Memory B cell
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Memory B cells are a B cell sub-type that are formed within germinal centers following primary infection and are important in generating an accelerated and more robust antibody-mediated immune response in the case of re-infection (also known as a secondary immune response).
During an initial infection (or primary immune response) involving a T-dependent antigen, naive follicular B cells are activated in the presence of TFH cells within the follicles of secondary lymphoid organs (i.e. spleen and lymph nodes) and undergo clonal expansion to produce a foci of B cells that are specific for the antigen. Most of these clones differentiate into the plasma cells, also called effector B cells which produce a first wave of protective antibodies and help clear the infection, but a fraction persist as dormant memory cells that survive in the body on a long-term basis after having gone through a highly mutative and selective germinal center reaction. Activated B cells that fail to undergo germinal center differentiation do not persist as effective memory B cells and are rapidly negatively selected against.
Within germinal centers, B cells proliferate and mutate the genetic region coding for their surface antibody (also known as immunoglobulin). The process is called somatic hypermutation and is responsible for introducing spontaneous mutations with a frequency of about 1 in every 1600 cell division (a relatively high frequency considering the low mutation frequency of other cells of the body being 1 in 106 cell divisions). Then after gaining a set number of mutations, germinal center B cells are subjected to a round of selection by TFH cells. B cell clones that have mutated and gained higher affinity surface immunoglobulin that better recognize antigen receive cellular contact-dependent survival signals from interacting with their cognate TFH cells and go on to one of three fates: (i) differentiate into plasma cells that have improved affinity towards antigen (therefore more efficient than their earlier the generation of plasma cells in clearing the infection), (ii) affinity matured memory B cells, or (iii) retained in the germinal center to re-enter another round of mutative replication and TFH cell-dependent selection. Therefore, as an infection proceeds, memory B cells selected in the later stages of a germinal center response are found to have accumulated the highest numbers of immunoglobulin mutation events with superior affinity towards their targeted antigen. Conversely, during the course of a germinal center reaction, low affinity or potentially auto-reactive germinal center B cell clones, or those that have gained non-functional mutations are out-competed by higher affinity clones and eventually undergo cellular apoptosis.
Secondary response and memory
With each such subsequent exposure to the same antigen, the number of different responding B cell clones increases to generate a polyclonal response and effectively a greater number of memory B cells persist. Thus, a stronger antibody response (i.e. higher titres of more diverse antibody molecules) having improved affinity towards antigen is typically observed in the secondary immune response. It is unclear at what stage such a model reaches saturation to provide an optimal level of antibody-mediated immune protection against the same antigen. However, the fact that all the accumulation of cells of a single clone population express many of the one same type of antibody and that these memory B cells survive for long periods of time in a body underscores their functional significance during vaccination and the administration of booster shots.
Abilities of memory B cells
A typical ability is long-lasting survival in quiescence; this can last for tens of years in humans. After re-encountering the specific antigen they are able to reactivate very quickly, propagate themselves, create plasma cells and reenter germinal centres to improve affinity of their antibodies. Thanks to this, every secondary immune response is stronger than the primary one.
The ability to proliferate and create whole B cell population specific to the antigen is sometimes called as a stemness of memory B cells. It seems, that IgM+ memory B cells are the best in this (they have not class-switched their BCR).
Long-lasting survival is dependent on metabolic changes and blocking of apoptosis. The presence of follicular dendritic cells (FDC) and tonic signalisation through BCR (basic stimuli from BCR independent on specific antigen) are necessary. These induce expression of anti-apoptotic genes in B cell. The specific antigen does not have to be present to keep memory B cells, neither T cells are necessary.
Strong and quick response could be a result of switched BCR. Some isotypes do have a cytoplasmic part which can signal into B cell - mainly it was studied on IgG1. The cytoplasmic domain of IgG1 can interact with components of MAPK cascade and so potentiate the signalling when antigen is recognised. Apart from that, the stimulation history of memory B cell is critical - thanks to that the B cell has changed levels of transcription factors and it`s threshold for stimulation is higher - easier to overcome.
Reactivation of memory B cell is dependent on interaction with their cognate memory TFH. Both cell types are present in secondary lymphatic tissues in B follicle and so they can quickly interact, when specific antigen is present. The interaction works probably both sides - first the B cell works as an antigen-presenting cell and activate the TFH, second activated TFH activates the memory B cell. Important role have also FDC, which quickly grab incoming antigens and store them on their surface for B cells - mainly when the antigen is in immune complex.
Reentering germinal centre reaction is typical mainly for IgM+ memory B cells. Germinal centres sometimes stay functional even after the end of primary immune response, then the memory B cells can join again. They can go through isotype switching and somatic hypermutation and afterwards differentiate into plasma cells. Another mechanism which can improve affinity of memory antibodies is the necessity of TFH help in reactivation process. This selects memory B cells with high-affinity BCR.
Markers of memory B cells
Typical surface marker in humans is CD27. Also the type of their BCR can be detected. BCR is usually switched in memory B cells - that means not IgD or IgM. But also IgM+ memory B cells do exist and they have special abilities - they are similar to naive B cells, proliferate a lot after reencountering antigen and usually reenter germinal centre reaction. IgG+ and IgA+ memory B cells can both be found in humans.
On the other hand IgE+ memory B cells have not been detected in vivo. If they do exist, then in very small amounts. Memory IgE antibodies are more probably produced by IgG+ memory B cells, which encounter isotype switching again in secondary immune response. These can produce high-affinity IgE which is the essence of allergic diseases.
Other types of memory B cells
Not all memory B cells are created in germinal centre reaction. We can also find memory B cells independent on germinal centres and memory B cells independent on T-cell help at all.
Memory B cells independent of germinal centres
These cells are differentiated from activated B cells before they enter germinal centre reaction. Their BCR has lower affinity to antigen and so the interaction with Tfh is weaker then in classical memory B cells. That is because Tfh interacts with a B cell via its MHCII glycoprotein-peptide complex. The peptide comes from the antigen captured by BCR - so the weaker affinity of BCR to antigen, the less peptide-MHCII complexes on B cells, the less Tfh help (CD40L interaction and cytokines). The lack of Tfh help results in no creation of germinal centre by this B cell. They can sometimes switch antibody isotype, but they never encounter somatic hypermutation. As a result they stay with low affinity to the antigen, which can be actually beneficial - our body keep them as a backup for pathogens only similar to the one which raised the first immune reaction.
T-independent memory B cells
These are actually B1-memory cells. B1 cells are B cells, which do not need any T cell help in activation. They produce so called innate IgM antibodies. These antibodies recognise usually sugars, which has polyvalent epitopes and so can crosslink BCRs enough to provoke strong activating signal into a B cell. These sugars can have both non-self and self origin. The self-recognising IgM can be helpful in opsonisation of apoptotic cells and their removal by phagocytosis.
B1 memory cells are kept in peritoneum, here they can be activated after repeated encounter of antigen. But unlike classical B2 memory cells, they do not have any special abilities to provoke a stronger and quicker response. The memory is created only by a larger initial number of antigen-specific B1 clones.
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