of antibody - releases SSL10 which binds to Fc region of IgG antibody that is opsonising the bacteria and stops it being detected by neutrophils
Main ways bacteria evade opsonisation
Hide antigens
Disrupt function of antibodies
Prevent detection of antibodies
Degrade antibodies - produce proteases to cleave AB’s
Modify antigenicity - can switch antigen expression to a different variation
Give examples of pathogen recognition receptors (direct) - on neutrophils
TLR receptors - bind to conserved microbial structures
CLEC receptors - bind to microbial carbohydrates
FPR receptors bind to formylated peptides (residues that come off bacteria)
Give examples of indirect neutrophil receptors
1) Fc receptors - bind to antibody opsonised microbes
2) complement receptors - bind to complement opsonised microbes
Give examples of neutrophil receptors invoked in regulating the balanced immune response
Some are activatory (enhance immune cell activity) some are inhibitory (suppress immune cell activity)
Eg
Cytokine recpetors - TNFR/ ILR/ IFNR (tumour necrosis factor receptors, interleukin receptors, interferon receptors)
Chemoattractant receptors - chemoattractants (C5aR, PAFR, BLT1, BLT2)
LILR receptors
SIGLEC receptors
LAIR receptors
CEACAM receptors
Strategies of S aureus neutrophil evasion
1) evade chemotaxis: produce CHIPs which bind to C5aR and FPR on neutrophil to prevent them binding to C5a and FMLP (formylated proteins). This prevents activation of neutrophils and their migration to site of infection
2) evade phagocytosis: produce FILPr which binds to Fc gamma receptors on neutrophil, preventing IgG binding to neutrophil
Produce SSL5 which binds to Fc alpha receptors on neutrophil, preventing IgA binding to neutrophil.
This prevents detection of IgG and IgA opsonised bacteria by neutrophils therefore reduces antibody mediated phagocytosis of S aureus
3) killing neutrophils by producing toxins
4) inhibiting function of neutrophil receptors by producing neutrophil receptor antagonists
Other strategies of bacterial immune evasion
Bind inhibitory receptors
Modify intracellular signalling
Modify bacterial surface
Inhibit effects of anti microbials
What are Koch’s Postulates
How do we know if a particular organism causes disease?
1) found in large numbers in diseased but not healthy individuals
2) can be isolated from the diseased individual and cultured outside
3) if re-injected into a healthy person, it should cause the same disease
4) isolate from this new individual and compare to first strain - they should be identical
What are the main 3 types of viral structures
1) non enveloped —> symmetrical protein capsid
Eg adenovirus, calicivirus, picornavirus
2) enveloped —> lipid envelope derived from host cell membrane
Can be
Pleiomorphic (can change shape): measles virus
Have a typical shape: Ebola virus
3) combination of capsid and envelope
Eg Herpes virus
Describe the basic viral life cycle
Attachment of protein to host cell via specific protein or glycoprotein receptors
Entry of virus
Capsid falls away, exposing the genome
Formation of early regulatory proteins
Formation of late structural proteins
Formation of virion
Exocytosis by budding or cytolysis (host cell explodes, releasing all newly formed viruses)
Describe HIV life cycle
gp120 on HIV binds to CD4 receptor on host T helper cell and then to co receptors CCR5 or CXR4
HIV enters by fusion with membrane, instead of endocytosis
Capsid falls away, exposing genome
Reverse transcriptase converts HIV RNA to doubled stranded DNA
Integrase inserts it into the hosts DNA
Formation of viral proteins by host
Leave by budding
Describe influenza life cycle
Influenza virus has haemagglutinin spike which attaches to sialic acid receptor on host cells
Virus enters cell by endocytosis
Capsid falls away, exposing the 8 segments of the negative sense RNA genome of Influenza
The RNA is converted to mRNA using RNA dependent RNA polymerase
Viral proteins are made use host ribosomes
Cytolytic release (cell breaks) of virions using neuramindase (cleaves the bind between haemagluttinin and host cell receptor, releasing the virus molecule)
Which area of the influenza life cycle are targeted by antivirals
Amantadines block the uncoating of the virus by blocking M2 channels
RNA polymerisation
Neuraminidase inhibitors (leave virus bound to sialic acid)
State 5 methods for viral diagnosis
Detection of
Viral genome - PCR Viral antigens - ELISA Viral particles - electron microscope Viral antibodies - serology Cytopathic effect - isolate suspect virus and place onto cultured cells - see if produces cytopathic effect
What is the cytopathic effect and why does it happen
Cell dies due to infection with virus
Due to either the virus trying to stop the host cell synthesis proteins
Or excessive production and accumulation of new virus particles (causes cell to burst open - cytolysis)
What happens when a monolayer of cells are infected with a virus
Lysis occurs due to shutdown of protein synthesis or virus particles using cytolytic exit
Death of cells causes formation of plaques (clear areas on a layer of cells where the virus killed of the cells) - serial dilutions can be done of viral solutions and the number of plaques each dilution forms can be recorded - can quantify initial viral conc —> “plaque assay”
Or instead of dying, the virus can cause the cells can fuse together forming syncytia. A syncitia assay can also be done to measure how many virus particles you have. Syncitia develop with HIV infection
4 qualities needed for anti viral drugs
CASS Cost - needs to be affordable Administration - easy to administer Safety - most important Strains - does it deal with all the strains
Why do antivirals need a higher specificity than antibiotics
Bacteria are prokaryotes so are completely different to human cells so abs can just target these differences
Viruses however, enter host cells and replicate there using host machinery - so need to be v selective to damage as few of our own cells as possible
What is amantadine, how does it work?
