Memory and vaccines Flashcards
What are the key features of a secondary immune response?
1) Faster
2) Stronger
3) More effective
What is the basis for vaccines?
Immunological memory; memory can be lifelong, meaning patient may not show any symptoms upon repeated exposure.
What is the basis for vaccines?
Immunological memory; memory can be lifelong, meaning patient may not show any symptoms upon repeated exposure.
Vaccine immunise patients with benign form of pathogen to induce immunological memory against disease.
What was Edward Jenner famous for?
1780: vaccination against small pox (using cowpox)
What was Louis Pasteur famous for?
1880: Developed vaccines for chicken cholera, rabies and anthrax.
What are mechanisms of immunological memory 1?
1) Long lived Plasma cells which produced continual low level circulation of specific antibodies.
2) Generation of memory lymphocytes during adaptive response
What are the characteristics of memory cells?
1) They are long lived
What are the characteristics of memory cells which make them more efficient than naive Lymphocytes?
1) They are long lived; they survive even in complete presence of antigen
2) They are more sensitive to low doses of antigen than naive B/T cells
What is essential for the survival of B cells?
prdm1 is the gene that encodes a transcription factor Lymph1 needed for survival.
No gene, means there is no memory cell marker called CD38; memory cell proliferation is low. When antigen (NP) added to knockout the response of memory cells is lower.
Describe an experiment to show memory cell sensitivity.
-purify naive and memory T cells
-immuno-labelling using Ab against T cell marker and conjagated Ab with gold particles
-stained cells with gold Ab
-visualised by electron microscopy
The memory cells have more clustered TCR, therefore more effective T cell activation
What are the three characteristics of memory cells which make them more efficient than naive Lymphocytes?
1) They are long lived; they survive even in complete presence of antigen
2) They are more sensitive to low doses of antigen than naive B/T cells
3) Their response is faster and stronger
Describe an experiment to show memory cell sensitivity.
-purify naive and memory T cells
-immuno-labelling using Ab against T cell marker and conjagated Ab with gold particles
-stained cells with gold Ab
-visualised by electron microscopy
The memory cells have more clustered TCR, therefore more effective T cell activation
-increased activation shown by CD25 or secretion of T cell cytokine IFN-gamma.
Why are memory cells faster and stronger?
1) There is higher frequency of antigen-specific memory cells as a result of previous clonal proliferation; There is more!
2) They have already undergone isotype switching so memory cells are primed to make correct antibodies with the best affinity for antigen (hypermutation) and so more effective
3) It is only memory cells that take part
Why are memory cells faster and stronger?
1) There is higher frequency of antigen-specific memory cells as a result of previous clonal proliferation; There is more!
2) They have already undergone isotype switching so memory cells are primed to make correct antibodies with the best affinity for antigen (hypermutation) and so more effective for T cell binding.
3) It is only memory cells that take part to save time activating a naive B cell, when tried and tested B cell awaits.
Describe the mechanism involved in secondary immune response.
Only emery cells participate.
-naive B cells bind to pathogen-Ab complex. Negative signal to naive B cell so it is not activaed, there is no production of its low affinity initial IgM Ab
Describe the mechanism involved in secondary immune response.
Only emery cells participate.
- naive B cells bind to pathogen-Ab complex. Negative signal to naive B cell so it is not activaed, there is no production of its low affinity initial IgM Ab
- memory B cell binds to pathogen-Ab complex. Memory cell activated into plasma cell which makes correct (rearranged) Ab immediately.
Describe the mechanism involved in secondary immune response.
Only emery cells participate.
- naive B cells bind to pathogen-Ab complex. Negative signal from Fc-gammaRIIb (FcyRIIB) to naive B cell so it is not activaed, there is no production of its low affinity initial IgM Ab
- memory B cell binds to pathogen-Ab complex. Memory cell activated into plasma cell which makes correct (rearranged) Ab immediately other than IgM.
What is FcyR2B?
Inhibitory receptor which binds to IgG on naive B cells that prevents their involvement in the secondary response.
The receptor has ITIM as a signalling motif
FcyRIIB is downregulated on memory cells so these are not inhibited.
Why are memory cells faster and stronger?
1) There is higher frequency of antigen-specific memory cells as a result of previous clonal proliferation; There is more!
