IMI7: Immune memory and vaccination Flashcards
What did the German scientist Emil von Behring and the Japanese physician Shibasaburo Kitasato discover in 1890?
that the transfer of serum from a mouse immunised against tetanus to a non-immunised mouse could completely protect the latter from a normally fatal challenge with virulent tetanus bacteria.
What did Emil von Behring and the Shibasaburo Kitasato’s observation support?
Paul Ehrich’s model of humoral factors being the critical mediators of immunity, and is relatively short-lived. .
What did subsequent adoptive transfer experiments show? (where various sets of cells from immunised mice are transferred to immunologically naive mice)
That certain subsets of B and T lymphocytes are the key elements in the potentially life-long immunity that we develop after infection or vaccination.
What is the primary role of B cells in immunity?
the development and production of high affinity specific antibodies.
Why do B cells need to have the ability to develop and produce high affinity specific antibodies?
To be pre-armed against re-infection, the body needs both an abundance of antibodies in the body fluids (be it blood, lymphatics or mucosal surfaces), and cells that can accelerate the production of more antibody when a re-infection occurs. For any given antibody, these two jobs are done by different B cell subsets.
Where are high affinity antibodies produced?
Germinal centre of the secondary lymphoid organs
What are the two cell types that emerge from the germinal centre reaction?
Effector B cells that make antibodies
The resting cell that is ready to respond next time
What is the effector B cells that make antibodies called?
Plasma cell
What is the resting cell that is ready to respond next time called?
Memory B cell
What is the quickest response that the adaptive immune system can provide? Why?
Having sufficient levels of antibody when a pathogen invades - If the antibody can intercept the pathogen before it gets a chance to properly invade or proliferate, then the infection will be stopped before it even begins.
What is opsonisation?
Marking a pathogen for phagocytosis
What is complement fixation?
Promoting the rupture of membranes
What is neutralisation?
Preventing the successful invasion of cells by the pathogen
The antibodies in our body fluids are produced mainly by what? Where do they take up residence?
long-lived plasma cells
in our bone marrow and mucosal tissues (gut, lung)
Despite being a _____ _______ cell type, long lived plasma cells appear to be able to survive extremely long periods of time.
terminally differentiated
Why do long-lived plasma cells survive a very long time?
In part, because they express very low levels of the B cell receptor (BCR), which means they are not easily activated when encountering antigen. thus the long-lived cells do not boost body-wide antibody production, but rather are responsible for maintaining a baseline of antibody production in the long term.
What are long-lived plasma cells responsible for?
maintaining a baseline of antibody production in the long term.
Early in the response, many of these memory cells will retain what type of immunoglobulin production, having not class-switched?
IgM
Later in the response, the majority of memory cells leaving the germinal centre will have class switched to what? depending on what? What has happened to the affinity?
IgG, IgA or IgE, depending on the nature of the signals provoked by the pathogen. These will also have Ig with a higher affinity for the target.
What kind of metabolic rates do memory B cells have?
low
Do naive or memory B cells have a faster rate of response to a pathogen?
memory B cells
Why do memory B cells respond more quickly to pathogens than naïve B cells?
In part because they have more of the activating receptors such as CD40, CD80 and CD86 on their surface. They are also more sensitive to stimulation by PAMPs.
What restrictions to proliferation and activation do naïve and memory B cells have in common?
They require T cell help, BCR binding and an innate signal (through cytokine signals and/or sensing of PAMPs) to trigger their activation and proliferation.
When B cells are activated what happens to them?
Some of these cells then differentiate into plasma cells to produce antibodies, while others – particularly the lower affinity IgM subset – will migrate to the germinal centre to undergo further affinity maturation.
Why would a memory B cell, which has already undergone affinity maturation, return to the germinal centre for more?
To adapt to pathogens mutating – particularly to antigenic drift:
- It keeps diverse Igs with low affinity as memory B cells, making it more likely that some of those will still be able to recognise a modestly mutated antigen.
- This will then act as a basis for producing new high affinity immunoglobulins against this modified strain of pathogen, protecting against a wider variety of virus strains.
Once a pathogen has been defeated, what happens to the amount of antigen present?
It reduces
What does the reduction of antigen in the blood do to B cell production?
It first triggers more of the cells to leave the germinal centre as plasma cells, some of which will migrate to the local mucosal niche or the bone marrow, to become long lived plasma cells.
Once the pathogen has been defeated what happens to the remaining cells in the germinal centre?
Most of the remaining cells in the germinal centre will stop proliferating and die, so there is space in the lymph node for a new germinal centre to form around the next batch of antigen to arrive.
What controls which memory B cells and plasma cells remain as the long-lived memory?
This is not yet known
Why are memory B cells easy to identify?
Most B cells undergo modification of their Ig genes (through somatic hypermutation and often class switching) after encountering antigens, and before committing to become memory B cells.
Why are T cells that have encountered an antigen previously less easily defined?
since their TCR remains unchanged. Nevertheless, the body wants more ready access to those T cells whose TCR has already recognised antigen, thereby proving itself to be potentially useful in future.
What are the subsets of memory T cells defined based on?
Their locations in the body and their cytokine, receptor and metabolic profiles -> These properties will give them different roles in subsequent immune responses.
Do naïve T cells or memory T cells respond more readily in response to their TCR being presented with antigen. ?
Memory T cells
All of the memory T cells are relatively long-lived.
How do the different subsets of memory T cells relate to each other?
It is still not fully understood but there appear to be subsets that are more pluripotent (i.e. more able to give rise to many different cell types) or closer to terminal differentiation than others.
What are T stem cell memory cells?
TSCM cells are memory cells that are capable of differentiation into the various other types of memory T cell. This subset was discovered in mice, but its existence in humans has not yet been proved. It may be that this type of cell is the origin of the other types, which may be constantly replenished in the blood.
What are central memory T cells?
TCM cells are found in both secondary lymphoid tissue and in the circulation. They are the most long-lived T cell type, and secrete relatively few cytokines at rest. They can give rise to both TEM and TRM cells. It is this subset that is most likely activated for helper functions in the lymphoid tissues (eg helping B cells refine their antibodies). This location allows them to be rapidly activated when peripheral dendritic cells arrive in lymph nodes with antigen that their TCR can detect.
What are effector memory T cells?
TEM cells are memory cells are found in tissues or in the circulation. They lack receptors that would drive them to relocate to the secondary lymphoid organs (eg lymph nodes). They will respond to APCs (CD4+ memory) or infected/cancerous cells (CD8+ memory) in the blood or tissues.
What are effector T cells?
These are the T cells that we have largely spoken about previously, the T cells that are activated and get out and do the job of detecting presented antigen, either to provide help (CD4+) or kill offending cells (CD8+). Memory cells can change into effector cells in response to stimulation. It is not clear whether they can return to a memory state once they have changed. It is thought that a CD4 memory T cell can become any one of the various subsets of cells (TH1, TH2, TH17, Treg etc) that are effector T cells. This will depend on the nature of the response and the cytokine environment.
What are resident memory T cells?
TRM cells that are present in tissues, in a position to respond locally to an invasion of a pathogen. They tend to be more mobile – actively patrolling tissues – and more metabolically active (and as a result perhaps more short lived) than other memory cell subsets. As a result these are likely to be the first to come across antigen at a site of infection