Antiviral for influenza
Sits in and blocks the tetrameric M2 proton channel which would usually have protons passing through as part of the process to uncoat the virus and allow it to enter the cell
Developed by random screening
Is functionally useless now as a single point mutation in the influenza virus gives it resistance. This mutation also doesn’t affect the virus’ fitness so it is rapidly spread through viral populations. Almost every modern flu strand is no resistant to amantadine
What are neuraminidase inhibitors
Antivirals for influenza
Developed by rational dug design - ie using knowledge of structure of influenza virus
Developed to be the shape of sialic acid - hold the neuraminidase so the virus is stuck into the old cell and can’t move onto and infect a new one
Examples
Relenza and Tamiflu
Baloxavir - binds to and inhibits PA endonuclease (subunit of influenza viral RNA polymerase)
What is acyclovir
It is a nucleoside analogue antiviral
Used to treat HSV 1 (cold sores)
It lacks a 3 hydroxy group and so, when inserted into the viral genome, it prevents formation of phosphodiester bond and acts as a chain terminator
Very specific - given in the unphosphorylated form but needs to be in the tri phosphorylated form to work. Only virus infected cells have the thymidine kinase needed to phosphorylate it
Further specificity comes from the fact that acyclovir tri phosphate has a higher affinity for viral RNA polymerase
Resistance is very rare, as the mutation for viruses not to produce thymidine kinase makes them less fit, so it’s not easily spread in the population - poor selection pressure
What is remdesivir
Analogue of adenosine
Causes chain termination 3 nucleotides downstream of where it was incorporated
Developed for use against Hep C
Tested against Ebola but didn’t meet endpoint
Being tested against Covid
State the three main HIV treatments
HAART - highly active anti retroviral therapy
Combination therapy of multiple (3) antivirals - incase your infection develops resistance to one of them
PrEP - pre exposure prophylaxis
Taken by people who have sexual relationships with HIV positive individuals to prevent infection with HIV
the drug used for PrEP is Truvada - a combination of two NRTI’s (nucleoside reverse transcriptase inhibitors)
AZT
Is a nucleoside analogue
Worked to start with but then became ineffective due to resistance - as used only as a single drug
Why is it so important that people have a HIV test before going on PrEP
If the person is infected, they may have a lot of HIV virus in their body already
PrEP is a combination of only 2 drugs instead of 3, so could lead to selection of resistance more easily
What are biologics and give example
Passive immunotherapy
Antibodies taken from recovered individuals or produced from immortalised B cells
(Always end in “mab”)
Eg palivizumab against RSV for infants - a humanised monoclonal antibody against the F protein
Why was relenza not such a successful drug as tamiflu
The chemistry of relenza means it more readily acquires resistance
What is the mechanism of action of tamiflu against influenza
It inhibits the neuraminidase enzyme that removes sialic acid from the infected cell surface and allows onwards spread of the new virus particles
What causes the common cold
Human rhinovirus
Why is making a vaccine against the common cold difficult
Because there are hundreds of different serotypes which are all antigenically distinct
What feature of HIV helps it evade immune response
It exists as multiple different classes/ quazi-species
How do Hep B and Ebola evade immune response
They secrete surface antigens out of them which bind to and mop up antibodies so the antibodies can no longer bind to the virus or to infected cells
How does dengue virus evade immune response
Has 4 serotypes and carries out antibody dependent enhancement (binding of viruses to suboptimal antibodies enhances their entry into host cells)
This leads to dengue haemorrhagic fever when you are infected with 2 serotypes (second virus serotypes notes cells via antibodies to first virus serotype)
How does influenza virus evade immune response
Mutation - antigenic drift (over time, accumulation of mutations) Antigenic shift (sudden recombination - happens with zoonotic infections)
What are interferons, when are they released and what are the different types
Small proteins released by virus infected cells
Initiate the antiviral state in infected cells and surrounding cells - protein kinase R, 2’5’ oligoandenylate synthase, activate NK cells
Types:
Type I = IFN Alpha and beta
Type II = IFN gamma
Type III = IFN lambda
Which viruses block production of interferons
Hep B : inhibits IFN transcription
Influenza : produces NS1 protein which counters RNA sensing and prevents poly A processing
What do dendritic cells do
Are antigen presenting
Produce interferons and cytokines
Initiate and determine the nature of CD4/8 T cell response
What class of antiviral drugs is found in PrEP
Nucleoside analogue reverse transcriptase inhibitors
What does MRSA acquire to be able to resist beta lactam antibiotics
PBP 2a (gene which encodes beta lactamase)
what are antigens
Molecules, mostly proteins, which are recognised by highly specialised lymphocyte receptors and act to induce an adaptive immune response
What initiates the adaptive immune response
Antigens (corresponding to a pathogen) encountering B or T lymphocytes which have receptors with specific reactivity
3 hall marks of adaptive immune response
Immunological memory
Long lasting protection
Highly specific
How is diversity generated in the adaptive immune system
Immunoglobulin gene rearrangement
During B cell maturation in bone marrow, the gene segments are rearranged
Problem with random process of gene rearrangement
Possibility of generating receptors which react against self antigens - autoimmunity
Differences between T and B cells
T cells mature in thymus, B cells in bone marrow
T cells are inside lymph nodes, B cells stay outside lymph nodes
T cells must respond to antigen presentation (antigen + MHC of antigen presenting cells), B cells can respond directly to antigens that have drained into the lymph nodes
T cells are to do with killing things, B cells are to do with antibodies
How do T cells differentiate and what can they differentiate into
Antigen binds to T cell receptor - cell proliferates and divides into
1) Cytotoxic T cells: kill infected cells or intracellular pathogens
2) Helper T cells: provide signals, often in the form of specific cytokines, that activate the function of other cells eg B cells to produce antibodies, macrophages to kill engulfed pathogens
3) Regulatory T cells: suppress activity of other lymphocytes, help to limit possible damage of immune responses
How to differentiate T helper and killer cells
CD4 receptor = T helper cell
CD8 receptor = T killer cell
What do T helper cells produce
Cytokines
Describe the function of Th1 cells
Macrophages, inflammation, B cell class switching
Produce IFN gamma, TNF, IL12