2) They have already undergone isotype switching so memory cells are primed to make correct antibodies with the best affinity for antigen (hypermutation) and so more effective for T cell binding.
3) It is only memory cells that take part to save time activating a naive B cell, when tried and tested B cell awaits.
4) They are hypersensitive to antigen.
Describe the mechanism involved in secondary immune response.
Only memory cells participate.
- naive B cells bind to pathogen-Ab complex. Negative signal from Fc-gammaRIIb (FcyRIIB) to naive B cell so it is not activaed, there is no production of its low affinity initial IgM Ab
- memory B cell binds to pathogen-Ab complex. Memory cell activated into plasma cell which makes correct (rearranged) Ab immediately other than IgM.
What is FcyR2B? How does it work?
Inhibitory receptor which binds to IgG on naive B cells that prevents their involvement in the secondary response.
The receptor has ITIM as a signalling motif; ITIM phosphorylated, so it recruit/docks phosphatases when which act to dephosphorylate signalling molecules and inhibit B cell activation.
FcyRIIB is downregulated on memory cells so these are not inhibited.
What experiment involving PKD can be used to show inhibitory FcyRIIb effect?
protein kinase PKD enzyme when activated in absence of FcyRIIB it autophosphorylates itself; activity measured in kinase assay.
PKD is blocked by engagement of the FcyRIIb receptor, despite initial autophosphorylation; activation signals are switched off over time.
Shows that negative ITIM dominates activation via BCR in naive B cell.
Why are memory cells faster and stronger?
1) There is higher frequency of antigen-specific memory cells as a result of previous clonal proliferation; There is more!
2) They have already undergone isotype switching so memory cells are primed to make correct antibodies with the best affinity for antigen (hypermutation) and so more effective for T cell binding.
3) It is only memory cells that take part to save time activating a naive B cell, when tried and tested B cell awaits.
4) T memory cells are hypersensitive to antigen.
What experiment involving PKD can be used to show inhibitory FcyRIIb effect in naive B cells?
protein kinase PKD enzyme when activated in absence of FcyRIIB it autophosphorylates itself; activity measured in kinase assay.
PKD is blocked by engagement of the FcyRIIb receptor, despite initial autophosphorylation; activation signals are switched off over time.
Shows that negative ITIM dominates activation via BCR in naive B cell.
What features of memory T cells make them more sensitive?
1) enrichment of Oligomeric T cell receptor complexes
What features of memory T cells make them more sensitive?
1) enrichment of Oligomeric T cell receptor complexes
2) They splice out CD45 mRNA so they express a different isoform
What is the role of CD45 in T cells?
It is a phosphatase which dephosphorylates certain inhibitory sites on kinases so they become active.
Therefore, it is important for positive regulation of TCR signalling
What are the 2 isoforms of CD45?
- CD45RO: on effector and memory T cells. This CD45RO causes increased TCR signalling.
- CD45RA: on naive T cells
What features of memory T cells make them more sensitive?
1) enrichment of Oligomeric T cell receptor complexes
1) They splice out CD45 mRNA so they express a different isoform; they express CD45RO isoform which has lower activation threshold, stronger TCR signalling, and more rapid up-regulation of CD40L
What are the 2 isoforms of CD45?
- CD45RO: on effector and memory T cells. This CD45RO causes increased TCR signalling, and activating kinases.
- CD45RA: on naive T cells
Why are memory cells faster and stronger?
1) There is higher frequency of antigen-specific memory cells as a result of previous clonal proliferation; There is more!
2) They have already undergone isotype switching so memory cells are primed to make correct antibodies with the best affinity for antigen (hypermutation) and so more effective for T cell binding.
3) It is only memory cells that take part to save time activating a naive B cell, when tried and tested B cell awaits.
4) T memory cells are hypersensitive to antigen.
5) Memory T cells migrate to peripheral tissue so they are ready for activation at the site in tissue.
What features of memory T cells make them more sensitive?
They splice out CD45 mRNA so they express a different isoform; they express CD45RO isoform which has lower activation threshold, stronger TCR signalling, and more rapid up-regulation of CD40L
What makes memory T cells persit in perpherial tissues?
Markers For adhesion: -CD44 For homing to lymph node: -CD62L -CDR7
What are the two subsets of memory T cells?