Act against microbes which can survive or replicate inside macrophages - recognise bacterial antigens on surface of macrophage and release IFN gamma which further activates the macrophage and enables it to destroy the intracellular pathogen more efficiently
Pro inflammatory
Promotes B cell class switching that favours IgG production
Describe the function of Th2 cells
Allergies and worms
Produce IL4/5/13 Help control infections from extra cellular parasites such as helminths by promoting responses involving eosinophils, mast cells and IgE Cytokines produced by secondary response are required for B cell class switching to produce IgE - fights parasitic infections and allergies
Describe function of Th17
Neutrophils, bacteria, fungi
Produce IL 6/17/23
Induces in response to extra cellular bacteria and fungi
Amplify neutrophilic responses to these
Describe function of TFH (follicular helper)
B cell support
Produce IL21
Interact with B cells to regulate antibody production
Describe function of Th0/Treg
no immune response
Produce IL10 and TGF beta
Anti inflammatory
Limit immune/T cell response
How do T helper cells contribute to B cell activation
Effector T cells express surface molecules and cytokines that help B cells differentiate into plasma cells or memory cells
The interaction of the antigen stimulated B cell with the T helper cell determines the fine tuning of the antibody response (increasing affinity of antibody for antigen) and class switching to most immunoglobulin classes other than IgM - B cells that haven’t been stimulated by binding to T helper cells can only produce IgM (IgM is not very specific, so T cell biding is v important)
How do CD8 T cells kill pathogens/infected cells
Apoptosis (programmed cell death) by fragmentation of nuclear DNA
Initiate lysis through pore creation:
Store perforin, granzymes, granulysin in cytotoxic granules
Release granules after target recognition
Perforin molecules polymerise and form pores in the pathogen/infected cell
Granzymes then travel through pores and stimulate the apoptosis inside the cell
Describe structure of T cell receptor
Top = variable region
Bottom = constant region
Part that inserts into T cell = cytoplasmic tail
What is an epitope/antigenic determinat
Small portion of the antigens structure which is recognised by the antigen receptor or antibody
(Has MHC on it)
Difference between MHC I and MHC II
MHC I
present on all nucleated cells (SO NOT RBCs)
Has a single variable alpha chain and a common beta micro globulin
MHC II
Only on professional antigen presenting cells
Has 2 chains - an alpha and a beta chain
What are MHC made of
Glycoprotein
Which antigen presenting cells can MHC II be found on
Dendritic cells
Macrophages
B lymphocytes
How does MHC interact with T cell receptor? Describe the differences between the interactions of MHC I and MHC II
Antigen from the pathogen/target (infected) cell is presented on MHC I to CD8 T cell - saying that it needs to be killed
Antigen from professional antigen presenting cell is presented on MHC II to CD4 T cell - to get it activate and initiate the immune response
Role of CD8 T cells
Scan cells, looking for MHC I showing non self (in uninflected cells, MHC I shows self peptides)
- antigens derived from viruses or bacteria replicating inside of an infected cell are displayed on the cells surface by MHC I
Role of CD4 T cells
Recognise antigens presented by MHC II proteins (expressed by antigen presenting cells: dendritic cells, macrophages, B cells)
- recognise antigens taken up by phagocytosis from extra cellular environment
How is MHC expressed
Co dominant - both maternal and paternal genes are expressed
Explain why, with reference to MHC, organ transplants can fail
Cells from transplanted organ are very likely to have different MHC a than your self cells
So your immune system recognises them as non self and will attack the transplanted organ
Give 2 properties of MHC that make it difficult for pathogens to evade immune response
MHC is
1) polygenic: there are several different MHC I and II genes
2) highly polymorphic: there are multiple alleles/variants of each gene
What are B cell receptors
Surface bound antibodies
What are the two ways that B cells can be activated/begin antibody production
Thymus dependent pathway:
- BCR recognises thymus dependent antigen
- antigen is internalised and degraded and expressed with MHC II on surface
- antigen MHC II complex is recognised and bound by CD4 T helper cell
- B cell is activated and produces antibodies (B cell undergoes class switching, produces IgG antibodies rather than IgM)
Thymus independent pathway:
- induces antibody production in the absence of helper T cells
- first signal from thymus independent antigens: highly repetitive molecules eg polysaccharides of bacterial cell walls
- second signal from microbial PAMPs eg LPS (activate TLR signalling in B cell)
- only leads to IgM production and no memory
*note that thymus dependent actually has nothing to do with your thymus, it really means T cell dependent
What happens once B cells are activated
Clonal selection (of specific B cell to that antigen) and clonal expansion
How are antibodies classified
There are 5 types IgM IgD IgG IgA IgE And 5 classes of each type - the classes are denoted by lower case Greek letters and are defined by the structure of the antibody’s heavy chain Mu Delta Gamma Alpha Epsilon
Someone has just been infected, what antibody do you expect to see
IgM (it’s the first antibody produced)
Which antibody is the best at opsonisation and neutralisation
IgG
Which antibody is the least specific and has the lowest affinity
IgM
Which antibody is involved in allergy
IgE
Which antibody is expressed in mucosal tissues
IgA
Describe the structure of an IgG antibody
Consists of 2 heavy chains and 2 light chains
The heavy chains are joined to each other by disulphide bridges and each heavy chain is joined to a light chain by a disulphide bridge
Their is a variable region (Fab region) and a constant region (Fc region)
There are glycosylation sites on the Fc region
There are 2 identical antigen binding sites
Two types of light chains in antibodies (lambda and kappa) - will never have both in the same antibody
3 core functions of antibodies
Opsonisation - for bacteria in extra cellular space: antibodies coat a bacterium to better enable phagocytosis by macrophage or neutrophil. Fc receptor on phagocytic cell binds to Fc region on antibodies and ingests the complex
Neutralisation - for bacterial toxins: antibodies bind to viruses/bacterial toxins and block their entry into cells - preventing infection and destruction of other cells, this complex is then ingested by macrophages
Complement activation - for bacteria in plasma: antibodies coat bacterial cell . This stimulates complement proteins and therefore stimulates complement receptors on macrophages. Bacterium is lysed by MAC and ingested by macrophage
Someone is suffering from an autoimmune disease causing vasculitis, increasing the number of which T cell could help?
Treg (decrease immune response, this is needed when the immune system is overactive)
A B cell was producing IgM but is now producing IgG. What has occurred
Class switching (Producing IgM due to thymus independent activation - by antigens going straight into the lymph nodes. Dendritic cells then present antigens to the T cells, activating the T cells. These activated T cells then cause thymus dependent activation of the B cells, which causes class switching)
What is the process by which B cell receptor diversity is generated
Immunoglobulin gene rearrangement
What type of immunity does vaccination provide
Artificial active
List features of an ideal vaccine
Safe Cheap Easy to administer Single dose, needle free Stable Active against all variants Life long protection
What is herd immunity
The more immune individuals there are, the less likely it is that a susceptible person will come into contact with someone who has the disease (to do with reducing the R0 number)
What is R0, what does it mean if R0 is <=> 1
The number of people an infected person goes on to infect
R0 < 1 : the infection will die out in the long run
R0 = 1 : each infected person passes disease to one person
R0 > 1 : disease spreads exponentially in population
Aim is to reduce it to below 1
What is found in a vaccine
Antigens : stimulate the immune response to the target disease
Adjuvant (normally alum) : enhance and modulate immune response (by replicating the danger signals needed to stimulate dendritic cells)
Excipients : inactive vehicle or medium for the vaccine
- buffer, salts, saccharides and proteins - maintain pH and osmolarity
- preservatives
- water
What are the 5 different types of vaccines and give examples
Inactivated protein : tetanus toxoid
Dead pathogen : Split Flu vaccine , Hep A
Live attenuated pathogen : OPV(Polio) / BCG / LAIV(influenza) / chickenpox / MMR
Recombinant protein : Hep B
Carbohydrate : S pneumoniae
Carbohydrate is a carb that the pathogen specifically produces
Recombinant protein is made synthetically to replicate pathogen
What kind of protein is the polio vaccine
Live attenuated pathogen
What kind of vaccine is tetanus toxoid
Inactivated protein
What kind of vaccine is S pneumoniae
Carbohydrate
What are inactivated protein vaccines and how do they work
Chemically inactivated form of toxin
Induces antibody, antibody binds to toxin and blocks it from binding nerves
What are the pros and cons of inactivated protein vaccine
Pros Cheap and simple to make Relatively safe High protective efficacy Highly immunogenic - stimulates immune response v well
Cons
Not all pathogens produce toxins
Need a good understanding of the toxin produced
Toxin may not be fully inactivated
What are lives attenuated vaccines and how do they work
Contain a mutation which prevents them from causing disease but can still replicate and be recognised by host immune system as foreign
Pros and cons of live attenuated vaccines
Pros
Replicate so a small dose is needed
Strong immune response - life long immunity
Induce a strong local immune response in the site where the particular infection is most likely to occur
Cons May lose key antigens on attenuation May develop virulent factors Can infect immunocompromised Can be outcompeted by other infections
What are dead pathogen vaccines and how do they work
Pathogen is killed either chemically (phenol or formaldehyde) or by heating
Antigenic components are still intact so can initiate B or T cell response
Pros and cons of dead vaccine
Pros
Effective in stimulating an immune response
Cheap
Simple
Cons
Antigen can be altered or destroyed in inactivation
Need to grow live pathogen which can contaminate the vaccine - risk of vaccine induced pathogenicity
How do recombinant protein vaccines work
Immune system generates neutralising antibodies against the antigens
Pros and cons of recombinant protein vaccines
Pros Pure Safe Good immune response Low strain variation
Cons
Expensive
Protein structure may not be exactly the same
How do conjugate vaccines work
Same as carbohydrate vaccines
Polysaccharide coat component is coupled to an immunogenicity carrier
This protein stimulates a T cell response via CD4 which improves B cell immune response
Pros and cons of conjugate vaccine
Pros
Improves immunogenicity
Highly effective against infections by encapsulated bacteria
Cons
Expensive
Strain specific
Carrier protein may interfere with immune response
What is an adjuvant
Substances used in combination with a specific antigen that provide a more robust immune response than using the antigen alone
How do adjuvants stimulate a more robust immune response
Activate dendritic cells, which then present the antigens to T cells
Extra info: not that important
(Potentate immune response by interacting with PAMPs and DAMPs which causes the cell to release inflammatory mediators. These are recognised by pattern recognition receptors on T cells)
Why do we need new vaccines
Changing age demographics Changing environments (disease moving to different parts of the world) Antibiotic resistance New viruses Old diseases we still can’t fix
Barriers to vaccine production
Scientific challenges
Infection safety
Logistics
Development issues - time / cost of vaccine development / cost of product
Public expectation of a risk free vaccine
Nancy is allergic to eggs and can’t have the flu vaccine. However she does not get flu. What could most likely explain this?
Herd immunity
What are primary lymphoid tissues
The sites where new lymphocytes are made - lymophopoesis
What are the cells of the lymphoid lineage? And what cell type are they all derived from
B, T and NK cells
All derived from common lymphoid progenitor cells
Which are derived from HSCs - multi potent haematopoietic stem cells
What are the primary lymphoid tissues
Bone marrow and thymus
(B and T cell populations originate in bone marrow. B cells complete most of development there but T cells migrate to the thymus, where they complete development)
Which cells mature in the bone marrow and which part of it
B cells
Bone marrow has yellow centre (fat) and red around that where haematopoiesis occurs
List the sites of haemopoiesis in foetus and adult
Foetus
Liver
Spleen
All bones
Adult
Mostly flat bones: iliac bones, vertebrae, ribs
What 2 selection processes do T cells undergo in the thymus
Positive selection: testing if the T cell receptor can signal/respond to an MHC (does it work positively ?)
Negative selection: testing if the T cell reacts against our own body (making sure it doesn’t work negatively)
(This is Central T cell tolerance!!)
How does the thymus output and the thymus itself change with age
Thymic output declines with age
Thymus itself degenerates - thymic involution occurs (shrinking and structural change of thymus with age) and functional tissue is replaced with fat
How does the number of peripheral T cells change with age
Remains the same
Number of peripheral T cells is maintained by the division of mature T cells outside the central/primary lymphoid organs
But this means you get less variety as fewer cells come from new lineages - so older people are more vulnerable to a new strain of pathogen
What happens to 1) thymus and 2) bone marrow during infection
1) no change to thymus (because this isn’t where the lymphocytes are interacting with the antigens)
2) increased white cell production
Most changes will happen in secondary lymphoid tissues
What are secondary lymphoid tissues
Where lymphocytes can interact with antigens and other lymphocytes
Name the secondary lymphoid tissues
Lymph nodes Spleen Epithelial barriers Gut associated lymphoid tissue Tonsils
Where are lymph nodes in the lymphatic system
At the point of convergence of vessels of the lymphatic system
Immunological function of spleen
Collects antigens from blood and is involved in immune response to blood borne pathogens
Lymphocytes enter and leave spleen via blood vessels
Describe the structure of the spleen
Majority of the spleen is red pulp - where haemopoiesis occurs
Arterioles run through the spleen and lymphocytes surround these arterioles, forming white pulp
This sheath of lymphocytes around an arteriole is called the periarteriolar lymphoid sheath (PALS) and contains mainly T cells
Lymphoid follicles occur at intervals along the sheath, containing mainly B cells
Which tissues are first line of defence against infection and how are they protected by immune system
Epithelial/mucosal surfaces eg skin
Protected by secondary lymphoid tissues - MALTs ( mucosa - associated lymphoid tissues
Skin can have cutaneous immune system
Give an example of a MALT and list it’s locations in the body
Gut associated lymphoid tissues
Includes tonsils, adenoids, appendix, peyers patches (in small intestine)
Describe the structure and functions of Peyers patches
A peyers patch contains numerous B cell follicles which contain germinal centres
T cells occupy the areas between the B cell follicles
Antigens are collected directly from the gut by specialised elithelial cells - M cells
Dendritic cells in the peyers patch present the antigens to T cells
Effector lymphocytes generated within the peyers patch travel through lymphatic system and into blood stream
They are disseminated (spread) back into mucosal tissues to carry out their effector actions
Summarise the cutaneous immune system
Langerhans cells (type of dendritic cell) Keratinocytes Intraepidermal lymphocytes T lymphocytes Tissue resident macrophages
How are the tonsils organised
Lingual tonsil (on bottom behind tongue) Palatine tonsil (on sides) Tubular tonsil Pharyngeal tonsil (on top)
All form the Waldeyer’s ring
Summarise the mechanism by which spleen, MALTs and lymph nodes operate
Trap antigens and antigen presenting cells from infected areas and present them to small lymphocytes to initiate adaptive immune response
Where do mature naive lymphocytes go when they are produced
Enter the blood stream and continuously circulate peripheral lymphoid tissues
Eg
lymph nodes
Spleen
Mucosal lymphoid tissue of gut, nasal, resp, urogenital tracts
Lee is infected with hepatitis, a blood borne pathogen. Which specific tissue will be most involved in the immune response?