1) Central memory T cell: where CD62L and CCR7 in secondary lymphoid tissues only (still better at upregulating co-stimulatory CD40L)
2) Effector memory T cell: there is no CCR7 which means cell can exit lymphoid tissues into periphery liked mucosal. Here, re-exposure to antigen causes differentiation into effector T cells
Describe an experiment that shows it is CCR7 that controls memory cell trafficking
- memory T cell with low levels of CCR7 treated with drug rapamycin with increases CCR7 expression.
- divide high CCR7 and low CCR7 populations and inject into a mouse
- there is 50/50 distribution in blood, and more low CCR7 in secondary lymphoid tissues
Describe history of vaccines
1885-1950: most of vaccines developed through trying to kill/inactivate pathogen but retain immunogenicity and inject this.
las 40 year: there have been new approaches involving genome sequencing to deermine proteins and biochemical analysis for immunogenicity tests
Live-attenuated virus vaccines like Yellow fever, or polio vaccines
A live pathogen that can replicate in body but it no longer has pathogenicity.
Loss of pathogenicity due to mutation after serial growth in non-human cells; adapting to different host, and so it can no longer grow well in human cells
What does attenuated refer to ?
pathogen can no longer grow well in human cells.
list some advantage and disadvantages of live-attenuated virus vaccines
Advantages:
- strong cellular/Ab response
- lifelong immunity
Disadvantages:
- needed to large doses, even multiple doses
- pathogen can revert back to virulent form
- cannot be given to weak immune system
- temperature sensitive; in hot, poor countries hard to maintain.
Inactivated virus vaccine like influenza
This is made from non-replicating viruses that inactivates nucleic acid but retains
Inactivated virus vaccine like influenza
This is made from non-replicating viruses that inactivates nucleic acid so they cannot replicate (virus is dead) but retains antigenicity
list some advantage and disadvantages of inactivated virus vaccines
Advantages:
- safe
- not temperature sensitive
Disadvantages:
-less strong immune response
list some advantage and disadvantages of inactivated virus vaccines
Advantages:
- safe
- not temperature sensitive
Disadvantages:
- less strong immune response
- multiple doses required
What are Subunit vaccines like Hepatitis?
These are made from antigenic components of a pathogen purified directly from pathogen or generated in lab.
Here, recombinant DNA technology has made the antigenic proteins more efficient.
list some advantage and disadvantages of subunit vaccines
Advantage:
- contain only the specific antigens needed
- less adverse reaction/safer
Disadvantage:
-the appropriate antigen has to have been already isolated to be immunogenic.
What is toxoid vaccine like tetanus?
These are made with chemically inactivated bacterial toxins that have retained their antigenicity
What is toxoid vaccine like tetanus?
These are made with chemically inactivated bacterial toxins that have retained their antigenicity.
The toxins create the disease phenotype.
What is conjugate vaccine like Hib (Haemophilus influenza type B)?
These are made by linking bacterial polysaccharide capsular antigens to a carrier.
What is conjugate vaccine like Hib (Haemophilus influenza type B)?
These are made by linking bacterial polysaccharide capsular antigens to a carrier. These are effective against polysaccharide antigens.
What are all the different types of vaccines?
1) Live-attenuated virus vaccines
2) Inactivated virus vaccines
3) Subunit vaccines
4) Toxoid
5) Conjugate
Describe how a Hib toxoid vaccine works?
1) the vaccine is a combination of a polysacc. and the tetanus toxoid
2) B cell recognise polysacc part and internalise via endocytosis.
3) peptides made and toxin is separated, loaded on MHC2 and presented to helper T cell
4) IL4 from T cell means B cell differentiates, and expands.
5) Anti-polysaccharide Ab made
Why are some vaccines not yet established for infectious disease like Tuberculosis?
1) pathogen Antigens mutate
2) pathogens have mechanisms to evade the immune system
(3) pathogen initiates a non-productive immune response.)
How are we currently approaching the HIV vaccine? Why has it failed?
Failures include:
- classical viral envelop antigens
- dead HIV1 does not retain antigeniciy
- live vaccines is too dangerous
- vaccine does not defeat latent reservoirs of infection
- The HIV is very mutable and rapidly changes under selection.
What is the basis for vaccines?
Immunological memory; memory can be lifelong, meaning patient may not show any symptoms upon repeated exposure.
Vaccine immunise patients with benign form of pathogen to induce immunological memory against disease; it activates both T and B cells.