Spleen
Lilia has an upper resp tract infection. What will happen to her submandibular lymph nodes
Increased size
Kyle is developing a vaccine against S aureus. What two barriers may he face (2)
Cost of production
Ease of administration
Staph aureus is a toxin producing bacteria. Based on this, what is the most appropriate type of vaccine for Kyle to develop?
Inactivated protein vaccine
Kyles vaccine is shown to be effective. A month after vaccination, they can produce an immune response. What cells are responsible? (2)
B and T cells
What processes have these cells undergone to produce this immune response a month later (2)
Clonal expansion and Clonal selection
Suggest where these immune cells may have encountered the antigens in the vaccine? (1)
Lymph node (or any secondary lymphoid tissue eg spleen)
Jeremy does not want to receive kyles vaccine. Can he be forced to receive it? Why and why not? (2)
No he cannot be forced
He has bodily autonomy
What makes the spleen so good at filtering antigens from the blood
Highly attached to the arterial circulation via the splenic artery
So it can filter blood rapidly and in large numbers
List 3 primary lymphoid organs
Thymus
Bone marrow
Foetal liver
Define a germinal centre
An anatomically restricted site where B cells undergo maturation and selection to generate high affinity antibodies
2 main steps in the extravasation of naive T cells into lymph nodes
Selectin binding
Integrin binding
Describe how lymphocytes get into lymph nodes
1) rolling along endothelial surface of HEVs (High endothelial venules)
Mediated by L selectin and CD34 (selectins)
2) activation of integrins
Mediated by CCL21(chemokine)
3) firm adhesion
Mediated by LFA-1 and ICAM-1(integrins)
4) Diapedesis into paracortical areas/ T zones
Mediated by CCL21 and CXL12 (chemokines)
Define antigen presentation
The display of peptides on MHC I or MHC II proteins such that the T cell receptor can attempt to bind them
How do antigens go from site of infection to secondary/peripheral lymphoid tissues, where they can activate lymphocytes
Professional antigen presenting cells - dendritic cells
Or
Flow of antigens by themselves into lymphatic system
Describe in detail how dendritic cells pick up antigens from the site of infection
Activation of dendritic cells’ PRRs (pattern recognition receptors) by PAMPs at the site of infection stimulates the dendritic cells in the tissues to engulf the pathogen and degrade it intracellularly
They also take up extra cellular material eg virus particles and bacteria - “macropinocytosis”
Describe the transport of lymphocytes and antigens in the lymphatics and blood stream
Free antigens and antigen presenting dendritic cells travel from site of infection through afferent lymphatic vessels into the draining lymph nodes
Here, activated T cells undergo proliferation and differentiation and leave via efferent lymphatic vessels
This carries them to the blood stream and towards the tissues where they will act
How does an immune response start
Detection of tissue damage - DAMPs (damage associated molecular patterns) eg DNA outside of cell
Detection of pathogenic structures - PAMPs (pathogen associated molecular patterns) eg peptidoglycan from bacterial cell wall
This initiates the innate / non specific immune response
These cells than communicate with adaptive immune cells
After some time, adaptive immune response is initiated
How does an infection stop
After a pathogen is cleared, some of the immune cells undergo apoptosis due to reduced signals to them
Therefore there is reduced production of inflammatory cytokines
The cell population “contracts” (ie shrinks in size) and some of the remaining cells form memory cells
Tissue repair and remodelling occurs
Innate immune cells have germline encoded receptors. What does this mean?
All cells of one lineage have the same receptors
What are the three main sections of innate immune system
Physical barriers
- skin
- mucous
- epithelial cells
Humoral barriers
- mediated by liver
- lectins: bind to specific bacterial carbohydrates, neutralise and opsonise pathogens for destruction
- iron chelation proteins: prevent formation of favourable environment for bacteria
- complement system :
Anaphylatoxins (increase vascular permeability)
Chemokines (attract immune cells to site of infection through conc gradients)
Opsonisation (by complement or antibodies, sets a pathogen up for phagocytosis)
Membrane attack complex - MAC
Cellular barriers - granulocytes: Neutrophils Basophils Eosinophils Mast cells Monocytes Macrophages NK cells (only innate lymphocytes) Dendritic cells
Which immune cells are the first responders
Neutrophils
Followed by macrophages
What are naive cells
Inactive cells
Haven’t yet come into contact with pathogen/antigen for which they have a specific receptor
Where are macrophages found
Are either tissue resident or circulatory
How do macrophages develop
From monocytes - monocytes circulate in the blood for a few days and then go back into tissues and become macrophages
What do activated macrophages display
Enhanced: Phagocytosis and migration Cytokine/chemokine production Expression of cell surface molecules Anti microbial activity Antigen presentation and T cell activation
What are interferons
Interferons are secreted by immune cells and non immune cells (infected cells) in response to intracellular infection - ie by viruses or gram negative bacteria
The interferons signal surrounding cells to produce proteins which stop the immune infection
Eg type 1 and 3 interferons promote antiviral responses
type 2 interferons promote anti bacterial response
What do antiviral genes include
Nucleases
Inhibitors of viral entry and exit
Inhibitors of viral uncoating and replication
Inhibitors of protein translation
Describe the evolutionary interplay between NK cells and viruses/cancer cells surrounding MHC I
Virus and cancer cells can evade detection by MHC I - could stop host cell producing it
So NK cells will kill all cells that do not express MHC I as the reason for this could be a viral infection or cancer
Describe the 2 parts of the adaptive immune system
Humoral immunity:
- antibodies
- complement (stimulated by antibodies via classical pathway)
Cellular immunity:
- cytotoxic T cells
- T helper cells
- T regulatory cell
- B lymphocytes
- Plasma cells
What are the 2 receptors involved in the adaptive immune system
TCR
BCR (which is basically a surface bound IgM receptor)
There are millions of variations of these but they need to be tested against self antigens first to make sure they don’t cause autoimmunity
The selected ones will undergo Clonal expansion and all cells of the same clonal lineage will have the same receptor
Where are memory cells found
In lymphoid tissues
- lymph nodes/ spleen/ GI mucosa/ mucosal epithelia/ bone marrow
And
In the circulation
- memory T cells can constantly migrate to and from lymphoid tissues
- memory B cells can differentiate into plasma cells which secrete abs into blood
How are T cells activated
MHC II + antigen complex from professional APC
Describe the positive feedback loop between APCs and T cells
When APCs bind to T cells they activate them by producing cytokines eg IL-12 which causes T cell replication
In response to this, T cells produce cytokines that activate the APCs eg IFN-gamma which upregulates MHC-II expression for antigen presentation
4 functions of T cells and which T cells do each function
Activate phagocytes: T helper cells
Activate B cells: Follicular T helper cells
Directly kill infected cells: cytotoxic T cells
Regulate immune response: T helper cells
2 main functions of B cells
Can function as APCs - present soluble antigens to T cells
Produce antibodies by differentiating into plasma cells
What are the target cells of Th1/2/17 cells?
Th1: macrophages - macrophage activation against intracellular pathogens
Th2: eosinophils - eosinophil and mast cell activation against helminths
Th17: neutrophils - neutrophil activation against extracellular bacteria and fungi
Describe what happens to a T cell during its life
Naive T cell - hasn’t encountered its particular antigen
Effector T cell - during the infection
Memory T cell - after the infection
Describe what happens to the number of naive and memory T cells during a persons life and explain why
Level of Naive T cells goes down
Level of memory T cells goes up
Because as someone ages they get thymic involution and the thymus stops producing naive T cells
And also as you age and encounter more pathogens, more of the remaining naive T cells will change into effector and then memory T cells
Describe the innate immune response and its transition into adaptive immune response
Innate immune cells recognise that there is a pathogen and become activated
They secrete cytokines (to recruit adaptive immune system) and phagocytosis the pathogens
The APCs travel into secondary lymphoid tissues where they encounter naive lymphocytes and activate them
The lymphocytes proliferate and differentiate into a specific type (type is based on the specific cytokines secreted by the phagocytes)
The activated lymphocytes can then start the cellular and humoral respond of the adaptive immune system
Why are some vaccines given in 2 doses
Because after RE-exposure, the plasma cells will continue to secrete protective serum antibodies - so the antibody level in the serum after the second infection will be higher than after the first infection - after first infection, level of antibodies returns back to normal level
Is this statement true or false and why
“MHC II can be read by T cells, whereas MHC I cannot”
False
MHC I can be read by cytotoxic T cells whilst MHC II can be read by T helper cells
Is this statement true or false
“MHC II shows pathogen peptides, MHC I shows own peptides”
False
MHC I can also show pathogen peptides if the cell has been infected
Is the statement true or false
“MHC I is on all cells whereas MHC II is only on APCs”
False
MHC I is on all NUCLEATED cells
Can B cells be APCs
Yes but it’s not their main function
APCs are mostly macrophages and dendritic cells
State 3 consequences of reduced immune function
Reduced removal of pathogens/ unwanted cells
Opportunistic infections
Cancer - cancerous cells will evade immune response and apoptosis
What is a consequence of increased immune function and what can trigger it
Can cause hypersensitivity- immune system attacks own tissues
Can be triggered by
- infection
- environmental factors
- female predisposition
- genetic factors
- hygiene hypothesis (we have such good hygiene nowadays that our immune system encounters much less pathogens than it used to, so instead it reverts to attacking our own tissues)
How are immune mediated inflammatory diseases a positive feedback loop?
Immune system causes damage to self tissues
Damage to tissues produces more of the signals/antigens that recruit immune cells
This drives an even stronger immune response
Complications of exaggerated immune response
Sepsis - immune cells enter the wrong compartment of the body, causing organ dysfunction there
Hypercytokinaemia (cytokine storm) - body produces too many cytokines, can cause organ dysfunction and sepsis
Organ dysfunction- can be due to cytokine storm and sepsis or can be directly due to autoimmune diseases eg type 1 diabetes, Hashimotos
Fatal damage to tissues - eg in MS, ALS (autoimmune diseases of nervous system)
How is over activation of immune cells prevented
Licensing of the immune response
What 3 signals do T cells need to be activated
Antigen (which they are specific to, on MHC I for cytotoxic or II for helper)
Costimulation (via receptors on APCs)
Cytokines (from immune or infected cells)
What happens to immune cells after the antigen has been cleared and they are no longer exposed to it and why. What is the problem with this
Apoptosis - prevents auto immunity
The problem is that antigens from damaged self tissue will remain in the body for a long time, until the tissue from which they are derived is completely destroyed. So the immune system needs to have a way to limit the immune response to these persistent antigens (break the positive feedback loop) - basis of immune tolerance
What is immune tolerance
The specific unresponsiveness to an antigen that is induced by the exposure of lymphocytes to that antigen
What could be the benefits of restoring tolerance
Could treat auto immune or allergic diseases
Could make organ transplants more successful
2 types of immune tolerance
Central tolerance - destroys self specific T and B cells before lymphocytes enter circulation. B cells destroyed in bone marrow, T cells destroyed in thymus
Peripheral tolerance - after lymphocytes enter circulation
Describe B cell central tolerance
If the IgM antibodies on the surface of B cells produced in the bone marrow bind to and react with antigens on the stromal cells of the bone marrow, they undergo apoptosis as they are auto reactive
Describe T cell central tolerance
T cells shouldn’t bind to MHC when there is no antigen presented or when the antigen presented is not one that they are specific to
So T cell tolerance has 2 stages
1) positive selection: does T cell bind to MHC at all. If not, apoptosis
2) negative selection: does T cell react to self antigens and MHC too strongly. If yes, apoptosis
If T cells are developed in the thymus, how are they exposed to antigens from all over the body to ensure they aren’t auto reactive against any of them in negative selection?
Thymic cells express a transcription factor called AIRE
This allows them to express antigens found on cells that aren’t in the thymus
What can cause autoimmune multiendocrinopathy
It is a very severe systemic autoimmune disease due to mutations in the AIRE gene
So T cells aren’t exposed to antigens from other parts of the body during their development, thus affects the negative selection process so some auto reactive T cells can be released
Some auto reactive B and T cells may escape central tolerance. How are these picked up
Peripheral tolerance
Why is peripheral tolerance esp important for B cells
B cells undergo somatic hyper mutation - “affinity maturation”
When a B cell is activated and selected it will undergo clinal expansion by mitosis.
The mitosis/replication of the variable/Fab region of the antibody/receptor on the B cells is made to be prone to mistakes
This is to allow for receptors with higher affinity to the antigens to be made (as well as those with lower affinity)
Only those with higher affinity will survive
This allows for B cells with higher affinity to the antigen to be produced
A problem with this is that some pathogenic antigens are very similar structures to self antigens
So affinity maturation could produce B cells which could be auto reactive against self tissues and cause systemic immune response
These need to be inactivated by peripheral tolerance
What is infective endocarditis caused by
Anti ‘streptococcus pyogenes’ antibodies can cross react with heart muscle and cause infective endocarditis
How do T cells differentiate into T helper or cytotoxic T cells
During positive selection
If they bind more strongly to MHC I, they become CD4 T helper cells
If they bind more strongly to MHC II, they become CD8 cytotoxic T cells
List the different types of peripheral tolerance
Anergy
Ignorance
Deletion/AICD (antigen induced cell death)
Regulation
Describe the anergy type of peripheral tolerance
Anergy is when a T cell can encounter it’s specific antigen but without co stimulation - “unresponsiveness to self antigens”
These cells, esp naive T cells, became anergic, ie they become less and less responsive, even if a later antigen with costimulation is encountered
Also occurs at the end of an immune response
Describe the ignorance type of peripheral immune tolerance
Can happen in 2 ways
1) T cells that encounter antigen in levels lower than the threshold response, will eventually either become anergic or undergo apoptosis
2) Naive T cells, that could potentially be self reactive, are kept out of important “immunopriveliged” sites eg in brain/eye/ genitalia (where you don’t want an auto reactive inflammatory response)
This is either by
- “compartmentalisation”: anatomical barriers preventing migration
Eg in testes
Or
- Anti inflammatory cytokines and apoptotic signals
Eg in brain
Also occurs at the end of an immune response
Describe the deletion/AICD type of peripheral resistance
T cell binds to APC, but instead of being activated by this, it is signalled to undergo apoptosis
This is induced by “Fas ligand” (FasL)
This reduces the number of auto reactive T cell
This also occurs at the end of an immune response to normally to T cells that are normally functioning, but you want to get rid of them after an infection
Describe the regulation type of peripheral tolerance
Carried out by regulatory T cells
Reg T cells bind to self antigen but don’t kill them as a response
They upregulate transcription factor Fox P3 which helps them develops into mature Treg cells
What happens if you are born with a mutation in the FoxP3 gene
Develop IPEX syndrome:
- immune disregulation/ polyendocrinopathy, enteropathy X-linked IPEX
Why are Treg cells only found in mammals
During pregnancy, mothers are exposed to their foetus’ cells which have a different MHC I
But their immune system must make sure they don’t launch an immune response against the foetal cells
Treg cells control this
What are the two types of regulatory T cells
Natural regulatory T cells (nTreg) - develop in thymus, reside in periphery
Inducible regulatory T cells (iTreg) - develop during T cell immune response
3 main functions of regulatory T cells
1) inhibit APC receptor expression
- affects costimulation etc
2) release anti inflammatory cytokines (IL-10, IL-35, TGF beta)
- blocks release of pro inflammatory cytokines
- stimulates expression of inhibitory ligands on APCs so cells that come into contact with the APCs become inactivated
3) mop up inflammatory cytokines
Describe the roles of IL10
Master regulatory cytokine
Is pleiotrophic ie has many functions
Inhibits production of pro inflammatory IL6/8, IFN gamma, TNF
Inhibits macrophage function
Some viruses will mimic IL10 in order to escape the immune system
What is the role of cytokines in lymphocyte differentiation
Once T helper cells have developed into different subtypes, they secrete specific cytokines
These cytokines drive more production of the T helper cell subtype that released them, but down regulate/ have inhibitory effects on the formation of other T helper cell subtypes
What is the main role of follicular T cells
They provide the link between the cellular and humoral immune response by activating naive B cells to become plasma cells, through interaction between TCRs and MHC II
Describe the interaction between Tfh cells and B cells that act as APCs
B cell internalise antigen and presents it on MHC II to Tfh
Costimulatory binding of CD40 on Tfh to CD40L on B cell - activate the B cell
Costimulatory binding of CD28 on Tfh to B7 on B cell - activate the T cell
Tfh then starts to secrete IL21 which amplifies B cell activation
What determines the type of antibodies that B cells produce
The interleukins secreted by the particular T helper cell
What feature if antibodies allows for Fc recognition
Different antibody classes (eg IgE vs IgA) have different constant regions
What is not a function of T follicular helper cells
1) activate B cells that present antigens on MHC complexes
2) determine the antibody class produced
3) provide the link between the cellular and humoral immune response
4) produce IL21 to stimulate B cell activation
2 The interleukins, secreted by the T helper cell that regulates the whole response, determines the antibody class produced
Which type of hypersensitivity is immediate
Type 1
How can you test for allergies
Skin prick test, checking for wheal and flare reaction to specific known allergens
Describe Type 1 hypersensitivity reactions
Immediate and mediated by IgE against environmental allergens
Two phases
1) sensitisation
Early phase (within minutes):
Leads to formation of Th2 cells (which recruit eosinophils) and follicular T helper cells specific to the allergen
The Tfh cells secret IL4 and 13 which causes B cells specific to the allergen switching from IgM to IgE production
IgE is immediately taken up and loaded onto cell membranes of mast cells and basophils through their Fc epsilon receptors
When the allergen is encountered again and a second antibody binds to the mast cell/
The 2 IgE antibodies cells cross link and this causes the mast cells/basophils to degranulate as they have been sensitised to the antigen
2) re exposure leading to anaphylaxis
They release inflammatory mediators, causing the hypersensitivity reaction at much lower antigen conc than normal immune reactions
Later response (within a few hours) :
Recruitment of neutrophils
Late response (within 3-4 days):
Eosinophils are recruited and Th2 cells are present
Name the inflammatory mediators released by basophils and mast cells after degranulation in type 1 hypersensitivity
Histamine: vascular permeability and smooth muscle constriction
Cytokines: recruit and mediate immune response
Leukotrienes and prostaglandins: vascular permeability and smooth muscle constriction
Proteases: break down ECM
Why can repeated allergic reactions lead to cancer
One of the inflammatory mediators released is proteases which break down ECM, constant breaking down and building up can cause cancer
How can anaphylaxis be treated
Adrenaline injection - because histamine released during the hypersensitivity causes increased vascular permeability and decreased blood pressure, adrenaline counteracts thus by causing vasoconstriction
Antihistamine
Put patients feet up - maintain blood perfusion
Why do patients who have had anaphylaxis need to be kept in hospital overnight
They could get a second anaphylaxis reaction even after they are stable - called “biphasic anaphylaxis”
Describe Type 2 Hypersensitivity
IgG or IgM mediated cytotoxicity reactions against either self antigens (self reactive B cells are activated by self reactive T helper cells) or foreign/extrinsic antigens bound to cell membranes
In Type 2, the antibodies are tissue specific, rather than systemic
Antibodies can cause disease by
1) ADCC - antibody dependent cell-mediated cytotoxicity
This can happen by 4 cytotoxic mechanisms, the first 3 use the classical complement pathway
Cytotoxic Mechanism 1
- antibodies bind to antigen on cell membrane and induce classical complement pathway
- this recruits neutrophils to the site
- the neutrophils degranulate, killing the cell
Cytotoxic Mechanism 2
- antibodies bind to antigens on the cell membrane and induce the classical complement pathway
- this leads to the formation of MAC which kills the cell by creating pores and inducing apoptosis by osmotic overload
Cytotoxic Mechanism 3
- antibodies bind to antigens on the cell membrane and induce the classical complement pathway leading to the formation of C3b
- C3b binds to Fc portion and acts as an opsonin around the cell - cell is now opsonised by ABs and C3b
- macrophages in the spleen phagocytose the opsonised cell
Cytotoxic Mechanism 4
- antibodies bind to antigens on the cell membrane
- NK cells recognise the Fc portion of the antibody and release toxic granules containing perforin and granzymes + granulysin
The perforin creates pores like MAC
The granzymes + granulysin induce apoptosis
2) Anti receptor activity (non cytotoxic mechanism)
Antibodies bind to antigens bound to cell membrane
and either block the receptor so other substances can’t bind (eg in Myasthenia Gravis, abs bind to Ach receptor)
Or abs activate the receptor themselves, leading to over activation (eg in Graves’ disease, abs bind to receptor on thyroid causing hyperthyroidism)
What is the difference between type 2 and 3 hypersensitivity
In type 2, self reactive antibodies bind to antigens on cell surfaces
In type 3, the antigens are soluble and are just floating around by themselves in the circulation
In type 3, complement is used more than in type 2
Describe type 3 hypersensitivity
Usually auto antibodies (but can in some cases be against foreig; antigens)
For auto antibodies: Self reactive B cells are stimulated by self reactive T cells to switch from IgM to IgG production
The antibodies bind to soluble antigens in the circulation and from immune complexes
Large immune complexes are quickly removed from blood by spleen but smaller ones are not - they are “less immunogenic”
These small immune complexes then deposit in blood vessel walls, kidney glomeruli (due to blood filtration there) and joints (synovial fluid is filtered from the blood), causing inflammation and damage where they deposit eg to the blood vessel wall
This leads to 2 problems
1) activation of complement system
2) activation of neutrophil degranulation
The complement is activated, leading to
-MAC formation
- which leads to oedema by anaphylatoxins
- which leads to neutrophil recruitment, the neutrophils are attracted to the site by chemokines
- the neutrophils bind to Fc portion of ABs and try to oahgocytose the immune complexes but are usually unsuccesful
- so instead, the neutrophils degranulate and release:
Lysosomal enzymes
Reactive oxygen species (can change DNA and cause nuclear damage )
Example: systemic lupus erythematosus (SLE) - auto antibodies against DNA and nuclear proteins
Or could be against foreign antigens
Example: serum sickness (when a person received antibody therapy for venom treatment, body produces antibodies against the foreign anti-venom antibodies. If the person is re exposed to the antivenom antibodies, they will mount a type 3 hypersensitivity response against the antibodies, leading to inflammation due to deposition in their vessel walls)
What type of hypersensitivity is serum sickness
Type 3
In what type of hypersensitivity do you get inflammation in vessel walls
Type 3
Which of the types of hypersensitivity is not antibody mediated
Type 4
What is another name for type 4 hypersensitivity and why
Delayed-type hypersensitivity
Because it is mediated by T cells and the recruitment of T cells takes time
Describe type 4 hypersensitivity
Mediated by T cells instead of antibodies
Damage can occur through CD4+ T helper cells or CD8+ cytotoxic T cells
Reaction occurs in 2 phases
1) sensitisation phase
Exposure to haptens leads to dendritic cell uptake
Dendritic cells present to naive T cells in the lymph node and cause differentiation into Th1 cells which can then form memory cells
2) re exposure and immune response
During re exposure, the specific memory T cells induce inflammation in the tissue by secreting IL2 and INF gamma which leads to Th1 cell expansion
This causes macrophage activation (macrophages secrete TNF, IL1, IL6)
These cause increased vascular permeability and swelling and redness
Other types of T cells can also be involved, depending on the signal received from macrophages
- Th17 can secrete IL17 which recruits neutrophils which can degranulate and kill the cell
- CD8+ self reactive cytotoxic T cells can directly kill the cells with the antigens
What are haptens
Small proteins that function as antigens when bound to other proteins
Give examples of where type 4 sensitivity can be seen
Poison ivy infection
Many autoimmune diseases
- type 1 diabetes
- Hashimoto’s thyroiditis
- transplant rejection
Which type of hypersensitivity can be used in the Mantoux skin test. What does a Matoux skin test check for?
Type 4
Sees if someone has been infected with TB
Inject a small amount of tuberculin (antigen from TB) into the skin, if they have been infected their immune system has been sensitised, so this is a re exposure which will cause type 4 reaction
You leave it for a few days and come back and if the6 have been infected, you will see an induration of the skin (hardness caused by swelling)
What type of hypersensitivity is involved in Multiple sclerosis and IBS
type 4
Th1 cells damage myelin around nerve fibres
Th1 cells cause inflammation of intestinal lining
What causes rashes and puffy skin during anaphylactic shock
Histamine
Cause increased vascular permeability and vasodilation - leads to oedema
Why is adrenaline given during anaphylaxis
Causes vasoconstriction in the peripheral areas - increases blood pressure
What cell is most likely to cause the skin redness and swelling in anaphylaxis
Mast cell (more in the skin than basophils)
What drugs can be given in injections during anaphylaxis
Adrenaline - cause peripheral vaso interaction and increases BP
Anti histamine - reduces inflammatory response
Corticosteroids- reduce inflammatory response
name a difference between prokaryotes and eukaryotes
eukaryotes: well defined cytoskeleton
prokaryotes: poorly defined cytoskeleton
what is the space that contains all the genetic material of a prokaryote called
nucleiod
name 3 features of a neisseria meningitidis infection
rapid progression
septic shock
severe inflammatory response
types of fungi disease
cutaneous
mucosal
systemic mycoses
what are helminths and how do they replicate
metazoa with eukaryotic cells
replicate sexually
life cycle of liver fluke which causes schistomiasis
egg miracidium (develops within small intermediate host) cercaria adult
